Event ID: 416940
Event Started: 10/19/2005 8:31:38 AM ET
Please stand by for the meeting. Welcome to the eighth meeting on the Secretary's Advisory Committee on Genetics, Health and Society. You might wonder who this imposter is. I'm Cindy berry and will be acting as chair. Dr. Tuckson had a family emergency. We typically begin with introductory remarks from the chair. We've modified the format slightly so that we can move quickly into today's section on large population studies. I'll review the rest of the agenda and provide updates later this morning. First, I want to point out the public was made aware through notices as well as announcements on the SACGHS. I'd like to welcome the public in attendance as well as viewers. I should point out, too, that on this day in history in 1812 na molion began his disastrous retreat from Moscow. Our general this morning will be Dr. Huntington Willard, chair of our large population studies task force. He will introduce today's session, review the task force work. We'll have a much better fate than Napoleon's grand army. So with that, I turn to hunt.

thank you, Cindy and good morning. I have been accused of many things. Having a napoleon complex is not one of them. Nonetheless, here I M I want to briefly, before we get into the major session to review what the large population task force has been up to and introduce the session today before we hear from our guests. First to begin and refresh your memory, especially to refresh the memory of those on the task force, this is the list of its members. We've convened several times over conference calls with a variety of assigned duties in order to get where we are today. I thank all the members of the task force, both those or members of SACGHS and the exofficial yos. The issue that was handed to us was to explore the issue of large population studies as within approach to learn more about the relationship among genes environment and common disease where the goals are to move towards improvement of health in this country with intermediate steps of determining the mechanisms underlying common and complex disease and ultimately informing we hope treatment and prevention strategies. What I would like to do in this, the next 20 minutes is to review the steps this full committee took in assigning the task force, go through the task force's review of a very helpful document that was prepared by an NIH work group that was made available to the public just about the time of our last meeting in June and then provide pan overview for today's section. The background is that we were requested back in the very beginning, some two plus years ago, to weigh in on the value of a large population study in this country. Through our priority setting process a year and a half ago, we decided that this topic did, indeed, warrant in-depth study. In October 2004, a year ago now, we formed the task force to guide the committee and to explore the different issues that would need to be tackled and in the February March meeting that we had, we spent a full day of hearing from presentations that provided us with a number of facts about the nature of large population studies and specifically looked at some existing projects both within this country and outside of this country in order to give us a sense of what some of the issues would be or could be that would come to the for. As part of that session, ended up facilitating a session of both scientific as well as ethical, legal and social issues. We decided at the end of the meeting, the next step would be to develop a report and today's session is one step along the way towards that report. The goal would be to eye done fight key policy issues around a potential large population study mounted in this country and to have the report outline mechanisms that could be used to address the identifying issues and thereby help the secretary in his deliberations on how to proceed. We were in touch with Dr. zahuni's office. We were not going to look specifically and we won't today specifically look at the scientific issues but rather tackle large are and broad are process issues that would need to be tackled in any event. So the major action items from our June meeting were that the task force would review the work group report that came from the NIH and provide an update this morning which I will do and then we would coordinate a meeting together, input from the scientific and ethics community as well as the public at large. However, the task force decided this wasn't in our purview our our area of expertise to move towards an in-depth public engagement on this issue but rather what we should do is provide the secretary with our advice about eventually what the best practices were in the area of public engagement and then allow him to decide what the right mechanism and who the right group or groups would be who would engage the public in their support and or concerns about the nature of a large population study such as this. So, first, let me kick off with a review of the work group report. The NIH brought the work group report to our attention at the meeting in March of 2005. Although, the report wasn't available at that time and became available just prior to our June meeting. We thought that this report, which is exceedingly comprehensive and was assembled largely through the efforts of nhgri a very impressive list of experts, that the best thing that we could do would be to review it as a task force and present to you, the full committee our sense of what the task force was all B as part of this, I want to bring your attention to a background paper that was prepared by a staff that's located in tab four of your briefing books. This presents the full report of the work group and many of the specific findings that our task force pulled out from that. I'll summarize the highlights. The full sense is found in than four. Also in tab four or somewhere in our briefing book is a copy vive an article that Francis Collins published which is very help follow us as well as the scientific community at larged should be considered part of the record from that perspective. So I want to review the goals of a potential study as outlined in the work group report. Look at the key characteristics of a potential study as outlined in that report and examine the key policy issues that were highlighted in that report as well. I will say that there were a number of issues that were raised in the working group report on the policy front. Our task force pulled out the ones that we thought that this committee could prioritize. So I'm not meaning to suggestion that everything that I mentioned is everything in the original work group report. It was a very comprehensive analysis and we're picking out the ones we thought were most sail yent to our efforts heemplt the work group is established to examine the scientific basis for large population study and examine some of the logistical outlines. Extensive power calculations on what might be gleaned from such a study, the number of individuals who would need to be enrolled in such a study and what we might expect given the known incidents of different common diseases that are found in our population and exactly what we might find out from such an analysis. As I mentioned before this involved a significant cohort of national experts in a variety of fields and genetics, genome Micks, epidemiology and medicine. The goals of a large population study in this country would be to ascertain all the genetic causes of illnesses in this country and to set a stage for a hopefully a future of preventative medicine and personalized healthcare and effective therapy to address and prevent the onset of symptoms in many of these common disorders. What that study revealed was that probably this would take in the order of a half a million to a million participants in order in a prospective man ter to look for clinical end points along the way. This half million to a million participants would have to be sampled from a number of different census tracks and would inevidently require door-to-door recruitment over a four-year period. There was a significant examination of, for example, how and why it would be necessary to oversample individuals from underrepresented minority groups in order to make sure they were well represented in a cohort of this size in order to provide the same level of power for detecting significant trends in minority populations as in majority populations. The data collection at entry for this half a million to a million participants would necessarily include a wide breath of environmental factors. One can imagine the largest issue is trying to decide what that list is of the phene know types that would would like to collect information on and the environmental factors in order to predict outcomes as one goes along. Necessarily having started the process you can't decide three years into the study that oh, I wish we had started collecting on another phene na type. All of this has to be balanced versus the expected cost, the potential burden on the individual participants and how much they're willing to tolerate and the power calculations of what you predict you'll be able to gain. The conclusion was a core group of baseline vair -- variables would be gathered. They would use hospital records as well as other sorses collected by CMS. There were a number of key policies. These are the most saily yent issues. And not the least of public engagement. A project like this would necessarily require that the public not only be well informed of what the nation of the large population study was to be but that they also be fully endpeajed in this and fully supportive and feel some sense of engagement and pride in participating in this type of a project. The same issues have been tackled by other countries, some with greater success than others. That's an issue, in part, we want to look at today in terms of the kinds of processes that would be necessary. How do you in a society such as ours begin to determine whether you, in fact, have a representative cohort. Do you oversample certain groups in order to achieve that and how do you get that balance. This doesn't stand on its own. Each of the groups will have histories own particular issues. So one will have to evaluate public engagement from the different groups that are being brought into this process. Clearly, there's a need to examine the need of collaboration on both an international and national scale. There are projects that are ongoing as we heard in our meeting back in March. There are other interings inial large population studies. The question from a process standpoint, is what kind of collaboration one would have in terms of data sharing or sharing best practices between these large population studies. Access to data in terms of privacy in terms of who has access, how it will be protected, do individuals get the data back, becomes a major issue for any project but become as particular issue for something has dramatically as large as this one is. Tied to that is the issue of notifying the results back to the individuals and the provises of genetic or genomic counseling to make sure the public is well educated about the data on an ongoing basis, not in your own little clinic but for a half a million or a million people as one goes through it. That was identified by our task force as a major policy issue. There are intellectual property issues as there are with all genome and genetically based research. A key it seems here in terms of the nature of outcome and discoveries, confidentiality and privacy, informed consent, which is a broad issue for all kinds of clinical research but in this case particularly I think takes on an acute sense of urgency. The task force also identified the concept of a central rib, where each institution involved in trying to collect samples sign up people into the cohort that this might be managed much more effectively from a central RIB standpoint. Then we, as everyone does, highlight the importance of medical records which is uneven at best in different parts of the country. Yet, in this context would need to be brought up to speed in a very significant manner in order to get the best use of the information that one would have to obtain over a half million to a million enroll Lees. So the list of issues that we spent time on was came from this review of the working group report from the NIH as well as the Francis Collins art keel as well as our own musings. There's a set, in addition to the policy issues that I've raised here, most of which are on the social and policy end, there's a set of research policy issues as well, some of which we highlighted but most of which were well taken care of by the NIH work group report by itself. So from this we identified four categories of issues that we thought needed further review and that we as a task force would present this list to the full committee for its consideration today so let me go through these in kind. First, broad social issues. Are there data to support the inherent value of such a large population study. Clearly, that's the goal that everyone considers such a study has. But are there data that would give us substantial confidence that at the and of the day or the end of the decades there would be information well worth the effort to emerge from such a study. Secondly, is the large cohort study the best way to get the information about genetic and environment hall influences on common diseases and given the nature of additional owe hoart studies that are already underway and a variety of different organizations within NIH, are there other ways to approach this issue. Lastly the 900 pound elephant in the corner is the cost of the study. How much will it actually cost and how does one balance the cost of that versus other priorities that one has in NIH in general or in the biomedical research community. Resource allocation. What tradeoffs would necessarily have to be made if this study were funded. That's always an issue, perhaps an acute issue. It's a broad issue that needs to be tackled. Race and genetics, an issue that has been raised before. Would such a study increase or decrease the potential stigmatization. And importantly, would this either reinforce or help dismantle the social concepts of race and how would one design or consider processes in the design of a large population cohort study that would tip the balance in favor of one or the other of those potential outcomes. Lastly, from a benefits standpoint, would the benefits be distributed evenly to all groups within society or would this exacerbate issues of health disparities rather than address those health disparities. At the public engagement end, the task force couldn't overemphasize the need for public trust and public engagement and prioritying the public welfare. How can the public trust the nature of this kind of project against a background where their trust of science, genetics in particular and the government in particular is not exactly at an all time high. How should such a study go about engaging the public as a single entity and as a number of groups. There's also engagement at the level of the scientific community and how can input from the broader area be gathered. The work group obviouslien engaged a significant number of individuals who contributed to the analysis that was released previously but there's a much broader scientific community that somehow needs to be heard from in order to either enlist their support or hear their positions on whether such a study is valuable and worth it in the context of resource allocation and the tradeoffs that are necessarily going to need to be addressed across the realm of biomedical research, both basic and translation. There are a number of access and healthcare system issues, some of which are issues that this committee has tackled before, but here in the contact of a large cohort study, the issue of health disparates and would the results benefit people and the issue of diagnosis versus treatment. How will such a project deal with the -- ethical dilemma between what could be diagnosed and predicted and what can the medical community do something about, a gap examine exists now but a gap which would be widened during the course of such a study. What is the cost of burden to the study participants. There are process points that specifically address the public and would necessarily be part of a public engagement process and how would it affect study participation across the different strata of hour population. How should minority communities be accessed. If the uninsured are part of it, how should they be accessed. Many are details but details which the task force felt should be brought to the front. There are also a series of research issues that the task force limited itself to from research policy perspectives, not the underlying basis per say of such a project. How would such a new large population study leverage the existing cohearts which are addressing many of the same questions and how can that full leveraging be insured. Wow will samples be collected, stored and disposed of. It becomes a process esh hue that needs to be addressed and the issue of family member notification which clearly is relevant to all genetic health issues and always has been but in this case with a half a million to a million participants with substantial amounts of genetic and genome Mick information, to what extent would that information be shared with family members beyond that half a million to a million and what would the process ease that would need to be put in place to deal with that particular issue. A detailed recruitment plan would have to be developed. That is both a policy question and process question as well as a specific issue dealing with the research itselfed we felt that guidelines needed to be developed and the anticipated technology development with particular athption paid toward avoiding discrimization. Necessarily in a project such as this which would like to look at the interface between the human genome and our environment, we know how to describe the human gen home, we're less certain from describing the environment. So we have to determine what the term environment means in this context and how should a variety of social, economic and behaviorable variables be measured on one side of the equation, to balance that with genomic information on the other side. We felt it was important to highlight the need for recruitment and how this would be kept free of significant incentives that were not somehow coherssive or deemed to be coherssive. It takes on more importance. Those are the general policy issues that the task force highlighted, many of which we hope will be informed during today's session and members of the committee can dig into more deeply, especially in Q and A today. So we thought today's session would be to gather key input and how to address them from the scientific and bioethics. We also wanted to gather input from experts in the nature of public engagement to share with us their thoughts on what the best practices are and the variety of mechanisms in order to engage the public broadly on this or similar issues. The purpose of the session is to inform -- to help us inform the report that we decided we would prepare for the secretary that would identify for him key policy issues around a potential large population study and outline some of the mechanisms that could be used to address those policy issues. It's equally important to highlight what we're in the going to do today. That is, we're not assessing the scientific need for such a study. Nor are we assessing the specific scientific aspects of the study, both because those were anticipated in the work group report from the NIH and because that is not in our immediate purview as the secretary's advisory committee. Although we are not going to be making a recommendation on the need for such a study or necessarily the best approach to the study design the committee may want to identify as the task force has, identify this as a policy issue that there is a specific need to address what the need is and what the study design should be for such a study. So today's session will consist of three different panels that we'll hear from rep sect the three constituencies. Each panel will be followed by Q and A. In the science panel there will be Q and A and at the and of the day we'll have a full committee discussion in order for us to reflect on what we've heard today and to determine our next step as the committee decides the nature of the report that we would like to prepare for the secretary. So that is the end of my comments and where are we on time?

Just a little bit over. As I just said we'll hear from initially three distinguished members of the scientific community. They've been asked to address their perspectives on policy issues surrounding the large population study. We ask that they offer us some insight on addressing these issues. We're first going to hear and sew on the screen Dr. Gerald ferchg. He is the American cancer society professor of genetics. He uses the common Bakers yeast tox lower cell growth and metabolism. He's addressing the genes and environmental issues in yeast. The applications of his research include cancer research and the development of antifungal drugs. He's also intimately familiar with the beginnings of the human genome project and the benefits that it has brought to the biomedical research community in general. So, Dr. Fink, welcome

Is there some way we can pan around so I can see you? Oh, that was -- you were a blur. Good morning. I was director of the whitehead institute from 1990 to 2001, and I should lay my cards on the table. I'm not in principle for or against a big science project or the kind of large population study which you're being asked to evaluate. In fact, I was the director of the institute and responsible for managing a portion of the human genome project that was spearheaded at the whitehead. It was a common joke that I was his boss. I think that the scientific community now is in general agreement, but in retrospect that the human genome project was successful big science and that Francis Collins was a wonderful leader in this effort. The fact that you can go back and read about the human genome project at its inception, the scientific community was not completely behind it. And for this reason I think it's worthwhile to use the beginnings of the human genome project as a guide to how a new project of the magnitude of the one you're considering might be successful. So I think one of the -- I'm just going to list some things that struck me when I considered this. The human genome project was very focused.

Are we back on? Hello. Are we back on?

Yes. You're live. We're back on. Yes.

We can't hear you. No, we can't hear you.

Can you hear me now?

Yes. We're good. So there were defined benchmarks, and in fact, the yeast genome was the first genome sequence but the genome began with a map of the genome. Then there were successsive increases in a tie to various benchmarks. There was an end point, familiar lit sequence of the entire human genome. There was a defined cost. I think the interesting thing is that the cost of the study kept going down. That; the price for every sequence kept going down rather than going up. I think this affected what I would say was the scientific community's trust in the project. That is to say, the benchmarks were met. The end points were reached. The costs came down rather than going up. So there was originally great skepticism about this project, both in the scientific media and in the public domain and there was even skepticism I would say about the science and the fate of the BR one, basic research grant. Would this take away from the signs that was brooded about. As each tier was completed and the promise realized, the basic scientists became the greatest supporters of the project because it actually added value to basic research. I think that was an extremely important feature, that; the feedback, from the human genome project into the basic research effort. Where would skepticism arise in the current project? And for this I have to take a slight diversion into some science, but I think it ends up being a policy issue because the science of quantitative atrait low sides, QtL's have a long history. I need to give you a sense of where I see some concerns about the scientific issue. This is not to say that this is an unsolvable problem, but this is not untrod territory. What do I mean. Many of the model organizations have been used to try to map complex traits. Perhaps the most well studied area is in plant -- in the plant field because the agricultural scientists have tried to breed plants for traits that deal with yield per acre, a very complex trait that has to do with productivity and so on over the years. So this is a very well developed field in the plant field. In the fruit fly field it's also well developed. I'm going to mention a study in an area that I know best, and that is, yeast. I should say in all the organizations that -- in which these quantitative things have been looked at and with great resolution, they're all sequence. All the data is computerized, and there are no ethical issues. So I'm going to talk about just briefly quantitative traits associated disease phene know types with Jean know types because that's ultimately what a study would like to do. I want to point out this has been extremely difficult even in model organisms. Yeast, as I mentioned, the genome has been sequenced. It has roughly 6,000 genes. It's possible to have all of the polyMoore fixes on a single chip and there are no ethical concerns about back crosses. Brothers can be crossed by sisters, by grandmothers, et cetera. This is not a big deal in this organization. Those crosses turn out to be extremely important for the resolution of quantitative traits. The trait that was looked at very carefully by terrific scientists was the ability to grow at high temperature, so what you see on the left is a Petri dish. On the left you can see a strain that doesn't grow at high temperature and two strains that do. Here, the phenotype is clear and easy to identify mongs -- amongst the cohorts that one is studying. The researchers wanted to know how many genes were involved. The difference is growth at high temperature and growth at low temperature. They did a cross and did all sorts of, I must say, extraordinary Jean know typing at a level that dwarfs anything that could involve a human population. It's possible to look at this, and they, the best they could do was to map it to 32kilobases of chrome mow zone. They localized this, but there weren't just simple differences between these, so they had to resort to even more exotic breeding experiments and genotyping experiments to Troy to localize actual difference in the genetic code that could account for the heat resistance, and their conclusions of the best study in yeast was they couldn't find a single difference that was necessary or sufficient for high temperature growth. They could not find any marker trait association and furthermore, they concluded that it must have required combinations of common and rare variants to underlie the quantitative traits and the number of genes that controlled this were far greater than expected. I went through this brief discussion because I think this system and many others point out how difficult it has been to associate these quantitative trait phenotypes with genotypes. So I don't want to minimize the -- it is a policy issue, which is what kind of data will we be able to get and how can we maximize the possibility of identifying the key genes that are involved in a multigenic disease, so my sense is that we should follow, one should follow the experience of the human genome project, namely, I think a pilot study would be the equivalent of the early benchmarks in the human genome project. Experience lets you recognize the mistake's specially when you make it again. So like the genome project, it seems to me that picking some multigenic disease with a defined benchmark, a target would gain the confidence that one is going to get statistically significant data. I think this is especially important considering less then 5% of medical records are computerized where all the data that I showed you for east is easily computerized. It's very clear. One would have a defined end point then. One could know what segment of the project could cost because I think, again, for the scientific community, cost is a big issue. Finally, what would the government do with the information where the particular variant genes increased the risk of disease a few percent. These are just questions. I don't have answers. Would that be a place to look for cures, collaboration from pharmaceutical companies. Finally, what would be the consequences for the RO1's. Would this take away from research. I think the project, like the human genome project would be viewed with some alarm because of the scientific issues I discussed and the risk of funding. The community would be much more supportive, I think, and reassured if there were proof of principle. A definition of -- a definition of the question, I think the goal, as listed in the information I got, of understanding the role of genes, health and common diseases, I don't think that actually works. It seems to general, certainly for the scientific community, and I think that a large population study to identify risk factors for a specific disease would be gained further trust in the scientific community. Just in discussing this idea, which is, of course, an idea that was generated from the onset of the human genome project, having discussed this idea with many colleagues, questions that have come up and of which I don't have time to discuss, and you obviously, have spent more time and have the expertise to discuss, is the NIH really the right organization? Others have suggested the CDC, pharmaceutical companies. I think this is an interesting question. And, finally, ethical issues. Clearly, I am not an expert in this area and many of you are, but my experience is that one can never anticipate the ramification of genetic studies that inevitably evoke race, gender and age. For unanticipated responses. This reinforces my sense that without a successful pilot program one could by indirection create antipathy towards a ladable goal. That's the end of my remarks.

Thank you very much. I would open it up. Can you hear me?

Slightly. Can you hear me?

More than slightly. That's fine. We'll open this up to the committee for questions and I think this would be help testimony under the circumstances if you identify yourself when you're asking the questions, so he has more to go on than just a voice.

Dr. Fink, in light of the data that you presented, is there any hope to find anything for a human disease? That is my question

I believe that the -- the short answer is yes, but I believe that these -- the nature of human genetics is such that techniques that have worked for plants and worked mar genally for yeast will need to be constantly evaluated, and so these are questions of statistical significance as one cannot do breeding studies. I was just at a meeting where people were looking at a very -- scientists reported data on measurable human trait high blood pressure in which he successfully identified in small population genes that affect high blood pressure in those populations and these were single mendelion traits but the -- it's still an ongoing research project, so I think the answer to your -- short answer to your question is I think these techniques can be refined. The question is -- if you get too many genes involved in a trait and it doesn't matter if it's yeast or humans, then each gene will have such a small effect that of force it questions the use of the study, but if there are a small number of genes that affect the traits then even given the limitations of the human -- our limitations in providing information to the human gen netist that one could extract the data

The next question.

My question was about pilot studies it's been brought up that there are some existing studies that could be used as a quote pilot study. For example, the framingham study and the women's health study. Do you think it's necessary to initiate new pilot studies or would a retrospective analysis of what worked and what didn't work in some of these other longitudinal population studies be sufficient?

I have some familiarity. A student of mine is involved looking at high blood pressure in the framingham data. The reason for initiating a new study -- and I'm not familiar. I don't have the dreadth of information to know -- bredth of information to know all the pilot studies. My visceral response is the human genome project has added a new dimension chronologically that makes some of the earlier studies that didn't collect information in the way that would be important to make statistical differences or don't even have the material, would make a new study amended. Again, I don't know all the pilot studies but this is a criticism of the earlier studies that either the material or the family histories were not adequate to provide the kinds of information that would enable a study like this.

The next question. You might identify who you're represents

Robin sue with bosey. Doctor, at the conclusion of your remarks, you briefly mentioned the ethical issues of race, gender, age, and I know that some speakers later on today will be addressing these issues in greater depth. I wonder if you could share with us a little bit more about your insights in this area and the ethical issues that you perceive.

I have to admit I'm somewhat naive about these ethical issues. I don't mean to sound simple minded, but I think that scientists and -- scientists are not always in control of the information and that information clearly can be used by the press and by anyone for their purposes, and I can -- I remember when there was testing for sickle cell anemia. It was at the time I was at corn them in university. There was a big -- it was testing for sickle cell anemia and George foreman, I believe, was on the front page of the newspaper bringing afro American children for testing for sickle cell anemia and he was an advocate of it. But the atmosphere quickly changed from being a positive public health measure to a negative one, and I think people might -- I certainly did not anticipate this, so I think it's these unanticipated aspects that you get top anticipate from a pilot study and you just can't -- you can't know them in advance

I think we have time for two more questions. First, Francis

I appreciate your thoughtful comments on this. It's certainly true. There are many issues that ought to be considered before undertaking a project on a scale like this and the specific identification of milestones is well taken. In terms of your proposal for a pilot project I think we're blurring a little between two study designs basically the case control study design, which is the sort of pilot which I hear you asking for where you have affected and unaffected individuals and those with a quantitative trait. Those are the kind of studies going on all over the place. Particularly with the of a map allowing people to do studies as opposed to linkage which has been underpowered. I would say that kind of pilot is not only getting underway but has succeeded in some instances. I would point to the dramatic evidence of age related macular degeneration where here's a disease which has a very late on set. The evidence of inheritability was spotty. We have not one but two low sides, one contributes half of the attributable risks from a sample variable. So for that example what we thought might be a complicated situation turns out to be simpler than losi contributing. You can look at type two diabetes where a lot of people have been doing case control studies based on link analysis and now on genome. We do have three variants for type two diabetes. They don't contribute a whole lot but they point you towards potential drug targets that could be valuable. In the quantitative trait arena, and I've seen data that suggests that it is possible to prove the principle that you're asking to us look at for a quantitative kind of trait. These are people or normal who had ekg's. Looking with a half map approach. So taking all your points about how hard this has been in yeast, maybe this time the proper study of humans will turn out to be humans and we're better model than realize. The advantage of working with a newly arrived population like homosay yens will make this study more attractability. I want top address the need that we need to carry it out in case this wasn't happening. It is happening all over the place. You can see signs of success, but the population cohort study has a different kind of idea in mind it. Is frankly not so much designed to do discovery of variants that are involved. I think a lot of that will come out of case cell studies. It's really designed to quantitate what does a vary yent contribute to risk. Most, especially, to assess gene environment interactions which are very difficult to do with case control studies because you often have a recall bias problem. Maybe some of these issues could be talked about during the course of the day. Again, I guess I think maybe it's a little optimistic but I think we can assume in the course of the next couple of years because of the tools that are available and the decreased amount, that the case control arena will provide the type of pilots that you're interested in to undertake a U.S. population cohort study will take a year or two of planning. That data will undoubtedly be in hand in considerable amounts.

I don't hear a response, so I will move to the next question. The last question

Yes, I'm from the Centers for Disease Control and prevention. I heard you mention in passing CDC. I wanted to pick up a couple threads about the major differences between the human genome project and the large population cohort. It's obvious from your discussion and from what has happened in sheens that the human genome project was designed with a very specific end points that were met under budget in shorter amounts of time. Here we are embarking on something open-ended. It's not clear how long and how costly it will be regardless of what the scientific merits are. You mentioned sort of benchmarks of success in such an endeavor. I wanted to sort of ask you what you might think as we plan ahead or plow ahead in this regard. What could be some benchmarks in this endeavor, and before you answer, just wanted to insert my public health perspective. There is a lot of data collection that public health agencies do like birth defects, cancer and population surveys in which they are hope ended and we collect information on large amounts of people and nobody says they have succeeded or failed because the end point are different. They are trying to follow the resource by which they can quantitate how many people are affected and what the relationship is. So I don't know if that kind of feeds into your idea when you mention CDC or not. So anyway, can you e lab rit on sort of what you think the parameters of early success, whening thises moved forward they were underbudget. There were some benchmarks. What could be some benchmarks in this endeavor that can gal vanize the scientific community and get them to buy in rather than be scared by such an endeavor

I think that's a question for Francis. I mean, I can think of some but I don't know what he would consider a benchmark for success.

I think we're asking you, Jerry, so

What do you think Francis would think?

It seems to me in the case of spina bifida, for example, if it turns out that one found in the population, people who were particularly deficient in feel lick acid, I mean it would be very useful to have the -- people with a vitamin deficiency, just to take off on your CDC study, which, in some way is hope ended because you can't identify subpopulations who are specifically at risk, but with these data you could.

Well, with that, I think in the interest of time, I want to thank you for your time this morning and for sharing your insights with us and doing it as you're teaching students. Thank you very much.

thank you all. . Okay with that and thanking everyone for their patients, our next speaker is Dr. Sharon card ya an associate professor at the university of Michigan in Ann Arbor. And codirector of the Michigan center for genome Micks and public health. She is particularly interested in gene environment and in modeling complex relationships between genetic variations environmental variation and the risk of common and chronic diseases. [ Please reset the audio line ] [ Please reset the audio line so captioning can hear the speakers ]

True interdisciplinary research from the influence of the Genome to the human ecology are just now getting started. and currently the two ends of spectrums the geneticists and the social behavioralists are pitted against each other at the funding tables of institutions. Robert Wood Johnson has showed me the genuine lack of respect that genetics commands compared to health effects of poverty, racism and unfair social practices. Through a lot of hard work, we are just now sitting down at the table and trying to work from the bottom up and the top down to learn each other's languages and methodologies. It is clear that we need new models, systems models, as an example and models that incorporate a person's lifetime of exposure to adequately understand genetic influences on health and disease. Geneticists are criticized for our lack of key social behavioral measurements, the lack of replicatable results. It's difficult in many cases to move from a statistical genetic to the mechanism of action that would suggest new therapies and preventions and with stand evidence-based regulatory decision making. The last point troubles me the most, because it means that genetic findings in complex disorders, especially again environment interactions are not likely to pass the muster that would allow them to regulate policies to protect people. Although there's been some progress lately in the field of gene environment interactions, namely people are starting to look at them, such as intoxico and genomic research, it has exposed immense problems into understanding the policies and methods. Traditionally public health policy has focused on the pop-ration-based solutions. The one -- the population-based solutions. No nobody would disagree with the anti-smoking campaigns. In contrast, genetic information is individual based, family based, ethnic group-based and we require intense research on the implications of specialized policies and regulations for the protection of vulnerable populations. What if we found that some people are sensitive to their environments and others are not? Is it the responsibility of the individual to take themselves out of harm's way, when the rest of society can ignore their vulnerability? Barbara Conig's group paper on smoking through the genetic Prizm, looks at the discrimination that comes with a difference in sensitivity to environmental factors. The current risk assessment paradigm in the EPA, the FDA are other examples of issues that are going to arise as we get more genetic information. How are they going to set standards and goadlines for businesses and -- guidelines for businesses and products based on complex, genetic subgroups? One of the other key issues merging with science then with the policy is that for every disease there's likely to be a different combination of genetic factors and so even defining a vulnerable sub group or susceptible sub group could be a nightmare in and of itself, especially when we overlay those genetic Steph in additions with already -- definitions with already existing definitions of vulnerable populations based on age, race and disability. The regulatory agencies such as the FDA, the EPC and the federal trade commission do not have the resources to tackle an upheaval in their systems and they often do not have enough staff that really understands genetics and genomics. This is slowly changing but, again, it's slowly and I worry that moving the science along in our particular culture, looking at genetic associations when our regulatory bodies are not ready for it would be a mistake. An example of that, that is already playing out is the current lack of oversight on genetic information, genetic testing and the lack of public education, which leaves the public vulnerable. Genetic testing companies can mark directly to consumers. They can market directly to doctors without any regulations at this point. There's no need for them to disclose the real utility or the makeup of their products. We haven't pushed any truth in advertising for genetic testing companies at this point, and guess what is happening, the American market system is working and Best Buy has released a DNA testing kit. There's not enough real evidence that would warrant such a direct-to-the-public testing kit, but on the alternative, people are insighted by knowing genetic information. The human Genome project has done a great job of moving genetics into the public eye and daily newspaper articles that are trying to show the public what genetic findings are out there, are in a sense, a mixed blessing because of their basicA dime of -- paradigm of reporting the news you can use, they tend to overstate the research findings and this leads to a whole cycle within our society of engrandizing simple solutions to complex problems. One of the questions that you -- the committee asked me to address was how much consultation is needed within the broader scientific community to inform a decision about undertaking a U.S. population study? I have to admit some skepticism here on my part as a researcher. I think asking for the scientific community to comment will lead to a biassed sample of very outspoken antagonists from the socioepidemiological field who are worried about the excessive use of resources by geneticists. It will also lead to the south spoken proponents who want to be part of such a large funding IE revenue source for their own operations. When the national childhood study started creating working groups to formulate plans for their large population study I was asked to be on the gene environment working group and participated for about a year before getting set up with the obvious, and I would say natural self-serving interest of the committee members. Another key question that you ask is there general awareness among scientists of the potential of a U.S. large population study? My experience, the answer is a definite yes, and, again, it is with some skepticism. Many of the genetic epidemiologists I know think that there is merit to the idea, but that this Mega science model will fund a few insiders very, very well and not leave much for the rest of the scientific community. It also won't build on the years and years of experience of doing epidemiological studies and especially, utilizing what genetic epidemiologists have already crewed in term -- accrued in terms of cohort studies such as the Eric study, the Kardia study, the Framingham study, and that those experiences, which have taken a huge amount of work to collect information on people and collect it well, makes many of us think that the 500,000 or 1 million person goal is an unrealistically large partlet to accomplish in a high-quality manner. I have been fortunate to be part of a blood pressure program over the last ten years that has collected 13,000 individuals in five racial and ethnic groups through over a dozen field centers. It takes a tremendous amount of effort to agree on what should be measured and how, and then how to package the results. Science is not value-free and neutral. We have a long way to go in terms of how to learn to collaborate together and use existing resources at hand, and this goes not just for the genetics dissocial epidemiological bridge but among geneticists. We are competitive and we often have strong opinions about what is right and what is not right. I think you can see that, you know from my comments that I just don't think that we've had enough time and resources to bill the necessary -- build the necessary infrastructure or structure to build this type of ambitious product right now. Maybe in five or ten year it's would be an appropriate thing. I think that there are a lot of intermediate steps that can be taken along the way. Just getting genetic researchers to work together so that they can use already existing cohorts that can be used to confirm and reject claims of genetic associations would be a major step. Getting genetic researchers to work with social and behavioral epidemiologists and researchers would be a major step. You know, another thing which we have not typically done in genetics research is engage the resources of departments of health, there are cancer registries and early death registries and environmental health that could be used the faifert wave of research. We are try -- first wave of research. We are trying to do that now in Michigan and there are bigga -- big gaps. It's amazing to me that we have not involved the public in this kind of effort. They have important roles, not only as resources but from a policy perspective. Departments of health need to be more prepared for dealing with the genetic information of common disorders and have working staff investigating the implications of state level policies on things like informed consent, and setting up mechanisms to handle the public need's for genetic services like counselling. In Michigan we had a case where a doctor did a die notic, which is -- die notic, which is direct-to-consumer advertising and did he not tell the individual that he was doing a genetic test. He then called up the individual and gave the person the results over the phone and said there was nothing he could do. This person had a genetic disorder that was basically going to -- well, ruin his life, and hung up. This family then contacted the Department of Health, who tried to figure out whether or not there was anything on the books in terms of what the doctor had done wrong. The family was left very devastated and according to Michigan's laws right now, the doctor was under no duty to provide an informed consent or counselling, and so this provides an example of things that can happen. We're lucky in Michigan that we have one of the most genetically progressive departments of health in Michigan and still they were left scrambling trying to figure out what to do with this family who faced employment discrimination and health and life insurance discrimination possibilities. To end, I think that, you know, one of the things that really needs to be done, if we are going to use genetics in this country is to invest in the infrastructure. And that that means the EPA has got to be ready, the FDA has got to be ready, the FTC has got to be ready, State Departments of health have got to be ready and the public has got to be ready. the last thing we want to do is repeat the sickle cell screening debacle in the '70s where well-intentioned legislators passed marriage laws to protect people. You know given the right social investment and the investment in new policy systems I would be greatly enthusiastic about this project. This is my field. I would love to have access to 500,000 people in the genetic information. I just don't think that the timing is right. Not right now. Thank you.

Thank you Dr. Kardia for your forth right comments. We have time for a few questions from the committee, and then there will be a -- a longer panel discussion involving both Dr. Kardia and our next speaker as well. So everyone will get their shot but I want to keep us back on schedule. Kevin?

Thank you very much, professor Kardia for those forth right comments. I just have a quick question. How much, roughly, of your comments do you see is specific to the United States and how much of this would flow over into some of the other large population studies that are being done around the world in different countries?

Well that's a difficult question to answer, because, I mean, in other countries they have very different systems. I mean in the UK, where they have a very different sort of regulatory system around genetic information, they are not going to have the same kind of issues. We could go piece by piece, it's very specific to each one, depending on how regulatory decisions are made and what their current standards are.

All right, Joseph and then --

Dr. Kardia, thank you again. My question has more to do with sort of practical applications. Awe lewded to that throughout -- you alluded to that throughout your discussion. And I'm wondering if you can give some specifics to this. I mean, so you concluded it's premature to mount such a study like this. But throughout your discussion, you were alluding to specific ways that the process may begin. And how things were done. You sort of -- sort of painted a broad picture TV, but I'm wondering, given your experience, particularly in Michigan, particularly with the group thatwork with, I think on community-based -- the community-based involvement part of it, where there are several principles with how you work with communities and those groups and there are ways of doing professional education. I'm wondering if your experience, and in your efforts have there been specific activities you have undertaken or specific efficacy, and are these successful in getting the things done? Could f you could speak to that.

Sure. Sure. No, I would be glad to because this is something I work hard on and I have been amazed at how desperate the solutions are. At the community level, my understanding of where to start is really on the relationship of genetics to self, to family, and to humanity. What are people interested in? How am I related to my brother and sister? Very basic concepts. Things that make them feel good about understanding, boy, I have Genome in every single cell. It's very basic. Okay? Because when you move to the here's a mutation and it causes disease, you have a 25% risk, all of a sudden, they have no context, no personal context with which to use the information. Now, if the doctor says, you know, take this pill, they can do that. But they don't retain their genetic information. Right? Now, health professionals are on the opposite end of the spectrum, okay? They wouldn't, basically the news they can use. I mean I have given many different sort of grand grounds to doctors on cardiovascular disease, the long QT syndrome, sudden cardiac death is a great way to get people excited about genetics but then they say, how am I going to use that? And now there's this gap. So I have got information, but how does it meld with my correct practices. You can see that the needs are very different. And I think that, you know, one of the -- one of the things that this also makes me aware of is that you can see by that big difference why the public would be suspicious. This public doesn't have the basics. The medical practitioners want to use the information and, you know there's not a connection in the middle even, where doctors and patients can really talk about genetics in a common language that would help them build that trust so that genetic information doesn't become a liability but an added value.

Okay. We have Francis first.

Thank you for a very thoughtful presentation and you covered a lot of territory in terms of topics that are at the interface of genetics and society and public policy that this committee has been wrestling with since their founding. And obviously you have a great deal of experience in the field of epidemiology, and I think your opinion carries a lot of weigh. Let me challenge you on the notion that if we just sort of put this off for five years, that might be a better solution than starting it now. Because I think a number of the areas that you have pointed to, as being potential barriers are unlikely to improve without some stimulus. And a project of this sort, in many ways could provide a useful stimulus, having been in Washington now for a dozen years, I can tell you that agencies and regulatory systems and even public policy decisions that relate to legislation being like genetic nondiscrimination rarely act unless they perceive a need and even then it takes a while. Public project with this kind of visibility would, I suspect, be a very valuable additional impetus for taking action to plug some of the many regulatory and regularive issues that -- legislative issues that you have touched on. And without this kind of project, I suspect they will go slower. Similarly, you point out the issues of public misunderstanding, of scientific can communities not necessarily understanding each other and working together, would not a project of this sort which if mounted would be a very visible national enterprise? I suspect more visible than the Genome project because it would involve lots and lots of people, just regular people. Would that not be a wonderful opportunity to try to achieve some of those educational steps for the public, for the media, for public policy makers, and for the scientific community? Because some of the things you said about inability to work together was said about the Genome project in 1988, as a reason why it was never going to work and it probably would not have brought those communities together had there not been a project to provide the glue. Furthermore, in terms of how this would stimulate the field, you mentioned the concern that maybe this will basically fund a small group of people who will get very rich on the funding from this and everybody else will suffer. Again, the model would be to have all the data publicly accessible. So having a data set of this sort, I would think, would be just as Genome si consequence has been -- si -- sequence has been, to have the data. So let me challenge new terms of the timing issue. This is a long lead time enterprise. You will not get anything out of this project until you have set it up and enrolled a lot of people and started to see a lot of incident cases. If we don't start now, we won't really have much useful information five years from now, if we don't start five years from now, it will be ten years before we have this kind of data. Are those arguments so compelling in your mind that it's better to wait as opposed to trying to use this, which I'm obviously proposing, as a way of trying to address some of the things that you are most concerned about? I would like to hear your thoughts on it.

Sure. I guess, as baseline, my -- I will call it opinion that we need more time comes from my just human experiences. That researchers not being able to work together because of the disciplinary disconnect and that, you know, that's a real issue as well as turf wars. Right now, I can tell you from an epidemiological point of view that I get funded for collecting data, not analyzing it. The NIH will cut off the fourth year where all the analysis is to be done as long as the recruitment is done. That there is not a lot of appeal for genetic epidemiologists who analyze data because we can't get it funded by our peers, okay? Collecting data is what does it. I think the other thing is that there have been some in-roads in terms of these regulatory agencies. I mean, the SCA is really struggling with this, even if it's in the bidill drug, but, that, you know, where in the plan is the resources for the infrastructure? Why aren't we doing a national genetics education? I don't believe education in the mix of research is the way to do it. Because it's at different ends of the spectrum. What you are trying to accomplish is about the genetics of disease and disorders, where people need to start is way far away from that in terms of their own personal relationship with genetic information. So it just seems to me that there needs to be some other things in place. And believe me, I understand in ten years of working on the family blood pressure program, we're now just getting to the point where we're get something exciting results and abilities to do things. But there was the natural pressure within the system to show just like a corporation quarterly progress that I think actually dismantled much of what would have been the -- well, basically, the advances that we needed to make in our complex understanding of genetics rather than going for the single gene paradigm. There's a huge amount of force to do the single gene paradigm. It is -- it is crazy, but you know, we are suffering. Science has gotten fashionable. It's -- it's the -- you know, from a human perspective, I think we have a lot to get over with this large population study.

Thank you for. That I will let you catch your breath and I will have others hole their question -- hold their questions until we come back to the panel discussion where everyone he will get another crack at you. Our next speaker is Richard Marchase. He's the vice president for research and the senior associate dean for research at the school of medicine at the university of Alabama at Birmingham, but today he's here representing FASB. The dead -- FASEB, and federation of American societies for experimental biology. His session will be followed by a specific Q&A for him and then we'll invite Sharon back to involve a broader discussion involving everyone. Dr. Marchase?

Thank you very much, the federation of American societies of experimental biology is a coalition of 23 member societies representing over 70,000 scientists, in diverse areas of life science and medical research. Prior to a decision about undertaking a large population study in the U.S. we at FASEB agreed that the broader scientific community should be given an opportunity to comment. I thank you for allowing us this opportunity toor today. -- today. Such consultation will surely be important for the technical and design considerations that will be inherent in this study but these are the not issues that I will be addressing or focusing on primarily today. In developing a response to the questions posed by the organizers of this session, discussions were held with FASEB's clinical research subcommittee, our NIH issues subcommittee and member societies including the American society of human genetics. I would like to begin by saying FASEB recognizes the potential of such a study to improve people's health. The policy issues raised by the committee's task force described in the background information that Dr. Willard already has described are all important issues to address. When we at FASEB looked at what the policy issues were that were most critical to us, as the broad representative of the scientific community, we focused on three. The pry prior ITization of this study relative to other large-scale studies, the study goals, how well the study is designed so the useful data can be produced, and the cost and the possible effects on research project grants, investigator initiated studies, and other initiatives at NIH. Relative to the first point, the prior ITization of this study relative to large Zale studies -- large scale studies we are interested in the dialogue that will allow us to put this study into perspective relative to the other large scale initiatives that are currently being undertaken, these include things such as children's health study, and recent initiatives towards increasing NIH's presence in clinical and translational initiatives. Doctors of road map initiatives are already on the table, as important ways for the NIH to expand the relevance of its mission and we are interested in seeing how this study will shape up relative -- what we priorize on what's already on the books at in. IH. the other -- NIH. The other point I would like to make here is are we sure, before we initiate this study, that the other long-term studies that have been referred to before have in mind as much as they could be, to allow the appropriate data that would set the stage for such a study as the one being described here? Second point has to do with study goals and outcomes. A major challenge to the usefulness will be how well will the outcomes of such a study be used by the scientific committee? Clearly, very well -- there's been a lot of thought that's been give tone the way the study would be designed, and we are not going to in any way doubt that this study would go forward in as efficient a way as possible but there are some questions. For instance those raised by Dr. Kardia that we think really do need to be considered in much more detail than they have to this point. How will the data be collected, stored and made available? The lack of appropriate medical, electronic medical records has already been referred to. There are questions about how environmental data would actually be collected and there was a lot of discussion in the background information, about the necessity to develop new techniques to, in fact, make sure that environmental data were going to be appropriately handled by these studies. How will the genetics and other personal information be protected, again an issue that Dr. Kardia has addressed very well. Does our current healthcare system have sufficient technology and infrastructure to support the data collection and the data sharing that would be necessary to make this study a success? Lastly there is this idea that a need might be found to restrict or focus the study more. We've talked about pilot studies and what advantages pilot studies might have, and this is going to plan to the last point that we are really going to focus on and that is the skepticism that Dr. Fink referred to, that was characteristic of the scientific community at the beginning of the Genome project, and which we are concerned would also be the sort of first stage of recognition of this project by the broader scientific community, not just those who are Jeanette geneticists -- geneticists and not those who have biassed against geneticists but rather the broader range of wet lab and scientists, to the large extent represents at FASEB.

The primary -- the primary problem that we foresee here is that this is a very expensive endeavor. And being proposed at a time when NIH funding is not increasing, and when success rates and pay lines for all grants, including R 01s are at a very low ebb. And if I could advance to the next slide, I would just like to show you some data that I think most of you are familiar with, but this has to do with the percent change in the NIH budget. Those numbers appear a little small but what you can see is in the mid'90s, there were percent changes that were on the board of 5 to 7%. During the doubling period, the changes went up to 14.4 and 15.9%, for 2004, there was a 3.2% increase in the NIH budget, the 2005 budget is not set, but it is likely to be zero to 1% in terms of where it will be relative to the 2004 budget. Now, these low increases in the NIH budget put a very significant burden on investigators who are submitting their own ideas for funding at the NIH. Much of the buildup that occurred in the Genome project and of the overcoming that Dr. Fink referred to took place during time when success rates at NIH were not being challenged by the lack of discretionary income that was available. The next slide, in fact, shows those success rates from 1995 until 2004, and you can see that during the very largest buildup and the completion of the Genome study, success rates ranged from 27 to 32%. During the period of the doubling, these success rates were very high. This allowed a third of the grants that were submitted to be funded. That's still not a very large number. But a lot of emeritorious research was, in fact, included in that one-third. If we look at the success rate for 20:04 you can see that there's a significant drop, about a five-point drop that we are suffering through the hard landing at NIH that's following the doubling. We expect the success rates in 2005 will drop even further. Now, as I said earlier, FASEB believes that the funding for investigator-initiated research projects should remain a high priority at NIH and therefore an important question to our community is. What would happen to success rates if r01 funds were cut in order to fund this study? And we've gone through a hypothetical scam tam's shown in this next -- example that's shown in this next slide. No one knows exactly what this stud I would cost. The estimated costs could be as much as $3 billion, perhaps even more. If we were to take roughly a tenth of that, $350 million were to be taken out of the R 01 budge that the would be approximately -- budget, that would be approximately 1,000 fewer grants that would be awarded. Based on 2004 data, the success rate for #R 01s would drop from 21.9 to 23.9%. We are very concerned that the allocation of this size of a pot to this project at this time, during flat funding periods, will be highly detrimental, both to generation of biological scientists, as well as to the next generation. It's already very difficult for a young investigator to think that as he submits a grant, he has a 24% chance of success. When that success rate goes down to say, 20 or even below, it can be a very discouraging thing and the late '80s and the early '90s, we saw how discouraging such success rates were to the influx of new investigators and academic research careers. We would not want to see this study be funded in a manner that would both hurt this entry of scientists into our research pool, as well as the human cost to our scientists who are already working. If 1,000 fewer investigators are funded per year because of this allocation, what does that due to the faculty in our biology departments and our medical schools that are currently already there and struggling in many -- in many cases to assure that their research careers are going to continue to flourish? This isn't a welfare program in any way. These are scientists who have been selected through a very highly, highly selective process, and they are talented. They are contributing to the kinds of advances that will allow the next generation of medical discovery to lead to real cures. FASEB's long-standing principal is the investigator initiated, competitive, peer-reviewed grants should remain the core mechanism for distributing research funding. This mechanic mix allows highly schooled scientists to propose a direction and priorities for future research based on their own expertise and preliminary data. Funding of these proposals occurred only after very rigorous peer review. These grants have been the foundation for data and medical sciences and by placing most of the resources in investigator-initiated peer-reviewed research, NIH ensures the federal taxpayer dollars will support the best science. Therefore, the study should be undertaken only if funded through sources that do not compromise investigator initiated projects. In conclusion, we recognize the numerous potential benefits of such a study for public health. We are not in any way disputing. That this is also a visionary type of study that, in fact corporation help to break -- in fact, help to break the flat level that we have been experiences. It could be the vision that Congress would get behind and new monies might be allocated. We are concerned, however, that in a time when discretionary spending is very limited, with the Iraq war and our response to our hurricanes, that there may not be new funds available, in addition to the existing monies that are already at NIH. I commend the committee for grappling with these issues now and thank you for the opportunity to bring these concerns of our best scientists to you today.

Thank you Dr. Marchase. First, I call to see if there are questions specifically for Dr. Marchase before we open it up more broadly. Emily?

So I guess I'm a little confused. Who do you think is going to get the $350 million a year if it's not people in the science community?

Oh there's no doubt that it will be people in the science community, but there's no doubt that this kind of a shift will cause a distinct difference in the funding that will be seen, for instance in the physiology community, or in the pharmacology community. We have many constituent society in FASEB, and a shift of this magnitude could very definitely disenFran franchise some -- disenfranchise some investigators and would empower what we would hope not be a small group within the genomics community, but there are concerns about the breadth of funding that would be taken away from other disciplines.

Okay. So it's just -- it's not the overall magnitude, it's the shift from wherever it is today, to a different people who would be receiving it.

Yes, there are cellular molecular studies which are very important to the way we understand diseases these are being carried forward by scientists who are not geneticists who are a bit concerned of a drop of the magnitude that might be seen, if this were done out of an existing flat budget.

Wayne first and then Francis.

Thank you for your comments. You kept hitting the word "Study" and you mentioned that this is a study. And I would like to react to this and get your -- some of your thoughts on this idea too. I have been interacting with a lot of the international biobanks and cohort studies like the one in the UK and the Canadian and other places and the way they send their studies is they don't call it a study. They call it a resource because collecting information on a large number of people to be followed over time is not an individual study. It's a resource that could lead to thousands, if not millions of studies that could be generated in the future. So in that context or prism, at least, I mean, would you still have the same -- I mean, I realize all the comments you said are probably true in terms of case shifting the funding on the short-term, but on the long run, if you think about a national effort, such as this, that could be a resource for studies, what -- how would that --

Right, absolutely. There's no doubt in my mind that in the long term, this is a very important resource that would be appropriately used by physiologists, anatomists, and the whole spectrum. We would applaud, in fact, the fact that this resource should be made available. We're just very concerned that as you say in the short term, it's not done in such a way that it jeopardizes the scientists who are currently working who are going to be entering the fields that are not necessarily going to be given the opportunity to do the short-term work. We would hope that as I said, this could be the visionary kind of link that would allow us to, in fact, increase funding for the biomedical sciences.

Francis and then Deborah.

So Richard, I appreciate your thoughtful comments and certainly all of us at NIH are deeply concerned about the trends in terms of support for r01 investigators the curve that you showed is likely to get worse in the opportunity circumstances. And yet when I talked -- current circumstances. And yet when I talk to leaders who are in a position to be able to turn that around, often what they ask for is, what is there out there in the way of a signature initiative that would enable some increased enthusiasm for biomedical research at a time where, frankly there is not as much as there was a few years ago? In a sense we gave you your doubling. Okay. That should be good enough. And as we all know, the benefits of the doubling have been subSam, but they have been -- substantial, but they have been eroded rather quickly as that very different kind of mind-set has been set in. I agree with you that it would be pretty much not impossible toy initialiate a program of this magnitude in the current budget climate. The idea of actually losing 1,000 new grants on the basis of this kind of a project is just not tenable. But I do think picking up on your remarks a minute or so ago that there's a real opportunity here for the biomedical research community to identify one or two flagship initiatives that are compelling in terms of their benefits for public health, whether this is one of them or not, is something for the scientists to be discussed and decided, but I think the worst thing we could do right now is hunker down and say, well, maybe we can somehow just get by with the current circumstances and not take the opportunity here to try to identify some new things, which are the only way I think we're ever really going to generate that kind of enthusiasm and energy for getting back on a more progressive course. So your points are very well Dane. Again, I don't think anyone -- taken. Again, I don't think anyone is proposing that a project of this sort could be initiated from existing funds. It would not be tenable.

I agree completely and I do think that this is the kind of visionary project that might move us off the stagnant place where we are right now.

Right. Thanks.

Deborah?

An underlying theme that I'm hearing both from Dr. Kardia and Dr. Marchase, that whyI don't think is being articulated is a strong holding to the current academic system as it exists. And I think there's an impetus of change from the NIH road map valuable large group efforts, collaborative types of efforts, and there's certainly underlying gender issues and minority issues that are not -- at least the gender issues are not supported by the current academic tenure system and the tenure clock. And I'm wondering if some of the disease with what we're talking about here, and moving towards with this initiative isn't shaking the underpinnings of the academic system of having to have two R 01s and a project on a P 01 or a score in order to get tenure within a designated six to nine years and does that system need to be reevaluated by the academic community in light of the funding and the research initiatives that are currently being valued by the NIH and other organizations?

Absolutely. And I think that our institution is one example, but you would find institutions across the country that are trying to grapple with this issue, especially in these departments and programs that are very highly leveraged because of their involvement with external funding sources such as in. IH. We appreciate many things that NIH is doing as recognizing principal investigators is a step in the right direction to I think, allow us what it is we should do to ensure that our academic enterprise is able to go forward in a manner that big science will be an important part of how we go forward. On the other hand, even if big science becomes an increasingly large part of the NIH budget, I believe that it is not a parochial interest for us to maintain an emphasis on the kind of research or initiated grants that have given us so much in the way of advancements and disease curing power. We have very bright people out there, both men, women, young and old. And we want to assure that the individuality of the way they think doesn't come aSunder because we go too far to the big science point of view.

Steve commiss can I. -- Steve commissy is.

Since you had the clinical group associated in one room, did they articulate whether they thought this -- if this were to go forward, it would be better as a transNIH effort or would it be best to actually place the project in one institute or one center from the standpoint of really maintaining a real focus on getting the resource out there and managing the resource, much like the human Genome project was back in the early '90s.

We didn't address that at all. I mean, I think that certainly this is an initiative that is going to benefit all the in. IH institutes if it go -- NIH institutes if it goes forward. Obviously we would like a management as reasonable as possible.

Sam, you are next up.

Thank you very much. Dr. Kardia, you had a number of very relevant points, important points raised about the infrastructure issues and societal issues associated with developing a large study but there's a great phrase "don't let perfect be the enemy of the good." And one of the concerns that I have in listening to your comments is an assumption, perhaps that we can achieve some perfect societal and infrastructure development in order to then begin this study. We understand that there needs to be significant progress made in these areas, for example, NIH is currently engaged in a five-year $2.4 million to educate educational professionals about genetics and the use of genomics in their practices but it's understood from the beginning that this is an iterative activity and this is not the ultimate, be all, end all for education, such that all health professionals in this country will know everything they are supposed to know in genetics/genomics. So I guess my question is: What are the activities that could occur in the next five years, say, that would need to take place in order to achieve this level of support that you are discussing in -- and what can realistically ab chiefed in the current systems that we have and what the current social activities that we engage in?

So, I mean, that's the key point.

The absence of the study.

And I don't think I'm being a proponent of perfection. But just in the example that you gave, the $3 billion price tag to the $2.5 million is the huge discrepancy. If you put $100 million towards genetics education of the nation, including health professionals, then you might actually get somewhere. But $2.5 million is not a lot of money. It's just not just policy. How much should be going to genetics policy? Shouldn't it be on the same scale? I mean, it's -- it's the out-of-balance and I know epidemiological studies are expensive and that's, you know, not the issue. The part about the academic. I would love to see academia change. I think the interdisciplinary way to do things is it. And yet, how do you get the funding to do that? It's not out there. I've been lucky enough that and I'm a whole Genome for this area. But the Goth is so big. I mean, I have to teach them what a polymorphism is 20 times before we get anywhere. And, I mean, putting some money -- I mean, it's like it's a balance. We'll spend $3 billion on something, spend $500 million on the infrastructure. Because that really then gives you something you can work on, but it looks out of balance right now. You will go do this great science, but the rest TV is not there. -- the rest of it is not there.

They are queueing up. I have Wayne and then Julio and then Deborah.

Sharon, can I pick up on the comments that were mentioned earlier and sort of try to reiterate it in a slightly different way? What I'm hearing you and others say is that a big science like this, in the absence of of the context where big bucks are going to create a resource that could be used in the future, is when you say all the things around it, like education and informed consent and the policy and the translation and the lack of health systems, and the infrastructure, and I think the committee is probably taking note of that, and will be further discussing it. One specific point I have in mind, and I wanted to ask you, what you meant by it, it's -- one of the things we have at CDC is think genomically and act locally. And I guess that's why we have kind of acted locally through the state infrastructure to sort of build up the capacity to do the good work that we come out from the human Genome project. You did mention that as we embark on studies like this, environments are local, result of changes in exposure, the ski Nomes are local, and -- the Genomes are local and how would you think about a two-pronged attack here. One is to build a big science, and at the same time, building that infrastructure and perhaps the science can go with that infrastructure, given the -- sort of the I hadio sinies of genes and exposures. If you develop a Michigan Genome initiative, or a Washington state Genome initiative.

Sometime I'm working on that for you.

Where you educate and you do informed consent and you collect data, how would that work, given all the stuff we have been talking about here.

Well, there's a lot of ways that it can work, because, I mean, for instance, the last three years, working with the Department of Health, creating relationships so that what we have is a broad access point, or bridge, between academia and the departments of health, and then allow us to, you know, really Garner the resources of populations that the Department of Health has and then use the good science and the measurement in the academia. And that one of the key things in the -- I will call it study design, is being able to have enough people that are representative of the -- basically the population you want to serve so that you can do the rep laycation studies within replication studies within that group. I have been struck over and over again how much we group unlike people. We say African-Americans in this country, there is a client of allyl and we tend to pool everybody together if they are in white this they are this group, and if they are in African-Americans they are in this group. There are genetic factors across populations and very big differences in environmental factors. And, you know, my sense is that if they are really going to do this well, you have to match the population you want to serve with the genetics research, and so, you know, I would say, you know, focus in on big cities, where the biggest public health burdens are going to be and try to do it well so that local and State Departments ever health, as well as local clinicians can actually use the information that is coming from their study would be one way to do that. And then it affects the local policy at that state level to be more specific in terms of the cases. In Michigan we have a huge dioxin problem, you know. Dioxin gene interactions would probably be top on the list. You know with the great technologies these days, I mean, the genomics, the protomics, I mean we can measure incredible things at all of these different levels that would be another suggestion. But right now it leaves a huge gap between finding an association and moving it into the treatment and the prevention without the biological causation to back it up.

Yeah, I think just to jump NanoProducts before we go to questions, I think in considering genetics and genomics we are inclusive about the particular technology and the level of omics that one might bear on the particular question.

Good.

Julio first and then Tampaah.

I have a comment and a question to you, Sharon, and hopefully Richard could also comment, which is this large genetic-based initiative have been mostly bench based so far like the human Genome, they didn't have to deal with living individuals. And this -- in this project, the playing field changed completely you are essentially proposing to follow people for a long period of time, and look at, you know, health outcomes in the context of their genetic material. So one analogy that could be made. What was said in the first presentation that a minority, and disability group may be overrepresented so that they can -- you can be sure that they are there in equal numbers. So think about this, you get -- and I work with one of those populations. And the rate of health insurance is very low. So if you are going to include people who only have health insurance, the study is very biassed. If you include the population at large, which includes a substantial group that does not have health insurance. You sit there and you are funded and you watch these people over time get sick and like in the inner cities we have high rates of asthma, depression and hypertension that's poorly managed, diabetes, that's also very poorly managed diabetes, that's also not treated and we watch these people get sick over time and document how sick they get and do nothing about it and then collect the DNA and try to find the cause of their sickness, I think it's unethnical, on the other hand, it's not possible to give health insurance to all people who are uninsured. You will find a very poor population in the third world, let's say India or Africa, somewhere and they are starting in the world, we will follow them over time, and you have your food and your cabin and you live a comfortable life, and, you know, document how these people are suffering over time. So it is what's happening in this country, but in a sense, let's say -- could you say if you don't go, they are going to have the same outcomes anyway so we are not doing anything bad to them. But once you get involved there's a degree of social responsibility that I wonder how you can justify spending $3.5 billion on the entire project, to watch people who have no access to Hale care get sick over time.

-- healthcare get sick over time.

Why not a model where the research is also healthcare? Why not have it incorporated as a doctor is going to give a clinical exam and make a determination, why not do the healthcare on the spot? It's one of the reasons why -- you know, I really,understand this and it's one of the reasons why I'm trying to move to the community-based participatory learning, how to do this, because the distance between the researcher and the participant leaves the participant basically isolated. There's no real engagement, and, you know, at the University of Michigan, we've got these incredible university-based participatory-based researchers and they are doing things I would never think of. Their asthma project has money in their budget to help the asmatics with whatever they need. If they need a new couchF they need a vacuum cleaner, if they need something to actually help, it's in that budget. and I -- I don't know why, you know, something like this couldn't be unique in the way in which they offer then feedback as, you know, the doctor is already seeing them what's the difference between writing a prescription and finding generics and working with communities? You would be surprised how much communities care about the people in them, even if they are dis advantaged. You can work with that. I mean things that have worked around, for instance, violence programs. How do you get inner city poor people to work together is by working with people to support each other. Genetics researchers have never done this before. Why aren't we using some of the things from the social sciences that have worked in terms of community support?

Deborah?

Well, Sharon, in your discussion, you rang a bell. The human Genome project, for instance, had 10% of its budget dedicated to Elsie issues, 5% -- 5%. Sorry I got the percentage wrong.

Better than nothing!

$20 million a year.

So can we redefine ELSIE for education so since education would be such an extremely important part of this project. I mean ethical, legal and social also are big but there's such an educational component to this that I don't really know if you have considered a portion of this budget going to these issues or not, but if you have, I would encourage education to be a significant portion of that.

Can I --

We'll let Francis answer that.

Absolutely! and, again, I hope people have had a chance to look through the details of the report that's under tap four. This -- tab four this group of month are than 60 experts that worked over a period of more than a year dealing with P.S.T. issues that we are -- with many of the issues that we are talking about this morning came to appreciate how complex this is and while all the nuances of those conversations are not captures in this 25 page document, I think there is a lot of information there that would be very relevant to some of these conversations. And certainly, the need for education as a component of this was absolutely clear, and as well I will talk about later on today, especially the need for public consultation about the wisdom of undertaking such a project before you even start it was high lighted by that group. I have to tell you, that group came into this discussion pretty skeptical about whether this was a study that had sort of found the right time in history to be undertaken, much in the way that Sharon has described. And many of them people, like Eric bullwinkel and Greg Burk are aware of the marrying together these disciplines. One of the things that I don't think it comes through very much in the document, and hasn't in the discussion is just how critical it would be to utilize this study as a means of improving our ability to do environmental assessment. This is not a study of genetics. This is a study of genes and environment and particularly how they interact with each other and if you don't have the environmental data, you don't have anything to study. I'm sorry that David Schwartz is not here today, because as the new director of NIHS, he's gotten very involved in some of these discussions has as lot of interesting ideas about how to improve the technology for doing that kind of environmentalment, not just -- environment, but Saming by-- sampling biological response and there's a lot that could be done there. So as we talk about this project, yes, please, think about all of these dimensions, the environment, the technology development which we need to be part of this. We don't have the right technologies to do any of this right now to do it really well. Does anybody in the room think we have a appropriate tools to measure dietary intake right now? They are ridiculously ante indicated and -- antiquated and we need to do all different types of approaches and there are possibilities to do that. So think about that. Think about the educational, the Elsie component. If this were tore get off the ground it would have to have that kind of very complex set of components in order to justify itself and in order to do the kind of public good that we want. And finally, I just got to say, if we say this is a project that shouldn't happen now, let it not be said that the reason was that somehow the scientific disciplines con get together to work on it. That would be truly tragic. If this is a project that is going to benefit the public and if we can figure out how to pay for it, let's do it. And not put up bear barriers about our own community of being stuck in models of how we can't get along.

So we'll let the record show that answer was yes to your question. Jim?

We obviously don't want to invest huge amounts of resources where we have not looked critically enough about the potential outcomes. So we are talking, for example, about the physician taking care of the patient and the patient with asthma, et cetera. As a practicing physician, I have a certain inherent skepticism about studies that require, say, 100,000 people to show a significant P value, because my question as a physician is: Is -- okay, that's statistically true, but is it relevant for my patient? And while I think there are some very tantalizing examples, for example, aids-related macular degeneration. I think that the unfortunate general concessions like diabetes and hypertension and I think the studies show, are going to be extraordinarily complex with many genes and many environmental factors contributing. So if we embark upon and are successful with the study that has a half a million people, a million people, and we are successful in identifying polymorphisms that contribute 2% or 3% of the genetic components to a disease, have we ultimately gotten good return on investment tore that? -- for that? I think that, again, there's some very tantalizing studies that I'm very excited about, that skate that, well, maybe if we take into account environment and genetics we will be surprised that an inordinate amount of Riis sk dictated by a -- risk is titcatetb -- dictated by others. To see if the -- the kind of return on the this time of thing about a tangible return, and a useful return for patients. Ultimately we are not going to be satisfied with extremely incremental, small, analysis.

Joseph, I have you next.

Thanks. Thank you. I actually want to go back to -- I appreciate James comments because they were relevant. I want to go back to something that I brought up a little bit earlier because I still am not satisfied with the answer. It has to do with just the practicality of this question. When you start, and that sort of deal. And I wanted to also address this both to Dr. Marchase and to you, Dr. Kardia. It seems to me that one of the things that we have to struggle with in terms of making this recommendation or even looking at our recommendation has to do with addressing the way that we sort of interact with one another, both as scientists and as scientists with the public. Clearly, in the presentation from Dr. Marchase, there was a lot of issues related to within that group of concerns about what is going to happen if, you know, this and this occurs. It seemed to me that words that -- you know, is that a question as Dr. Collins alluded to, something that is going to really limit us or not? So I'm going back to the question of how do we make it work? If people are concerned about those things, how do you sort of bridge the gap then? Because reality is -- reality is independent of where the fund is going to be, at some point you have to make a decision, you know, either you do or you don't. Either, you know, yes, we're going to try to make this happen or, no, we're going to continue to, now he -- you know, do what we are doing. And it seems to me for us to be able to make a good decision we need to have some real concrete, yes or no, you should go forward with this, yes or no you should not. It's a little frustrating to me toe kind of dance around it. I just like to get an opinion on that. So start with you Dr. Mar chaise and Dr. Kardia, if you want -- Marchase, and Dr. Kardia, if you want to comment. Change you.

Yeah. I think the bottom line is whether you go forward, whether you go forward now is going to be a very difficult situation. I would say the take-home message that I would try to bring to you is one in which we have to do this in a manner that does not completely disrupt the ongoing scientific community that has been so productive in the past, and that does not discourage new investigators from coming into the system. If as Francis suggests we can do this as one of the projects that really moves us off the flat line funding that seems to be the -- the way that biomedical research enterprises is viewed now by the government, I think we would be better off doing it. We need to assure for our country's good, for our patients' good that, in fact, we are going to have scientific progress going forward. We can not do this study if if means that we're going to be absolutely debilitating 90% of the scientific disciplines that make up the biomedical enterprise. If we can do it in a way where it's clear, that the skepticism by scientists who are not necessarily the Jeanette silts is going -- geneticists is going to be overcome, if it's going to be done in a way where other disciplines are going to be able to be funded at reasonable levels, then I think there are real advantages to having this resource being created. But the need for further investment in the biomedical research enterprise cannot be minimized.

I think I would agree with many of the statements that, you know, could you start right now, if there was basically the plan that really does the address the issues of how do you take care of the person, the participant, all the way up through the investigators, as well as then the system in which the results spill out. I mean, 5% on the Elsie was a great start but for something like this, with these implications I would say 25% of your money has got to go to the infrastructure of what are the results are actually going to end up which is in the public, in the regulatory systems. And that, you know, in terms of interdisciplinary work, you know, Playboy Enterprises it could be a -- you know, maybe it could be a model for doing that. Whether or not it was going to gut the funding of other members of the scientific community. I can tell you how many times the epidemiologists say it is a total waste of time and money. Why are you doing it? When you look at the polymorphism that explains this amount of variation and poverty, racism and other social policies, you know, I'm a logical person. I have to say, you're right. But if we integrate them, really integrate them, and this is where my skepticism comes that integration, you know, how long does it take to learn a field? To really get good enough that you can be a quality investigator, it takes years! I'm not sure just bringing people together on a particular project does it. There's got to be other mechanisms in there as well. The road map is great. How many people are they funding?

They are all excellent points and I know we're -- we have kind of been dancing around the point of a dichotomy of a yes or no answer. When do we move forward? What do we not with respect to a conTex question such as this -- complex question such as this. Let me put things in the context of history a little bit and then ask both of you to comment on this. We have already spent millions if not billions of dollars to get to the point where we are right now with mapping and consequencing the human Genome. Okay? I mean the benefits so far have not been great, but we're on the way. And I guess the -- the question is: How do we move forward with a bullet of investment that would allow us to translate the human Genome sequence and the related technology to population health. That's what we are talking about here, sort of how do we bring the Genome to the health of the population now? The initial project went on with the initial funding of the 5% of Elsie to appease some of the anxieties and the issues that were deemed to be too complicated in the ethical issues here. I heard already the -- the issue of the E being added to ELSI. But I'm hearing Sharon and others saying that in order for this massive public health research project to move forward, that perhaps one thing to be invested in is something more than just the education and the individual-based exLSI but more of a population level ELSI. That's what we are talking about which is probably policy, public education, sort of infrastructure for health department, et cetera, and now how do you envision that 25% would be invested? I mean, to -- assuming that our new money is coming. I mean, how would that work?

I plead the fifth. [ LAUGHTER ] I mean that's very complicated. You have to have some kind of, I would call it a strategic plan of where the greatest need is and where the greatest lack is. And there has to be that priorization. I mean not having regulatory bodies understand genetics seems to me a major liability. Not having health professionals understand genetics and not having the public understand genetics seems like a major liability. Not having departments of health have really anything more than newborn screening as their genetics seems like a major liability. The interdisciplinary stuff we probably could work through. But the others I think that would take a significant embracing of the issues.

Okay. Kevin and then Sylvia.

First of all, I would just like to ask Dr. Kardia, my understanding is we don't have your written comments. Would you be willing to give us a copy of what you --

Absolutely.

Great. Thank you very much.

And then secondly then, I would just like to pick on -- pick up on something that I have been hearing now more and more, and since we live in the world of acronyms here in Washington, I would like to ask a couple of people just around the table, would it be a deal breaker to pursue a SELSI, P-h-S-ex-l hismd-IE. Interest integral to the project would be the goal that we claim for the project and that is public health. Unless the structures were built in to say, if that individual is coming into research, then that Hale care is taken into consideration as part of the project. Is that a deal breaker? -- healthcare is taken into consideration, as part of the project S. that a deal breaker? I'm just wondering.

Actually, the term PHELSI has been used before. Toby Citrin has written a chapter in our genetics and puck lick health book in which he elaborated on the -- actually in some -- public health book in which he elaborated on the individual ELSI and the population ELSI. I think all the issues around policy and infrastructure, and healthcare systems are the kind of issues that the original human Genome project did not take on because they didn't have to at that point. I mean, they were just mapping and sequencing the Genome. So the world PHELSI already exists.

We're going to go ahead to Sylvia first and then Julio and then Joseph.

I have to echo what Dr. Kardia said that 5% of a research budget to deal with such broad and major important component, such as PELSI which you should add an "F" so. So now we we have FPHELS circumstance a 25%, you know definitely closer to the mark of the issues that we have to deal with. One of the other things that no one has December with is funding for genetics professionals to actually deal with all the public that is going to want these services. There is no funding for training. We are losing geneticists. We are losing genetic counselors. We do not have minority recutement of people to work with minority populations. I mean, there are -- there's not even a native American genetic counselor. You know, why don't we have that? Because people do not fund those training programs. And it's very expensive to be trained. You might as well become a doctor rather than a genetic counselor. You can make more money. We all work for very little money. The other part is we need to train genetics people to work in public health departments. One-third of state genetic coordinators have training in genetics. Two-thirds of states have state genetic coordinators that report they have no formal training in genetics. How can that be? They are running the state's program. Also primary care providers don't want another education in genetics. They are too business everytaking care -- busy taking care of patients they want the resource people to be able to contact and if we don't pay to train resource people, we are not going to have the primary care providers that want to provide genetic services to their patients. So I just want to make sure that the money is there for training and for the ELSI issues.

Julio and then Joseph.

Just to echo what you just said and to expand further, I think the human Genome, the 5% is perfectly legitimate. It wouldn't necessarily have to be done and it was and I think it really enriched the whole project but we are talking here of a very different ball game. For healthcare, you are going to offer -- the scam tam Sharon gave earlier -- example that Sharon gave earlier depression in minority population. It's possible to treat the people during the study and buy vacuum cleaners for those with asthma. You are talking about very limited integrations over a very limited time course and we are proposing a long-term follow-up in healthcare, it's extraordinarily expensive. It's not going to be 5 or 15 or 20, but maybe 200% of the budget because if you think about it, for example, for General Motors, the biggest expenditure is not anything to do with the cars. It's the healthcare for the employees by far and recently they were able to change it to increase the deductible a little bit and they are going to save several billion dollars over time and their shares went up because of that. But it's an enormous expenditure. If you are going to have a large project with a substantial minority of people that are uninsured, to have, to provide healthcare for these people over time is going to be extremely costly. You could say one idea might be to say everybody in the project is not just dying to watch them get sick and sick. But if you are poor, you go to Medicaid, if you choose not to, you don't get it. So it's a very difficult issue, and I think that the ethics of following people up without offering adequate healthcare, and the cost of that has to really be dealt with very up front and very clearly with both ethicists and health experts, otherwise it will become problematic.

Joseph?

I mean appreciate Kevin's recommendation because it makes a lot of sense. And if you stop and think about this, and what's been said afterwards. And I would actually draw people's attention to the institute of medicine's recent report on the public health infrastructure. They actually outline it very well, you know this integration that everyone is talking about in that -- in that report it actually gives particularly some of the things that have been said earlier, gives a real very concrete, very well done outline of pulling this information together. So I just wanted to add that to that. The second thing is I also an appreciation of what is being done, and Dr. Collins' shop with a lot of different groups in terms of bringing constituent groups together to begin to tackle the issue of bridging between the big scientists and the social and behavioral scientists on a lot of issues. Particularly one of the ones that our group was participating in was sickle cell disease and looking at exLSI issues related to that and bridging with the work that was done and it was very well put together, very well done and also tackled over a three-day period a lot of these issues and came up with strong recommendations. So in terms of models in pulling it together, there are models that I think this group can really amend to the things that we are considering as part of our committee. I wanted to add that.

Julio?

One additional comment is that since this issue, I don't think it's going to go away, we could also think about an alternative strategies, for example, you are going to follow people over time, to, you know, see outcomes, you have to wait a long time to see some meaningful outcomes on the population level in the young people. In the older people, those outcomes will occur much faster. So, yes, you would lose a lot of those in early adulthood but if you did a study in everybody over 65, everybody would have Medicare and then you can -- you jump a huge barrier in terms of, you know, following them. And you have the outcome set. I mean you lose something but at least the issues are not there. So I think every possible alternative has to be thought about because maybe including only people who have some type of, you know, universal type of care or veteran's or, you know, people over 65 or something, might be a very, you know, plausible strategy.

Without in any way trying to speak against the idea that a public health concern should be important here, I think we have to remember heiz enberg's tensetivity system. When you perTesh a system, you will affect the outcome: If it's designed in such a way that the public health of the participants becomes something that is treated, it will disenfranchise people who are not treated in some ways.

Francis?

So I think the point about what the obligation is of research to provide medical Ben benefits is a critical one but it's not a new one for this project and there's a large body of ethical debate and literature about this, because I think you can argue quite strongly that it is unethical to carry out research that does not offer research opportunities to people who don't currently have health coverage, because in that process, you may be neglecting important public health problems, and not providing the kind of opportunity for participation, which sometimes can be beneficial. So it always comes down to this sort of difficult decision about what is an appropriate kind of benefit that you offer to those who participate in research, that is not coercive, but is also by never lent and generous -- by never lent and generous. Again the debate we had about this over a year or so, it was clear that you would intend for all parentants to give back immediate information about data that's collected as part of the examination, both the physical exam and the laboratory exam, and that some limited additional medical benefits ought to be considered but would lead to very careful debate about just how far you can go. Again, both for cost reasons, and for coercion reasons I'm not sure that most of the people who looked at this issue would agree that you can offer full medical coverage to the currently uninsured in a project of this sort. But, again, we should look carefully at all of those discussions that have gone on in terms of studying diseases in the uninsured, and there's lots of studies that have had to deal with that, and, of course, this quickly gets into international research as well in terms of what are your obligations to give medical benefits to people in developing countries where nobody has much of what we would consider to be reasonable medical benefits and yet we are asking them to participate in research.

Deborah?

Well, part of this coercion aspect is we're controlling it. I noticed that in the report you say that institutionalized persons, long-term mental health or custodial care individuals would not be included in the study. I understand why that's done but it also concerns me that one of the issues of mental illness that is not really appreciated broadly as an illness as opposed to something that you could control are being excluded from the possibility of furthering the genetic understanding of mental illness by this exclusion and I don't know if there's some way to get around that from an ethical perspeckive but it is a bit -- perspective but it is a bit concerning.

Yeah, I agree and that was not an easy kind of discussion. Again, I think the concept issues dominated that part of the discussion, how could you really get adequate concept in that circumstance and people were uncomfortable with the sense that that would be meaningful and that's the main reason --

But it couldn't be for a family member or a guardian, or someone who --

Potentially.

Could provide that and basically, you're not allowing that family to benefit from the potential of giving their consent.

Mm-hmm.

That, you know, this person could reasonably be -- have at least samples taken or something.

I think that's entirely open for further discussion.

I we're -- we're drawing for a close here for this session. I want to take my prerogative to ask the last question and address it to Francis. Francis in your role as director of NHTRI, it's easy for us to forget that the reason that you are sitting around this table is that you are actually representing NIH, and not NHDRI, so I want to ask you during the past year or so, as thoughts of this large population study have been developing, so what extent you have had interest or positive feedback on the part of your director colleagues and whether this is truly something which is at least at the current stage receiving broad pan NIH support.

Well, it's very appropriate question. This project has been presented to all of the institute directors on a couple of occasions and there have been numerous conversations with specific institutes particularly those that have very large investments in this kind of research like the cancer institute, the heart, lung and blood institute and so on. Just to summarize what has been a very diverse set of discussions and opinions, I think it would be fair to say and I think my institute colleagues would be comfortable with this type of summary that there's enthusiasm for what type of a study this could tell us about the relationship in genes and disease. And a lot of recognition that a study this sort would contribute the kind of data that would shine a light into many different corners of our current ignorance, and a deep concern about the costs, and whether, in fact this is something that could be mounted currently in the current budget climate, without additional funds we talked about Early there err. I don't think there -- earlier. I don't think there's any institute director around that would say this is something we can mount right now. But I have not cited any major scientific disagreement that this would be an increasingly valuable resource as we discover about how genes and environment apply to public Hale and it would have many spinoff in terms of like nested case control studies that would come out of this that would provide the grist for a lot of other research that would go on and P.S.T. NIH institutes, if this particular study was going on would look at their portfolio and see that there are things that they are paying for that could be done more efficiently through a coordinated national study of this sort.

Thank you for. That and with that, this, the morning's part of this session will come to a close and I want to thank Dr. Kardia and Dr. Marchase and Dr. Fink, although he's long gone for his comments. I think this is -- we've touched on a lot of important points that the committee will have to -- to consider over the remaining course of this day, and then beyond, and I thank you for your participation. We'll now move on to a public comments period for this meeting. One of our critical functions is to serve as a public forum for deliberations on a broad range of human health and societal issues rayed by the development and the use of genetic technologies so we greatly value the input that we receive from the public at large. We set atime each day of -- set aside time each day of our meeting to share the views in interest of our full schedule I would ask the two scheduled commenters to keep their remarks to five minutes if possible. So today we'll first hear from Kathleen rand Reed, representing the Rand Reed group. So welcome. Maybe we can find a chair at that end. That would be great.

Can you push your --

Applied biocultural and ethno marker and I wanted to bring as I say today's presentations round table discussions and programs segments cover broad topics -- oh, okay. As large population studies and the subfocus on the scientific community, public engagements and bioethics. And tomorrow we'll cover genetic discrimination and farm could genomics. I won't be here so I have tried to bring to this far um, policies, perspective, information and mechanisms that related to efficacy of all aspects of this meeting. And they are specifically one, the need for inclusion of and outreach marketing to the 18 to 34-year-old hip hop, rap and urban or Hispanic urban generation for clinical research and genetic educational information. Two, the need to create a firewall between health and disease-oranted and genetic clinical research and the use of DNA analysis within the law enforcement realm. Specifically, CODIS, the FBI combined INDeX System, and three, the need for outreach to the premigration communities, families and kin relatives incorporating transnationality within the genetic educational models. I bring these up and I just wanted to be very quick about this because I'm very much involved in that community and especially I serve on an IRBB. When people are doing outreach to many of the minority communities they tend to go to faith-based organizations and churches, et cetera, but given that the rap and the hip hop culture are -- emerged out of the 1970s, we are talking about a popular culture, and a cohort that's actually, in many cases grown up over these last 30, 35 years. And yet, when you look at clinical research, and you look at the marketing and you look especially when you are talking about the new group in terms of starting families, et cetera, and genetic education, they are almost missing in action. The hip hop culture and its signature -- and by the way there's a lot of fear on the part of people to do outreach in this, because historically this has been stigmatized and linked with crime, violence and crude thug life, but today the culture has segmented to the point now where you even have Evangelical aspects called Christian hip hop. So the -- it's a popular culture, international segment of a cohort population that quite frankly, given the other things that are going on, are just not being served. The Latino aged 14 to 24 group that compromise more than 20% of the Hispanic markets and their new identity, they are now considered pan Latin in their identity, and they often speak with institution of Spanish and English, and many have never visited their parents' countries of origin and yet, they are an intricate part of the community. We don't have to talk about the growth of the Hispanic, Latino population that was 35.6 million in 2005, that is now $41.000000. And that's the -- 41 million and that's Rell side of the house so I would recommend we go to this cultural lifestyle and the reality checks on the effects of these discussions in this segment. The seconder part real quick, facts on the ground. Let me give you six points. Number one, in 2003, North Carolina technicians compared DNA left from a crime scene with genetic profiles in the state's database of convicted felons. The crime scene DNA did not match any of the 40,000 felons on file, but since it was remarkably similar to an inmate, the technicians concluded that the unknown man was from the same parents as the inmate. Florida's DNA database operators have been permitted give investigators the names of convicted offenders who match a crime scene sample at 21 of 26 alittles. It's been -- allyls. It's mentioned that 21 allyls in common are always brothers. African-American males are 12 times more likely to be arrested than not convicted than whites. And yet, a growing number of jurisdictions are collecting genetic information from arrestees, not convicted. And the materials are not destroyed upon establishing the innocence of the arrested person. Many African-American and Latinos are hypersegregated to the point of 99% and a growing number of children born in these hypersegregated communicates share known and unknown male parentages and in some cases are half siblings. The reason it is involved in looking at the establishment of DNA database for the reunification for children's families and children. One of the barriers I'm running into is that because there's no firewall between the CODIS and the law enforcement side of the house and the communities that -- where this word has spread and there's great fear, many people have not come forward to even discuss it because many people in many of these hypersegregated communities are terrified of the genetics side of this house. So this is -- this is an issue that has real effects in the reunification of many of these families of -- that have been separated even tragically with Katrina. So we need to investigate the use and the amuse of the familial searches and we are dealing with that in terms of anone mizing samples, et cetera and this being an ethical issue and a development of a policy position between the Hale and the disease oriented genetic and clickingal research and the use of dna analysis within the law enforcement realm and lastly develop policy that establishes the destruction of physical samples used in DNA testing. The very last, which will take less than 30 seconds, is the need to incorporate transnationality within the genetic educational models; in other words pluralist bioethics. Many discussions about outreach for genetic education to minorities, especially, genetic samplings and family histories still center on native African-Americans and to some extent the Hispanic population. However, one of the biases incorporated within those discussions and policies is the lack of understanding of the dynamics of transnationalism. Transnationalism being the ease with which immigrants live in the United States, but support relatives, run businesses, and participate in a two-way exchange of gifts, commodities and cultural practices in both the United States and the country of origin. In the development of policies and mechanisms for genetics, health in the U.S. society, certain aspects of transnationality must be taken into account. One which is critical is the outreach to not only the U.S. communities, but the prepie migration communities -- premigration communities, families and other persons who act as family, or effective kin to the residents in the United States and to provide the U.S. residents with information, developed for their premigration communities and family members in and it increases not only the efficacy and the effectiveness of the outreach but augments from a cultural Spehr speckive the underlying tenance of consent. There are people who will call grandma or call the Padres and asked them should they. And if they say no. Then they will come back to the researcher and say, thank you very much, and be very loving and very nice, but they will say no. So if this premigration information can be provided to the families and in the case of many Latino families, the God godparents, you may see the effective Cassie is and the effect -- efficacy and the effectiveness of the sampling go up. Are there any questions?

Thank you very much. Next is Joann bawfman, American society of human genetics.

Good morning. On behalf of the American society of human genetics and as its executive vice president, we thought it appropriate that we make some comments on the proposed large cohort study. I would like to thank Dick Marchase as representative of FASEB, an organization in which we are members that I think he's addressed some of the broad issues extremely well but we would like to make just a few comments. The cheese for large scale population studies to understand genetic and environmental factors that are involved in the relationship to disease is certainly evident to those of us in the feels of human genetics, medical genetics and genomics. The design implementation and analysis of such comprehensive studies are obviously as we heard many times over, of enormous complexity. As with any group of scientists, the human genetics community does not speak with a unified voice on the promise of such studies or the priority assigned to them. The leadership of ASHD, has discussed the cohort study. While there's wide spread and general support for the conSeptember, as expected there's some diverse views the Indevus sill always in the details in the manner it would be implemented and the nature of the data collected and to the extent of which the data will translate into the promise of treatment or prevention. ASHG, applauds you for convening working groups and gathering remarks from those inside the NIH and we also commend SACGHS for sinning this dialogue, the gaining of the interest and the communication among the scientists will be enhanced by every one of these dialogues that we have. The design of the study including ascertainment of systemic data, structured collection of variables and quality controlled data analysis should be of enormous benefit. Nevertheless, it's clear that the design of this study is an immense challenge because the specific aims will not necessarily evolve with time. In contrast to the human Genome project as we have heard which had a specific and designed endpoint in the case of this cohort study, the good news and the bad news, if you will, is that the goals must be broad, and many specifics cannot yet be defined and the data gathered would need to be broad enough so that jet undefined or currently unrecognized questions could eventually be asked and answered. The strong interest and general support for the large population cohort study derived from the widely held conviction in our community that such a rich data set should have important clinical implications that we hope can be translated into general benefit. And the hope is underlined there as we have -- as you all have discussed earlier this morning. That's one of the challenges is the translation of the results of such a study into action in inclinical practice. We see the challenges proposed to the study coming in at least four forms and in some respects this becomes a summary of this morning's comments. Would or do existing data sets have sufficient breadth and depth to provide some of the information as proposed in this study? And if not, are there ways that the existing data can be further mined to limit the costs of the cohort study? And in the written remarks I have listed a few but a few others have been named this morning including the Framingham study the, the children's study and Haynes and the veterans study. There are ways we could further mine some of those data sets to ask new or better questions? And this -- the second point is a major one. Given the current tractous state of healthcare in the U.S., can a truly coherent cohort study be designed, data collected and analyzed and benefit returned to the participants and others in the U.S. at a reasonable cost? For example, it is proposed that information would be collected from medical records a daunting challenge, as we might expect. Or would the healthcare system itself have to be revolutionized to benefit from such a study? Many in the genetics communicate wonder if such a systemic study can be carried out in a way that can be fully utilized in the United States. In our patch work system, absent systemic electronic medical records and any realistic vision of a uniform or universal delivery of healthcare, the direct applicability of the results to the broader community, must be appropriately questioned. In other health care systems around the world, the implications of study results could be more quickly, efficiently and effectively utilized integrating the results of a well-designed stud Nye the point of practice -- study into the point of practice much more directly. That doesn't mean it shouldn't be done. It just might be done quicker and more effectively elsewhere. In contrast to the human Genome project which required a development and I'm amazed that these are the terms that my colleagues used which required development of relatively inexpensive computation tools to assemble, compare and analyze digital data, the cohort demands the identification of a population that has sufficient breadth and depth to allow analysis of've myriad of relevant questions the identification of numerous biologicable variables to be measured and their tabulation and the creation of robust computational tools to define, measure and assess the environmental changes over time. Compared to the human Genome project, these perceived requirements are far more complex. Fourthly as spoken about by Dr. Particular chase, the -- Marchase, the cost of the project will have to come from funds outside the usual funding mechanisms aas they are likely to be so large that the effect on usual biomedical research funding could be highly deleterious or devastating. It's anticipated that this study could not and would not directly deterror -- deter the medical research funding. Finally as recognized by others the choice of individuals in populations to be included and their relative representation is far more complex in our highly heteroRowe genius group in the United States and the need for diversity and the manner in which that diversity needs to be handled need to be carefully considered prior to the identification of those to be actually included in the study. The many issues related to the recruitment, ascertainment and consent and privacy will be addressed by others but remain in the forefront and concerns of the human genetics research community. Our researchers and clinicians have been consistently in the lead on addressing and discussing openly ethical and legal and social implications of our own research and we maintain that this endeavor along with the educational issues are of the utmost importance. We generally support this concept and recognizes the importance that results in the proposed study would provide to all of us. We encourage individual members of our organization to remain active in the process, of the design and the development of this proposal and today we would like to, again, commend the SACGHS on the development of timely and important questions to consider in the analysis of this proposal and bringing them to the public and support your effort to analyze this proposal in detail. Thank you.

Thank you Dr. Boughman. Thank you both for your comments and input. We appreciate it. We'll certainly take all of those comments into account as we proceed. At this time I would like to return to the chair's introductory remarks, those that we glossed over when we first began in the interest of everyone else's schedule, and talk a little bit about the work that the ex officio agencies are up to in order to enhance SACGHS's currency and ability to stay abreast of develop 789s. In -- developments. In August, you might remember that Dr. Tuckson asked the ex officios to provide us on updates on the relevant activities in their departments and these updates can be found at tab three of the briefing books. And our thanks go out to the ex officios for reporting to us about those developments, the information will be very, very useful and relevant to our work. I know in requesting these updates reed was hopeful that they would be a resource to each of you by increasing your awareness of relevant activities across the agencies and perhaps revealing opportunities for more interagency collaboration. Now I would like to take a few moments to highlight some several of the agency initiatives. You may recall that in our meeting in of course of last year, we learned about the surgeon general's family health initiative. The family Hale initiative is a -- health initiative is a transdepartmental program, aimed the increasing public awareness of the importance of family history and health, and providing the public with tools to be able to gather, understand, evaluate, and use family history to improve the individual health. The family health initiative is gearing up for its second big national event this coming Thanksgiving day. We wish the surgeon general and all the agencies involved in supporting this important health promotion message, great success again this year and we look in order to hearing how it all goes. A few weeks ago, arc sponsored an important meeting on gene-based discoveries. The agency's goal was to identify knowledge, gaps and barriers to the Chenical use of gene-based discoveries and overcoming the barriers. Dr. Chesley, could you tell us a little bit more about the meeting and outcomes?

Sure. I would be happy to. On behalf of Dr. Clancy, want do convened this conversation, whose objectives you mentioned. One important thing it was titled genomics and medicine one. It was titled that way to reflect the reality that we saw as the first sort of dialogue and ongoing conversation, both with our partners within the department, as well as key experts outside of the department, the conference included representatives from across the department, FDA, CMS, NIH, HERSED, as well as others. The first day focused on genetics and the second day was farm could genetics --pharcogenetics. We'll have a detailed summary by mid-November and that we can make available to this group. One of the things that I think was key during the discussion and during the meeting is pointing out some gaps between what we know and how we can use that information. One of the things that we were looking for at ARC, as well as with our collaborators across the department is how to sort of build on some synergies that may exist in ARC programs such as our HIT program went we talk about the need for an electrical medical record in the context of the study we were talking about this morning and so whether or not there is a role to develop such or facilitate such an electronic medical record is something that we chatted about in the conference and but also the intersection between -- or I should say with some of the evidence based conversations with the EIC program and others. One of the things that I think was a key point made during the discussion and by participants was their interest in having methods workshops and conferences to discuss issues involving in linking the information and data sets both from genetic, the lab tests and clinical databases in order to do research in this area.

Thank you very much. aparishiate it. -- appreciate it. At our February meeting we heard from Dr. Steve grove, the NIH offer of rare diseases and Dr. Joe Boone about a national conference for access on quality testing for rare diseases. The conference was held last month. Dr. Groff perhaps if you could come forward and give us a brief report on the outcomes of the meeting. Thank you.

Good morning and thank you for the opportunity to come back and report to you on what I felt was a very enlightening meeting and quite a bit of participation. We had over 150 registrants for the meeting representing clinical geneticists, patients themselves, the clinical laboratories, federal government employees and program officials and the professional organizations, so I think we -- we tried to focus on a number of different areas including infrastructure, the current models for test transration from the research -- translation from the research laboratory to the clinic applications. We also looked at quality assurance and quality control measures, and including the international aspect of test flow and sample flow. And the major focus was on the need for educational efforts to assure and promote quality in patient testing and in the test gran ration process -- translation process. So it was a busy couple of days and evenings, as we started and some of the outcomes you have received, I think, a copy of the set program, the collaboration, education, test translation program, I think that was provided to you. You got that? Okay. And that's something that is under development and we to have it implemented and open for business by January of 2006. Dr. Giovanna spinella and several other doctors from the human Genome were involved in developing this. And we are'll be going through -- and we'll be going through processes that are identified there in the -- in the description of the project, and we hope to start to stimulate the development of genetic tests for the rare disease. I think four or five years ago the feeling was that nothing really could be done. There wasn't much interest in the rare genetic disorders and I think by the last two meetings that we've had, the first one in Atlanta and then here in Washington, there's considerable interest. It's just a matter of bringing the people together, focusing on the issues and the concerns and the needs and then having individuals who are committed to finding answers, to work together to get things moving and I think we have been able to do that. And as all good groups, you always want room for another meeting. So we are planning another meeting in 2006, and I don't think we can get away from that. But there's going to be presentations at the American society of human genetics and the American college of American genetics so we are distributing the results and looking for more input from different people as we go along. Another recommendation related to education we thought that awareness campaign about genetic testing and genetic counselling services was necessary here in the country. There just seems to be a tremendous absence of adequate information to the public, to clinicians, to the researchers about the requirements and the needs related to genetic testing. So I think we'll be focusing on that; however, we can, with whatever partners we can gain as we move forward. And there's considerable effort already devoted to the development of international quality assurance and quality control guidelines and I think that will continue. The OECD group from Europe and others Joe Boone is intricately involved in this and we'll continue working that area and just -- just facilitate the development of the genetic tests across borders and see if there's -- the currently the focus has been on molecular DNA-based tests and we will -- we are hoping to expand or consider the development of new Sean expanding networks to focus on biochemical and genetic procedures, I think there were two groups that sort of felt that they were maybe on the periphery, but after the last meeting, the feeling of inclusion, I think is there and we hope that they either will form new networks or we'll just incorporate them into the existing network. And we based manufacture our proposed activities for the said program on activities that -- many of our proposed activities for the said program on activities from the human Genome institute, and we used that as a model or a pilot to see if we could utilize commercial laboratories academic laboratories to develop genetic testing. During the past two years we have developed 21 or 22 different genetic tests and we are using this as a model. So we would like to extend this a little further so if we can expand this out into the community further and a couple years from now see what the possibilities are for maybe a little bit larger initiative throughout the entire in. IH structure. -- NIH structure. There's some more qualified people in the audience that can answer questions but if you have any questions we'll try to answer them.

Thank you so much, Dr. Groff. Appreciate it. Next I will attempt to report on the activity of several SACGHS members and staff, folks who have been up to some very interesting things and we'll start with Dr.telfar is a SACGHS to the HHS advisory committee on heritable disorders and genetic diseases in newborns, what the acronym? How do you pronounce this?

I'm only a liaison so -- [ LAUGHTER ]

Well, the committee held their fifth meeting in July so we'd like to hear.

Well, in the packet is a summary of a condensed version a much larger report, and so I won't -- I will highlight a few things, just the bolded parts of this aspect and so there's much more discussion in there. This is a committee that it has -- it has -- the last meeting I went to was their fifth meeting and actually this week is their sixth meeting this. Very been very active and their -- they have been very active and so their primary sow fuss is on newborns and childhood. And the committee Caribana its deliberation a long-term follow-up to many discussions with the public comment review from the American college of medical genetics report on newborn screenings and reported the Arthur born screenings were -- newborn screenings were uniform panel. And the notes from that and what proceeded on that is in the handout, but just three sort of things that I just want to highlight with that was the focus on improved assets and the other ones is to ensure services are of high quality, particularly those that have a high level of scientific merit and the other aspect was to look at shires related to cautiously competent care, that includes like health literacy and giving consideration to a parent who had to make treatment decisions. And the canmittee itself reviewed a very large number of public comments that came in, over a -- it was presented and the puck lick had been given about a two-month time period to review the document which they could access through web sites and then other means. I forgot in my report to sort of research the actual number, but Dr. Mike Watson is here and he could -- I'm sure he could tell you how much comments they got. So I would leave it up to. That the committee itself, actually had other business that it dealt with. It is because of its relationship with HERZA and with the -- within HERZA, Dr. Peter Van Dyke, who is the associate HERZA administrator over that unit has a high degree of responsibility and interaction with that group and Dr. Michele courier who is the director of the genetic services branch within the DHHS, HERZA -- [ Big sigh ] Is in charge of that. So it's not fit. I have to get used to the acronyms. But, anyway, within that group, a major focus was on the issue of screening and Dr. Van Dyke's primary comments as -- as his role was to discuss with the committee a means by which the -- a letter will be drown that will go to secretary Levitt but at the same time, how he will be involved in communicating the information from that, and also looking at the recommendations from that particular study. And I would encourage everyone to really review that report if they have not already done so, to look at that report. And Dr. Betsy Rowe meets with this group. She's with the genetic resource center and their main responsibility is to track the activities that the state health directors with newborn screening there and in the report I refer everyone to the two handouts that he gave, which basically updates the status of the the newborn screening at the different -- at the state and then how many -- well, the number of conditions as well as the number of states now would do universal newborn screening on key -- in key areas. And also he provides in great detail a -- a detailed map as to look at that as well. There was an issue that came up in prior meetings related to the role of evidence, and other factors that influenced evidence, in relationship to public policy decision making, and several times they were asked to come and give presentations on those and those are listed in the report as well. And then the -- there are several committees that are -- that's within the -- the committee -- the subcommittees that exist within the committee itself, and each one of those committees there, and the committees are education and training subcommittee, that was led by Dr. Jen they are Howell, who is machine Jennifer Howell, who someone else will take over that role, because her time on the committee has ended and a subcommittee for laboratory standards and procedures. And then the -- there's a public comment period always and I listed a large number of the persons who allowed to do public comment but it was also a relationship with the -- the American college of obstetrics and gynecologists who were able to give a little bit of time to discuss their ACMG report. I tried to be brief.

Thank you very much. Dr. Lyons is up next. She was recently appointed to serve as our Leason to the C.DC working group and she can provide us with the group's progress.

Well, please feel free to jump in here because I feel like I'm usurping what has been done by you and Linda Bradley. They are now a ear -- year old. Al Berg is chair of that working group. And the working group has had three meetings to date, in addition there are subcommittees of the EGAP working group working on various subprojects of EGAP. So overall, just to bring everybody up to speed who may not know what EGAP is, it's evaluation of -- already genetics and principal and practice, is that right? What is it?

Evaluation of genomic applications and practice and prevention. Double P.

Okay.

But you must have somebody who stayed up like all night designing logos for you because I was very impressed by the logo with the big E and then GAP and then a big P with a DNA going between evidence and practice. I mean who came up with that?

We love to do this in the government. [ LAUGHTER ]

Francis, maybe you need a percentage of your budget for logos. [ LAUGHTER ]

It always results in a war between the staff. So you also have to put in some money for employee counselling.

Sorry. Sorry, I shouldn't have gotten side tracked there. But it was quite impressive. So the working group spent time developing methodologies because they are approaching application of genetic applications in a different way than some of the more stringent groups and it's really delightful to see them considering some of the more social and knowledge-based aspects rather than strictly defining utility or benefit-based on medical treatment availability. So they have developed an entire process, a process for selecting the genetic applications that they want to evaluate. So there was a whole group of how you choose these priorize them. And then there's a request for task order, RFTO, it's like an RFP that goes out to evidence-based review centers, requesting them to do an evidence-based review on the particular topic that's been selected by the working group. And then there's a whole description of what is needed and the evidence-based review center will provide that evidence-based review back to the committee in a specified a.m. of time. That working -- amount of time. That working group will then take that evidence-based review, which will have its own conclusions about you the working group will then make recommendations based on that evidence-based review. And the -- and the recommendations they are now developing how they are going to make these recommendations and they realize that the recommendations have implications for physicians, as well as for individuals and how they Taylor the different needs of those -- tailor the different needs of those groups and so they are being very, very thoughtful about the needs for this entire process. So they are looking at the benefits in terms of the medical benefit, diagnosis, prognosis, treatment options, patient benefits both medical and personal, family benefits, societal benefits and public health benefits. So they are being very broad in the range of benefits that they are looking at. So there are two evidence-based reviews that are far enough along that I think I can mention the specific topics. The first has gone out for request for task order and I believe at this point, the specific evidence-based review center has been selected and that one is looking at site toe chromosome P 4 for those being treated on SSRIs or on treatment for SSRIs and the second topic -- and that one will have a nine month review process for the evidence-based review to be completed and that will then come back to the committee, to the working group. And the second topic is HOBCC testing algorithm from springing up Bibi fez dah criterion -- by Bethesda decree tearion screening testing and chemistry to full gene screening for those who are positive this entire algorithm. Since this testing is more complex and this is for patients with newly diagnosed colon cancer. So since this is a more complex testing algorithm, there's a 13-month time frame being given for this and this is about to go out for a request for task order response from the evidence-based centers. And finally the working group is considering if they can do fast track options. So these are -- these two that I mentioned are full blown evidence-based reviews, but they are considering the possibility of fast track topics when they want a narrower evidence-based review, or if there's a much more limited amount of literature and they are having discussions about how to do these. But those would be more on a time frame of three or four months. So it's very exciting to be a liaison to this group. I think they are doing some really good things and definitely thinking outside of the usual evidence-based review box.

Thank you, Deborah.

And meeting was Monday and Tuesday. You will get my report later.

Okay, it's in the mail.

I also want to take note of an interesting policy research project being carried out in the UK on the Al valuation of clinical genetic testing for complex conditions. The welcome trust is funding a project and scholars from Cambridge and extra universities are leading the projects and last month the project team carried out focus groups with a number of U.S. experts to gather perspective about how et inic tests can be did -- genetic tests can be evaluated. And how regulatory and healthcare systems can assure the availability of valid information for genetic test results. Emily windinE participated in the consultation and a number of ex officio agencies. Emily, could you give us a brief summary of how the focus groups went?

Yeah, so I'm not really in a position to summarize the focus groups because these were designed as a series of focus groups where each individual subgroup didn't Rell hay have access -- really have access to what happened with the others. I think Stewart would be a much better person to give us summaries since he has sort of ran all the focus groups. I can say in the focus group that I participated in, we raised a number of questions without coming to any clear answers. And part of what the group running this focus group was trying to do was to pull together the the sort of common threads and what things are common threads across both the U.S. and the UK and, you know, other countries, what things are unique to a country like the U.S., that has diversified healthcare as opposed to nationalized healthcare. I would rather let Stewart give a little overview if you don't mind. Stewart do you want to defer? [ Inaudible ]

Can you come up to the microphone and just give a little overview of what the point of it was and where you are in the process?

Yeah, first of all, thank you very much for Sarah and Amanda to invite me to the meeting. Hi Nott come prepared to talk about the research, but -- I had not come prepared to talk about the research, but it's a three-year project and we're talking to all the stakeholders who have an interest in the evaluation of clinical genetic testing. So that the government agencies, health technology assessment, regulators, clinicians, patient groups and also industry, and we have run two focus groups at CDC last month and we had some really stimulate stimulating dis-- stimulating discussions with diverse sets of perspectives from the stake shoulders and we are about to run out to UK Europe focus groups which will be very interesting because we will really start to see the differences in how the kind of healthcare system structures and the different regulatory environments -- I mean, there will be issues addressed very different in Europe and the U.S. I have just come back from Canada, where I have been speaking to people there to try to get a take on that country's approach to these problems as well. What I would say at this stage is that coming out of the two U.S. focus groups this was a very strong discussion about infrastructure issues around the need for translational research and the lack of support for getting basic research findings through into clinical practice and how there might be some kind of a need for a change to the whole infrastructure, where all the different points of control, the different gatekeepers involved whether that's people in the reimbursement side, which that's people in the regulatory side, whether, indeed, that's the professional of a very important role to play in terms of clinical guidelines and can somehow actually be coordinated. And that idea was actually coordinating activities with different groups, and is, I think, a crucial one. And aside from that, I think I have probably better stopped rambling on, actually. Thanks.

Thank you now doing a much better job summarizing than I could have from just one slice of the pie. I think that the one thing I just want to point out is what -- what Stewart made as one of his last points there, about the need for coordination, is something that our committee has also identified and so I think that's one thing that we should continue to have as an underlying theme for all of our deliberations on whatever topic that we just need to continue to push for coordination at least among the HHS agencies for whom we can advise formally.

And just to clarify, Emily, you participated as an Visudyne in your individual capacity.

I participated as a member of the diagnostics IED assay community and so, you know, it wasn't as a -- an officialio or ex officio or representative or whatever with SACGHS.

One more item before the magic hour begins. In September, at the western states regional genetics SUMMIT, Susan goodwin gave a report and the assume IT -- SUMMIT was organized by Sylvia au and wanted to make sure that we recognized that work and that SUMMIT. There are other activities that we're going to talk about and rather than going through all of them now, this relates to Reed's custom of putting up our priorities chart and seeing where we are and where we've been. We'll defer that until after lunch. So there's more work to talk about. For committee members and ex officios, the lunches you ordered will be brought here. For members of the public, lunch is available in the hotel restaurant, as well as a number of nearby restaurants and we will reconvene, shall we say 1:05? 1:05 to give everyone a full hour. [ Lunch break ] Please stand by. Please reset audio.

Let's get started. We will dispense with the chart, but I will highlight just a few key points and that is some folks have mentioned the coverage and reimbursement report that we worked on at the last meeting. That is being finalized. Staff had some additional editing recommendations we anticipate having finalized activity on that and get the report out in short order. For members of the committee there were some editorial recommendations. We'll get copies of those and redlined tonight, ask that everybody take a look at those. Tomorrow we'll go either yes or no. We'll move the coverage and reimbursement report forward. Another item I wanted to call to everyone's attention is the fact that the committee deferred consideration of the issue of gene pat tenting until the report is issued. That report is due out next mon, November 9th. Given its imminent release it might make sense to task a small group to review the report and provide us with some input about its recommendations and findings and whether there are issues this committee should take a lock at. I think, Debra, am I correct that you will graciously agree head up a working group for that purpose? So anyone interested in volunteering to work with Dr. Leonard on the little small work group and analyzing that report, see Debra and that will move forward. Another cleanup item I wanted to draw to your attention, a survey that's in the table folders. Hhs would like feedback from members and ex-officios. So we'd ask that you complete that survey and hand it to Abby Smith at the registration desk before we adjourn. Finally I will turn over overing to Sara Carr, who will give us kind of an update on what we should already know and be acting upon with regard to ethics rules

In the interest of time I'm not going to go through my usual reminders because I know you are very atentive to the con flikt rules. We will also hear about legislation tomorrow you'll want to remember that you can't lobby while you're here. I also want to mention in June I also sort of lectured you about the clause. There has been a development since June, the Justice Department has issued a ruling that the amol you must clause does not apply to certain government employees. It's not across the board. It depends on the nature of the committee but an analysis has been done of our committee and the members of our committee are not subject to the amal you must clause unless you are on another committee. If you're on another federal advisory committee, then you have to be -- don't assume you're not covered by that committee. We'll be getting you more information about this as the implementation of this significant change is carried out, but I did want to mention it because I had brought it up in June and I know a number of you from time to time think about doing work overseas. The last thing I'll say there's still a form you will probably have to fill out about this so you're not totally off the hook, but anyway. Thank you.

Welcome back. We'll continue with our session on large population studies and specifically now we'll hear from four expert in the area of public engagement who will together make up a panel, who are waiting patiently at the head of the table. I think from an organizational standpoint we will not have questions following each presentation, so committee members, if you can take notes and save them up, and then we'll have a panel discussion when Paul four speaker -- when all four speakers have completed their presentation. Joan Scott is a certified genetic counselor and in genetic policy and now the deputy director at genetics and public policy center at Johns Hopkins university. Joan, thank you for joining us

Thank you for the invitation. I elected to come up here so that I can drive. I appreciate the opportunity of coming to talk with you today about public engagement to engage on this subject. I have divided my time up into three areas. First of all, I'd like to spend a couple of minutes talking about some general principles about public engagement because we hear that term used a lot and it can mean a lot of different things to a lot of different people on many different levels in which you can engage the public. To help inform hour discussion later on it would be useful to take a few minutes to just talk about what the universe of public engagement is. Then he'll talk about hour experience with the town halls and how information we learn might inform a public engagement activity around large population studies and specifically the committee had some questions they wanted to address and I'll close with those. So, first of all, just from a very basic perspective, what do we mean about public engagement because you can, as I say, engage the public in a lot of different levels. At the very simplest end you can simply want to inform or educate the public. We heard that that's a necessary thing to do. Someone argued as to whether or not that's not public engagement because you're not requiring much work on the part of your participants. But nonetheless in your overall strategy that is one method where at times it will be an important component. It does, however, imply that you've got a one-way communication going on whereas a more conservative approach to public engagement assumes that the public brings some very valuable experiences and perspectives and values that will help inform your overall policy issue or whatever it is you're consulting them about. That said, however, again, there's a lot of different levels in which you can engage the public. Doing surveys can help inform the public on a particular top being. Doing focus grouped. Moderated focus groups will give you a more nuanced understanding about the public's attitudes towards issues and the values that shape those opinions. You can ask the public to do a little more work in looking at the issues through workshop and scenarios. In deliberative democracy you're providing an opportunity for your participants to learn more about the subject, hear from the experts, heart different point of views and to deliberate about those issues. Then ultimately, you can ask them to do the ultimate work in coming to an agreement on what the best policy action is. So there are lots of levels in which to engage the public. The one thing that's common about these particular approaches that I discussed is that the issues identification and agenda setting tends to rest within the hands of the organizers whereas a more colab ative approach to public engagement invites the community, however you want to define that community that you're engaging, early on in the process in the issues identification, framing the issue, prioritizing the issue. Helping set the agenda. Helping device outreach strategies within that engage M the farthest end you can not only empower your participants to make the decision, you can agree to aby by the decision they arrive at. I suspect that will not be the method chosen here but you can do that

With that as a background, there's lots of different ways of engaging the public. When you hear that term, it can mean a lot of different things depending on what your ultimate goals are for the engagement, where you are in the maturation and how far the public has come in the evolution of their thinking on that particular issue and very importantly who you are engaging. In the case of a large population study, for example, are you aiming your engagement to the communities from which you want to recruit participants or are you looking at a more national or regional conversation about these issues at large, very different communities there and different approaches that you're going to want to use. So that serves as a background. Let me talk about what we did and why we did it the way we did it. Our experience with the genetics town hall which we held in six sit tips around the United States during the summer of 2004. Over the same time frame we held 15 discussion groups online. Now we had -- the topics that we were specifically engaging people about was reproductive genetics technology. We had already done a great deal of background work on what the public thinks, knows and feels, on several surveys, interest groups, et cetera. So we did not use the most colab ative approach where you go into the community to help identify the issues because we pretty much knew what the issues were. One of the criticisms of the approach in getting feedback from the public is that you're sometimes asking people to comment about technologies or issues about which they may have little personal experience or have had little time to reflect on in depth. So a deliberative approach to obtaining information back from the population set the stage where you provide your participants, as I said before with more in-depth background information about the topic at hand, what the issues are. They have an opportunity to hear experts, debate about the various perspectives and have an opportunity to deliberate with the experts and with their fellow participants about these issues. To have a credible deliberative process really requires four things be in place. First of all, the participation must be broad and representative. I'm speaking of that from two per specttives. First of all as your initial outreach into the community. Everybody should have the opportunity -- should be aware of the engagement and have the opportunity of participating. Within the engagement process itself all voices should be there in the room so that the people more participating have an opportunity to hear what the range of perspectives are to help inform their own opinion making. The information that's presented should be balanced and accurate and fair and then the environment needs to be such that there's a safe, an ample opportunity for everyone to hear and to be heard. The fourth point we think is equally as important, that policy makers, the decision makers are part of this process from the beginning. If you're going to ask people to take their very valuable time to think about these things and deliberate about them they should know there will be an impact from the time that they're spending. So this is what we did. In order to ensure that the content was the same and balanced and fair and all of the locations where we held the town hall, rather than fly our expert panel across the country as much as we would have loved to have done that, we packaged them. We carried them around in a little DVD. The first one was an animated overview of what reproductive genetic testing is. Then we edited together comments from experts conveying various perspectives on the three issues that were the topic of those town halls. We partnered with a group in D.C. called the public forum ?iew. the recruitment for the town hall was through local coordinators who knew their communities. They use add variety of outpreach strategies, including putting notices in high traffic areas such as libraries, hospitals, clinics, grocery stores, community centers as well as more targeted outreach to community organizations and leaders. We also did a media push in each of the locations that we were going by placing ads, talking with local reporters, talking on local talk shows, placing ads in the newspaper, et cetera. So we ask people to register ahead have time so we can monitor our recruitment. When people came to the town hall, this is what it looked like. They were able to sit at these round tables of about eight to 110 individuals. We started -- eight to 10 individuals. We started with knowledge and attitude around these issues. We asked 36 questions up front, eight of which were repeated at the and of the session to see if there was a shift in attitudes. The town halls were about three and a half hours long. They varied between presenting some of the content and the participants taking part in small and large group discussions. All of the participants were given these hand held electronic devices so we could collect the data and periodically throughout the sessions we asked groups to call out, if you will, things that were of concern to them. I don't have map pointer, but those would get entered into the computer and shown at the front of the room to help inform the large group discussion and people could vote and then rank order on those issues. The last half hour of the -- thank you. The last half hour was always an community panel of community leaders. The online group met for three one-hour sessions over the course of three weeks. This was through a web enabled panel which is representative of the general population. These are over 30,000 households. If the household did not have internet access, they were given internet access. Because we were doing this online for those people who agreed to participate in the discussion groups because we're doing this online, when could do more data collection, so they took an 80 item survey in front, up front and then selected the time spot. We have 15 different time slots they could choose from and mail them the instructions ahead of time. This is what it looked like on the screen to them without all of the little boxes there. But on the side with the list of the names of who was participating and we kept the groups together over the course of three weeks. So John and Sally and Mike all got to know each other pretty well. Participants could request the microphone and then speak in turn. The majority of the engagement was through audio but on the side was a box to do text messaging. Usually we had two conversations going on at the same time. For those who have a hard time walking and chewing gum at the cammed time you -- at the same time you had the audio going on anded text messaging. Then some of the questions were receipted again. Another one of the advantages of doing some of this online is you could run a control group. We had 400 individuals matched the participants that took the pretest and post test but did not participate in the discussions in between. So we collected a lot of data. One is who participated because it was slightly different in the two groups. We had 133 that we ended up counting. And they were fairly representative of those small number representatives. The in person participants differed in three areas, first they were more highly educated, they were more likely to have a college degree or higher than the participants in the on loon group. The religious distribution was different. They were less likely to say they were Protestant but more likely to say they had no religious background or self-identified as evangelical. The third major difference is that the in person participants were twice as likely to either have had a genetic test or someone in their family have a genetic test. The point is people who take three and a half hours out of their very busy schedules to come to an engagement are more likely to be stakeholders and more likely to come with a particular background or a perspective. The second point about what we documented is we did document shifts and opinions before and of a terms of the I'll show you one data point. We asked individuals whether or not they aproved of the use of prenatal diagnose for fatal childhood disease down to a more high threat Cal trait. You can see that the on loon group started off a little more approving but they both followed that general decreasing level of approval. With significant -- what's significance though at the and of the engagement process the control groups. Time one is solid. Time two is hatched. The online group did not or the control group did not shift in their opinions over that month to six weeks the way they thought beginning with the way they thought in the end. The participants in the discussion group, however, with the exception of the testing for fatal childhood disease, there was a significant dropoff in all, approval for all of the other technologies. The moral of the story engaging the public does not necessarily make them approve of what you're doing. The last point I want to make as far as some data that we collected, the topic was reproductive genetic testing but the topics ranged from all areas of advances in genetics and people's optimisms and concerns. We kept hearing themes come up. One was the use of genetic testing and I believe Kathy Hudson has presented before this group previously some of our findings. We also heard concern about all segments of the population having access to benefits. So both of the methods did allow for nuance reflective conversations. There are some advantages and disadvantages of both. The online group allows you to collect more data. It's possible to track that over time. On the other hand, the inperson town halls had a wider ripple effect because we were involving community leaders. There was media involvement. There was a wider ripple effect of the in that particular community. So what does that -- again, you're going to be talking to different segments of the population at different points in time. There's going to have to be different methodologies that are appropriate over your entire engagement strategy. The methods we used are exportable and expandable. Our six town halls were held independently of each other. You could link up the town halls and have all six going at the same time and devote part to a national conversation and some to local issues. They have increased media involvement, would also have a wider benefit in reaching a wider audience and having this broader ripple effect. I do think that tracking over time is important so you can monitor what the effect is that you're having on a particular population and that's very doable using web resources or to use that as a tool to have support of information for the community and participants. We were asked specifically to adress whether or not in our experience of engaging the public we felt that the public would be receptive to a large population study. I have to say it's not a question that we asked, and that would be the reason for doing a public engagement activity is to find out that very issue. I will say again, in general, we found that people were very optimistic about advances in genetics and the potential health benefits where they become concerned is where the rubber hits the road so to speak and making sure that everyone has equal access. Some challenges are always, of course, ensuring broad representation. That's always difficult. So engaging the community in which you are trying to -- engaging the community early in the process and having them part offed decision making and agenda setting is very important. The oth major difference is we came into a community once. We were not having an ongoing receipted conversation with that community. That's a big difference between what we're doing and other efforts. The last thing I mentioned bears to the credibility issue. People look at who is sponsoring an engagement activity because they're expecting that there's going to be a point of view and perspective that they're going to try to be persuaded about something. I have to say one of the most gratifying comments a participant came up to me and said they will be balanced and fair. If you get there and if it's subtle there's a point of view. That all voices were heard. That was very gratifying to me because we have spent a great deal of effort, but it does require effort to have that sort of credible balance. So I think with that I will stop, thank our supporters who helped with this project and others and turn it over to the speaker. Thank you

Our next speakers will be a team presentation from Evonne Lewis and Toby Citrin. She previously worked with Mr. Citrin on the genetics policy at the university of Michigan where he is director of the center of community based public health at the university of Michigan school of public health. A lot of public health here. This, stwot of you will have a half an hour. You can divide that anyway you wish

Good afternoon and thank you. It is our pleasure to be here. We are a tag team with the work that we've done over a number of years now in Flint, gen they she county, partnership with the community, with the school of public health and hour communities. Our purpose this afternoon as you can see in our outline here is to talk about three engagement projects that we actually utilized, to talk about the issue of genetics and other chronic health issues. We want to share with you what we've learned from those projects and then we also want to make some suggestions on how we might be able to apply what we learned from this large population study. It is an interesting project and we hope that what we share with you this afternoon will stimulate some even more interesting conversations

Thank you. Thanks, also to the secretary's advisory committee for this presentation. We want to do a -- from which we think we can learn a lot of reel lep Vance for this large scale population study. In the first of these -- is there someone still pushing the button? The first of these projects is the one labeled community of color and genetics policy. Its goal was to engage communities of color in -- want to get back where we were. Exactly. It's goal was to engage communities of color, in this case African-American and a toon know communities at the grass roots level to engage in die loge -- dialogue about genetics issues and formulate recommendations for policies that would enhance benefits. The project followed a partnership model. Partnership between three universities, Michigan state, university of mish and Tuskegee. Each of which had con -- constituencies and served a population either in the African-American or a toon know Hispanic community. As your chair suggested, miss Lewis played the leadership role at the community organization in Flint, Michigan. A couple other people who are probably going to be in the room or presenting were involved in the project. Played the role of researcher and facilitator. Dr. I lar Ossorio. We started with a series of focus groups in order to tease out issues of concern on genetics research, the path that it was following. And then following those focus groups each of the community organizations hosted and son Ford a series of five dialogue sessions attended by 20 members of their community most of whom made repeat presentations to the dialogues, so it involved a little over 200 people and the sessions typically ran a couple hours each. The community organizations and miss Lewis will say more about their critical role, were partnering with us in all aspects of the partnership design including facilitators and the selection of the place, time and mode of dialogue, so in our case the place where dialogue took place was the place where dialogue typically takes place in the communities who were engaged in the project as hosted by their community organization. Community organizations work together with the kak deem Mick team in developing the process in implementing the process and extremely importantly in crafting the summaries and the reports and the ultimate recommendations which were used to describe what came out of the process. So that the voices of the community were heard through outthe project from beginning to end including the ultimate and of the project where the community organizations and academic partners met with policy makers in Michigan,al bam marks sharing their recommendations and had a two-Davis sit to Washington where we met with power community partners with members of congress, advisers, again, sharing the policy recommendations that came out of the project. I'm not going to go through the recommendation, what we were asked to do but to tell you they all fell into seven topical areas. The area of access, education, playing God perfect children, the right to genetic privacy, genetic research, which was very important in terms of the presentation we're make today, genetic testing and process perhaps the most important of all issues of trust and disstruft

As a result of one of those policy decisions one of those important components that Toby mentioned was the education. When we were engaged in the project in those dialogue groups some of the information that came out, particularly indicated the need for additional education and we've heard that already today. So as a result of being involved in this project we have the opportunity to become involved in the genetics education needs of the project which was funded by Hersa. There were two one in Michigan. We built on the original project to develop the gene project in Michigan but we added an L it's important to identify those groups that are going to particularly affected by the information that will be shared. There were several community-based organizations that included churches, that included social organizations Greek organizations and adding to that was the school self-the Lansing school system was brought in to look at the needs of the African-American. We continue top bring together representatives from the community to work through what those needs are. How do you determine what the educational needs are. Part of that assessment was -- a part of that assess mat was -- assessment was providing information about genetics and then asking them the question what do you think you need to know. What are some of those important conversations you believe need to happen and how might that be facilitated. From that a collaborative process and then we culminated that with a town hall meeting reporting back to the community. The most important element is that it was not a one-time event. The same people were brought back to the table several times to work through their recommendations and suggestions. So you flush those out, come back and hone in on what you think is mostly important. Following that small group discussion, a formal town hall meeting was organized to help the broader community understand what the elements were of that project and how to best communicate that particularly what we call checking in to see if what we said in the smaller groups are representative of the larger groups. One of the things we found at the meeting was in Flint, the quotes and the information that was shared, they responded. I wasn't at that meeting but I can relate to those comments when people were saying things like we need education because we're not sure what jee net tinction mean. We're not sure how it will impact us. Who will be responsible for the information once it is obtained. The collaborative process is very, very important. That further led us of using this same kind of concept in another statewide initiative in Flint that looked at improving the cancer outcome of African-Americans. Community is responsible enough to help determine what its needs are and how those needs can best be addressed, so from this, working with hour department of community health and a number of community leaders across five cities within the state of Michigan because we realized that African-Americans particularly are dying 33% more often from cancer than any other ethnic group but hour question remains how aware of this is our community. We need to raise the level of awareness of knowledge and communication about this to reduce the myths and engage people in screening programs. Often the issue of genetics would become a part of that conversation. The concern about total health would become a part of that conversation, so when you move from a particular issue, if you're talking about genetics, this conversation process can be used to talk about larger issues as well. So we learn quite a bit about that. We'd like to share some of the specific lessons that we have learned from the three engagement projects

So one of the things we learned certainly from the communities of color project that addresses the first question that we were asked by your staff as to whether the public would support a large scale population, I think it's fair to say on the discussion on genetics research that took place in all the communities, the answer is yes, that there is as Joan Scott just mentioned, an underlying faith that science has a lot of potential to alleviate human suffering, reduce disease and reduce health disparities and that we should allow science to progress, provided itses' done in a way that's attended to the issues that you have been bringing up and that we're bringing up in this presentation. We learned that if we are to achieve full engagement of the community, the community needs to be involved in all stages of the particular project or study. This means involvement as the study is designed, involvement in developing the various instruments and materials that are going to be used in the study, involvement in the way in which the results of the study are going to be reported to the public at large and to various subsets of that public. Next item

As though bi mentioned being -- as Toby mentioned being involved we're talking about as an equal partner. As a result of that we understand that distrust comes from a history of a concept of them studying us with the benefits being for them and not for us. The conversations so often happen and we had this a knew days ago when we were talk binge faint mortality. 20 to 25 year there is has been a lot of research and we're still seeing the same results in our community. Where was the research and was it translated to the community. We have to answer the question that it was not and did not benefit the individuals who were being directly affected by it. So there's this huge question. Who's going to be really responsible and are we going to be intricately involved in discussing how this will work. The other great segue from that is all the history around race and racism in this country, particularly in the United States of America where it was a constitution hall issue as it relates to African-American, and it still is today. Those things are not erased. They're not erased in individual minds. They are not erased in the institutional processes which continues to keep that asen issue issue from being successful because the trust isn't there. If we can work on being very open, onest in and frank -- honest and frank that it is purposely intended to be a part of the conversation because trust comes from co-ownership. It comes from really believing that you are an integral part of it. So for me personally I'd like to thank this committee because we went through little bit of a discussion trying to get here today and you made some allowances of that. But as a representative of my community I can atest to the fact there are opportunities for us. We'll talk further about what that really means for the community has we think about the importance of engaging a large number of individuals across this country to address this issue

We learn something about education that most professionals in the field of education already know. That is that education is most powerfully done if it follows engage M if students are engaged in the subject they will hunger for learning. In they aren't engaged, it will not have much result. The sequence of our project actually was from an initial recognition of relevance of the project to the community which brought engagement in the project and having been engaged there was a continuing desire to learn more.

The other thing that we learned as a part of all of this is that the community's expectations are raised when they have been engaged, and that is clearly a difference in whether the amount of involvement a community might give. We still have individuals -- this project was almost five years ago now. We still have individuals who meet us on the street and say what's the next thing happening in genetics. What are we going to do to follow-up on those issues, so being involved from a community-based per spective keeps it relevant and in the forefront. So having raised that level of expectation it's clear that they must understand what the expectations are. What was the pumplt how was it designed. Why was it designed o will benefit from it and what will be done with the outcome. What's the purpose, what's the ultimate goal. So not fulfilling these expectations continues to lead to distrust and ultimately opposition. Additionally community based organizations -- it's not going to be the case that you will be able to engage every individual of this 500,000 or million folks, but certainly there will ab need for some organized group within the community to maintain some synergy or some consistent engagement, consistent opportunity for dialogue. So as we develop our projects overtime they were designed so organizations could be seen in a leadership roam and continue -- roam and continue to be partners. One thing that is beginning to evolve is the understanding of these issues particularly as this relates to research and prevention research. We are a part of the prevention research of Michigan funded by the Centers for Disease Control. As a result of our involvement since 1999 there is now a national community committee that is representative of community-based individuals who are considered advisory board members of all of the centers as a part of that. We have been meeting regularly for the last few years looking at how we can gain some understanding on how to engage in the research. It's important to develop the capacity of individuals within our community top understand the research process. We use a phrase in hour community bench and trench. We believe strongly that science has its place. We call that the bench. We also believe there is expertise within communities that represent the Trent where the work is -- trench where the work is going on, outside of a research framework within an institution but bringing that into the community. So when you work W. community-based organizations at these levels, when you're looking at a project like this you're looking at the opportunity to expand the level of involvement and collective thoughts about how this will continue to happen

As a footnote to these comments on community-based organizations, we found that there was quite a differentiation in our experience of who comes to sessions, on site sessions when they're hosted by community organizations as distinguished from people coming to sessions that are losted by other organizations from outside the community. Here we did depart from aspects for instance the Oregon health movement. It's the more highly educated people who have a particular stake in this or that genetic disease or in the health system itself who come to the dialogue. When the community hosts the dieing to through their own organizations you avoid that kind of differentation because people are coming to where they normally come to discussion and to formulate recommendations and to formulate advocacy. Miss Lewis mentioned the work we have done over the years. It's probably clear that the large scale population isn't going to be conducted exactly with all of the characteristics but there's a lot to learn from that research that is of relevance. The way in which knowledge is bidirectinal coming from the community to the researchers and from the researchers to the community can make a project much Morrell vents, make the instruments much more powerful and accurate. The ability of people from the community that's being studied to actually have a voice in the project itself and what it leads to can help bring the participation in the first instance. Here, I would suggest that there is a role that this style of research can play in education. I guess I part cop in some ex-- if the project, in fact, does engage the community and is fully participatory, then the project can be a vehicle for community education as it moves along as it's being planned as it's being implemented. One does not have to have the education first if the participation is going to be there. So the ultimate summary and it as why we chose the title that we did, of what we learn from these projects is encapsulated in the word partnership. If a project is going to be successful it has to be a true partnership between the researchers and those having a stake in the research. We really don't like the word consultation. Consultation sounds like a train is running over here and periodically you check in and ask for advice. We love the word partnership. We believe that's what will lead to full par tisation anden gagement

The partnership building must be evaluated continuously because at times it's not so much how -- well let me rephrase that. How it's being done, at times it's more important what's being done. Unless people are feeling a strong sense of involvement, what you and up with still may not be the product that you want, still may not be utilized in a way that would be of the best tr. along with researching, we suggest that continuous evaluation of the process and the partnership building be done as well. That will help lead to develop lag common language, developing a common understanding and ultimately developing a common gold and achieving that common gold to ensure the progress, the progress, identifying what the stumbling blocks are over time and when those identified stumling blocks become clear then there's the pos tobility develop strategies along the way so you don't get down to the end of the project and say oh we should have fixed that five months ago. We're continuing to find that evaluation in large scale projects like this are a real challenge because when you're working with people over time, particularly when they may be in a volunteer situation and just being asked --ed they're not seeing the true benefit. They're not sitting around the table like this hearing the ongoing dialogue, something gets lost in the translation. There's a need to work on that because community involvement is such an integral part of the process of capacity building. If we can build the capacity -- and I may repeat this a number of time. If we chan billed and maintain the ability of people in the community to understand when you get ready for the next part, it's not as difficult because the language is clear. I've heard a number of acronyms this morning that I have never heard before. Now that I've been exposed to them I'll go back and read a little bit and figure that out but this raises my ability to go into the community to say here's what's going on here's some potential implications and here's some things we need to think about, so having the ability to do that ensures that when research is done in the community you have a higher level of understanding which means the project can move more swiftly and more effectively

Now our final comments are an attempt to apply what we've learned through these three projects to the proposed large scale population study or resource. It's clear and you've already identified this that this large scale study poses a major risk of generating distrust among vulnerable communities particularly communities of color. The reasons you have identified and we've spoken, too, so I need not repeat them, but it's also clear that the avoid dance of na distrust is dependent on the co-ownership across the communities that are most at risk from the study or that perceives the most risk. On the positive side if you do achieve this kind of co-ownership you have powerful advocates for what Dr. Kardia referred to as infrastructure, as the two-prong approach. What Dr. Collins referred to as the need to address these issues of education and policy. These chan all be done with power testimony jointed a vow ka si if one has the engagement to start with

Another very important thing that we would want to have considered in applying what we've learned is that the decision hang and planning needs to start now. And having community engaged, and just to phrase it. If you start right you can end right. If the train is already rolling down the tracks, there's no room for any modifications or adjustments. There's no room for voice. If, in fact, we want to be effective at all levels at the federal level at the state level and the local level -- and I recognize individuals come into the community. You have a conversation, and that's wonderful because people do feel like I had something to say but they're going to sit back and wait and see what happens next. When that same thing comes around again, the question becomes is this the same thing or what did you do with the information we shared with you the first time. At a local level that happens. It needs to happen more at the state and federal level. When policies are made, that's some of what happens at that local level doesn't get filtered up. Unless the voices are there at the time some of those final decision are being made things may get lost that are so intricately important when you get back to the local level.

If you can finish up in the next five minutes or so

So, particularly, tas relates to the health of disparity it's important tat study project is specific and that the individuals are an intrigrail part.

This is a national project. Therefore, it's necessary to do the kind of connection at the national level as well as regional and local. The number of organizations that have local chapters can become partners in this project. As an example the national urban league, the NAACP, the ame church, national medical association and on and on. These are organizations that can create the buy-in for the project. They're interested in health issues that chan filter down through organizations into the grass roots dialogue that we have been talking about. The national community committee of which Ms. Lewis Spokane be a valuable resource. Here you have community organization representatives in 20 some states all of who have a great sent of the world whileness research.

It talked about community-based stakeholders as well as community based dialogues. To say the community signature must be there and part of the engagement process to keep the process -- the dialogue keeps the process goirngs keeps it open and flowing, so there needs to be a continuous opportunity for this exchange.

You have to emphasize along with the word partnership, the word dialogue. We like that word because it has to do withen exchange of perspectives and the ability to try to understand what the other perspective is. Dialogues that involve shine tis, professionalals, practitioners, public health people, grass roots people can get a better understanding of what the project is all about and what people's concerns and interests are

Our next slide focuses on the role of media. We all recognize how important media is in maintaining the messages in individuals' minds. It's important to have a concentrated focus on how the media is utilized to ensure that lack of trust and fear do not become a predominant part of what people understand

Mention was made earlier today about a national review board. Much has been written about the kinds of studies that pose risks to groups as well as individual in the need of irb's. The need for informed consent materials to reflect the culture and the sensitivity and the language of the communities and to reflect these group risks as well as individuals and to ensure that IRB's do have a review role are reflective of the communities who have these risks. Next slide. The study design -- and this is spoken of earlier, does need to have a process to give some confidence that the results of the study, both the ownership of the data and how this data is going to be used are for the benefit of the community and will not be used only for people, for instance, who have access to healthcare benefits et cetera. It may be difficult to give these kinds of aassurances at the beginning, but the process of the project, the very fact that it sai partnership that there is advocacy built into it in that there is, pass doctors Collins mentioned, the recognition up front that the ownership of this project is in the public and will remain in the public, these can go a long way in alaying concerns that the results of the study are going to be used for somebody else's benefit and not ours

I want to summarize the next two slides, the evaluation by the participants. Again, we cannot wait until the end. Capacity building is very important to engage trust along the way of research itself and the importance of a shared language. The next slide talks about the fact that even the language being used is critical. Moving from calling the participants as subjects and engaging them in the project and so there is an open understanding of what's going on. So in conclusion we'd like to say that we believe the successful implementation of this contemplated large population study depends on whether the studies are perceived as a project being carried out by or conducted by the public or conducted on the public. Is this truly going to be a project that is fully engaging and that partnership is absolutely the key to success.

Thank you very much. That was wonderful and thank you for sharing the experience you both had in Michigan with this. The final speaker for this session before we open it up to a panel decision is Mary Woolley, the president of research America, served in that capacity since 1909. Research America has been probably the strongest advocate of the bioresearch community nationally. Mary has personally been tireless in her support not only for biomedical research but in engaging the public and finding out what the public is thinking and bringing knowledge back to policy makers of exactly how much support the public has for biomedical research. Under her leadership research America's membership has or than quadrupled. It has earned the respect of research and community leaders in general with public opinion surveys. So, Mary, thank you very much for being with us today.

thank you Dr. Willard and thank you to everyone on this committee and guests. I've had a wonderful opportunity this morning and the first part of this afternoon to learn from many of you. I have en indeed learned, I will be modifying some of the things as I go along to put that in practice. I'm going to talk to you about some but not all of these 10 considerations that my colleagues at research America and I laid out as things that occurred to us as we took a look at the plan for this study which I've also learned now we might want to think of as a resource rather than a study. So starting out, one that doesn't need anymore explanation from me because you heard it quite eloquently from several people is the importance of earning and maintaining the public's trust. This comes from co-ownership in our experience and I would say from everwithin's experience in life and as I say you have heard this eloquently from many others. Secondly ashiewrg the broad support of the scientific community. It's important for many reasons starting with it takes a broad scientific effort to assure that better health can be ob caned for all the members of the public. It's in the about one project or two or even a thousand. It's about many aspects of science proceeding along in partnership and all of them by the way women funded which I'll get to at the and. Now I do want top spend just a moment on some big picture context issues which have to be considered, not just now in the beginning but on an ongoing basis. This has also been touched on by several of the speakers. At the moment we in partnership with you and others trying to get this study this resource on the public agenda we would be competing with a lot of other things. That is likely to be the case for sometime into the future. It's also true, and this has been mentioned, there is a general distrust of the government now apparent among our population and finding a way to position this new program in a fashion that will underscore the fact that researchers work for the public and not the other way around, would go a long way toward addressing this distrust problem, at least in the part of this that we were have some ability to influence it. At this jung clour one of the things that we say over and over again to the research community is we need to get better at saying and conveying to the public and its decision makers, I work for you. I work for you. Then wait and see what the questions are that come back from whomever you're addressing and anes those questions rather than the ones you think or are afraid or are guessing that the public has in mind, so I work for you will go a long way towards minimizing our distrust of government. We also have a big picture context issue and we have for quite some time. Science literacy are not highly valued by many people in our society. This needs to be addressed as well. We all have to keep it in mind. Then there's the issue of the overall healthcare costs. Most people, when asked how they feel about medical or health research of any kind, immediately bring healthcare concerns to mind. So these things are connected. One of the ways that we've seen this and others have as well is in a national survey conducted earlier this year where you can see where medical and health research ranks in comparison with other issues very much on the minds of the public in terms of health issues as national priorities. This is -- this does not mean that research is low would say that 66% is a low number, but we all of this happens in the big overcall context of things people have in mind, research happens, I mean, in the big overall context of healthcare, healthcare delivery and the costs. It's also a fact right now, another piece of not so good news but part of the context people now, 60% believe that the United States does not have the best healthcare system in the world. This is an indicator not of whether they're right or wrong about that by the way but of a perception that things aren't so good right now. I would say that the public is catching up to oar maybe preceding expert opinion. This is a big problem. So on to another consideration, the importance of identifying an urgent compelling goal. The reason people get excited about something, want to participate in it, want to help plan it, want to be part of it in any shape or form including paying for it or benefiting from it eventually is they want to be associated with something that is exciting, that they can understand immediately even to the bumper sticker level and get behind and some candidate goals na certainly need addressing in this country whether through this project or until other ways are the importance of eliminating health disparity childhood obesity assuring an indoorly different kind of goal but assuring the mains Nance of U.S. global competitiveness and finally saving lives and saving money. I thought that bono expressed the importance of having a big exciting goal indee.d he was talking about his own work, which has been substantial in calling for 100 management, not 10%, not 30% or even 80%, 100% debt cancellation. What he said, the goal has to feel like history. Incremental leaves the audience in a snooze. That, by the way, why doubling the NIH budget over five years was a much more successful strategy. People want to feel like they're part of history in order to get behind something. Now I've already mentioned and it's been well covered that there's a lot of reasons to address unequal treatment or healthcare disparity. The public by the way strongly supports that. Let's put research to work to eliminate health disparity. I mentioned fighting childhood obesity. Research shows the best way to fight it is to prevent it but the dollars we put toward it are quite trivial. Getting people to understand that paying for prevention and there's a lot of different ways to go at prevention. It's tricky communication, but if more people are involved in figuring out how to communicate it and are agreed upon the goal, we can get there. I mentioned global leadership. The public very strongly supports having the U.S. maintain its role as a global leader in medical and health research. That leadership is by no means assured anymore. There's lots of indications that it's at risk. It's something just as important to the public has it is to decision makers. Saving lives and saving money, very important simple messages about saving lives and saving money is another way to demonstrate to the public and to decision makers about the value of the program you're talking about or any other research project for that matter. I think this point has been very well covered. The importance of the involvement of the public at every step, every step along the way, and of constantly keeping one finger on the pulse of public attitudes and responding to real questions that the public asks. I think mark Twain said this better than anybody perhaps. Supposing is good, but finding out is better. It's very much what interacting with the public is about as a researcher. You can do a lot of imagining or supposing about what the public thinks or will do or how they will be involved but there's no substitute for finding out. Are's going to hear a presentation tomorrow with some up to date data on concerns the public has about relevant issues. I'm going to show you a few things from our own work. First of all an open-ended question which is always useful. What's on people's minds when they hear certain terms or about certain kinds of activities. It's very important to pay attention to open-ended data and information. What I'm going to show you is just touching the very tops of public perceptions. It's not in-depth in ways that Joan was talking about earlier, but it's worth considering nonetheless. People say they are willing to be genetically tested, for example, but a substantial portion says no. Again, a lot of depth about this. People say they will contribute a sample of their DNA to a national data bank to be used only, emphasis on only, for health related research. People are a little more closer to slit on this one. It's how it's used that has been touched on by oarghtses. Then we've also, as have others, asked questions about personalized medicine which has the very great attribute of have lag great name. It sounds good and I think that's what people are responding to in a positive way. They probably have very little real life experience with what it means. In fact a lot of pus probably don't know what it means but we'll get there. New public engagement -- one of the things it doesn't mean is public relations. By the time you're doing public relations you're in a different area of exspeer teels. It's important. It's necessary but it's not the same. I think always still should be driven by researchers saying an and -- and conveying I work for you. Words matter. Words matter a lot. This has been discussed -- some of these points have been directly addressed. One of the points I would change now and will for now on in this presentation is instead of saying volunteers instead of subjects in projects, we should be talking about partners. I certainly subscribe to that just never thought about using it in this -- a as a better descripttor for subject. A few other things here that we're familiar with overtime have really made a difference even as simple has talking about research projects rather than grants. Grants convey an entitlement mentality that too many people associate with the medical community. Finally the few per the words the bet are. We do a lot of programming around the country to help researchers get comfortable about talking about their work in three short sentences or less. We're not talking about Faulkner here. Messen jeers matter. The first point to make the community, the authentic messenger make as great deal of difference. That point has been very well described already but celebrities matter, too. This is important to dpleep mind at the right time at the right place. Celebrities in this case we're talking about Nancy Reagan, talking about stem cell research which made a huge difference to the passage of prop 71 in California about a year ago. She was not the only person who made a difference. You can also get into warring celebrities and the appropriate use of celebrity spokes people is something to get help with rather than guess about. It's a job for experts advice but it does make a difference in pretending otherwise is not useful. Media matters. This has also been touched on by several speakers. That follows the celebrity piece because the media pays attention. The media pays attention to controversy and conflict. It cannot be ignored. Again, some expert help make has lot of difference. Times topics around ready for prime time media. Stem cell research was one that wasn't ready. As we all snow very much in the news now. This was the cover of parade magazine back on July 10th. We've been work, researchmark has been working with parade for sometime now, many years, and we're aware from talking with the edittors and writers and others there of how important it is not to prematurely try to engage the public before they're ready and parade magazine is the most widely read weekly mag discone. So when parade magazine ready the public is ready. Once, not only because it was in parade, of course, but from the middle of the summer onward you probably noticed stem cell has been in the media every single day. That probably can and would help with a project of the magnitude that you are considering but it wouldn't happen at the beginning. Finally, I'm going to say a few words about funding. I consider funding the least significance of these. That's why it's number 10, of these considerations because I believe if the value has been established and the need and the confidence of come people in the public and across the decision maker and the scientific community, the money will follow. It's been demonstrated over and towser over again it's the case. It's not about robbing Peter to pay Paul. It's dangerous to get into that mind set where we begin talking about x number of one kind of grant compared to a big project. There is plenty of historical precedence when the need is real and palpable and the public supports it. We have a lot of public opinion data that gets at this point, the sort of rubber meets the road question when we ask people if they would pay more per week in taxes, imagine raising taxes to pay for medical research, but that is very well supported by the public. By the way, we've been asking this question for 12 years. This is the highest level of sporks fax dollar support that we have ever seen but it's never been below 50%. It's sometimes shock together research community to realize that the public would be very willing to pay for more research because fundamentally down deep they subscribe to the fact that without research there is no hope. Without research we wouldn't have better health. We would have a consideribility amount of confidence to deliver on that hope, and they will pay for it. Just to underscore the point that there's a lot of money out there. This is a wealthy cub. It is, I think use follow think what we use money versus what we pay for with our federal tax dollars. These are a couple of examples that illustrate the amount of dollars that are actually there and I think can and will be ultimately tapped to help pay for a program of the caliber that I'm con if I didn't all of you will design and implement. When you do so I'll be very proud to represent it to the American public and their decision makers, thank you.

thank you, Mary. Thank you to Paul four of hour panelists. We're now going to have lap round table discussion with all of the presenters and committee members. I'll turn it over to Kevin Fitzgerald who will referee

I didn't bring my whistle. I would like to thank again the presenters for a wonderful presentation. Perhaps we can get into what miss Lewis said. Ill ale look around for people. Okay.

Sop Francis, I hate to keep prescribing what you have to do with your $300 billion. It's an interesting thought that Ms. Lewis raised and Mr. Citrin of having them do research on us to benefit them. This is a large population cohort database that will be created and researchers are going to be accessing this database through projects, not randomly but I assume fund projects that will be supported by grant funding. Is it possible to prescribe that the research will be funded to reflect the's nis ti of the project to be comparable to the ethnicity of the database so that if you have 40% Hispanics or 30% Hispanics, then 30% of the projects that are funded to access the database have to be towards the Hispanic population. Is there a way to ensure that it's not them ding research on to us Bennett them. I don't know that that's been really addressed in how the day that base will be accesseded how the research will be do on that database.

I think the idea was that anybody with IRB would have access so you don't have high school students busying themselves about phenotypes and genotypes. The sense that the planning group had, you want to empower anybody with good idea to deal with what will be a massive amount of data

Sometimes money empoirs people.

certainly. Lots of these people would be funded but it would not be a requirement. I would like to hear the panel's reaction

That's an excellent question. He work on genomics. We've often talked about applying to all gen knowics research is this more likely to reduce or exacerbate health disparates down the road. I know it's very difficult when you're doing basic research to look that far down the road but I think it's a useful test to apply on how Ledee that base -- how a data base -- it's got to be there if it's going to be justifiable. This can bring community engagement and it can also bring community support

There is not an equal distribution in the research community among different ethnic populations, so ur leap going to get the disparates created unless there's some motivation to do the research on the nonrepresented groups and issues and diseases that affect these all different kinds of ethnic populations

I think this also speaks to the importance of how the proposals or requests are designed and that there is specific language that requires engagement of those community representatives because as we look around, it's clear that we don't have enough African-American researchers. We don't have enough in this field native American researchers. So for us to think we well put a frog project out there and -- will put a project out there and someone will gravitate to it is not very likely. So the language we spoke about, the language needs to be very explicit. There needs to be some measures that ensure that anes which gets to the continuous evaluation. If it doesn't, it will show up that it's not there

I have a knew different questions. I will just throw them all out and see how the panel handles them. I dit did some of the first community engagement work with genetics in L.A. Some of the issues is this. Who speaks for a diffuse community? Let's say you have Indian tribes, which is like a defined group with a self-governoring body. When you have let's say Hispanics in Los Angeles and you're talking about community groups, who's speaking. Then how do you handle difference of opinions in the community. You're including minorities because a simple majority rule would not be fair, so within the minority how do you handle 70% thinks one way. 30% thinks another way. There is no simple answer to inclusion versus exclusion. It is very real so that Francis has made a contribution to legislation. If there was no threat, there would be no need for the legislation. There is a potential problem, so if you include the my north group, they can be and the health findings come out that relates it to a problem that's more susceptible to this or that, they could be genetically discriminated. If there a a health advantage, they would be included. If advances are made, it would not be applicable to them my final question, I'm curious to know the following. United nations and the world bank has ranked the quality of healthcare in different countries and the United States is consistently ranked 38, 39 way down next to Cuba. The first time are Italy land France respectively. I'm astonished that 34% of the public think our healthcare is the best in the world. How is that possible? How can people think that when it's so down the list.

Anybody jump in police

Let me address that plans point, please how people can think otherwise. There's evidence of in so many ways that the public doesn't know what the facts of the matter are. And this is just one more case of that. In addition, I would say there are at least 34% of the American public who would like to believe that and long for the day when this country does have the best healthcare system in the world, and I think it Ames important to hold on to that belief.

The other in your earlier questions which always pose a great dally a who speaks for which groups, I guess part of my answer, if we don't follow a model of community approval or of some kind of voting or balloting, while it's a significant question, it's not as significant has if you were following that kind of approval model. Near the Ms. Lewis or I are talking about an approval model but one that would engage sufficient stakeholders so this would be a project of all of us. Yes. If there is some kind of stakeholder group at the national level that is formed to represent this partnership, there will be people in it and out of it. In different part vufs the country if there's a regnal approach as well as a national approach. There well be regions where some groups will have more of an input and others will have less. Here again I think the max sim that was mentioned, not everyone will be happy, but it is sufficiency of that kind of stakeholder representativeness that will give a sense that this is a project of all of us.

I'd like to add it that that our communities are not hoe pope Jean us in. In no way are they all the same. I'd like to make sure before the end of it I give respect to the community for which I represent because they give me privilege to represent them and they share with me their concept. So I share a perspective of the community because I cannot speak fully in total for everybody. It is a catch-22 because we find today that because and I speak particularly for the African-American we share the challenge of so many issues because we have not been directly involved in much of the clinical research, so when things come forward they're utilized. They don't always work the best. You can't follow it back and say these are what the outcomes were. So a project leak this provides an opportunity for multilevel intervention and conclusion. These help to raise these issues so there can be some thought has to how to address them. It would be wonderful to have the opportunity to go into each community that is identified to be a part of this and understand hot people are that help make decisions for the community. They're not your traditional people. They're not necessarily your pledgetors. -- legislators. They are the church mothers who sit in the church mapped make decision. They are the individuals who run the corner stores. They are the individuals who have influence and help make decisions on a regular basis who may never be viewed as a community leader, but they are the person who can help us effectively engage, but they will only do that if they have a basic understanding of what they're being asked to do and they can trust that process. That is why, as we mentioned earlier, the process is so important and cannot be dismissed as an intrigal part of what will happen, those various levels are necessary to identify who it is and how it is they will be brought in handfully engaged. I think we mentioned earlier, engagement sometimes is a word that has different meanings to different people, but we're talking about people really being respected for what they have to clone tribute to a process of understanding. And if we can think about it in those terms maybe we'll address some of the issues that are raised.

Joan?

I was just going reecho the fact that we as a public and even communities are not always easily identifiable as what is a community, and therefore, being open to a wide variety of approaches, I think is going to be really critical

I want to thank all of you for a very stimulating discussion. I learned a lot. The first thing I learned is encreemental change leads to a snooze, along those lines. I want to pose a question to all of you, but I'd like to preface it with a couple of statements here. If we were able to sell the human genome project 25 years ago as an initiative that is going to be far reaching as far as biology, medicine and public health which is only the first step IE creating the alphabet, the book of letters, we could sell that. Our leaders solid that research to the world. We are at the fork in the road in the sense that this next initiative is going to lead to the translation of that first phase from the gene see Gwen si to the characterization of what genes mean for the health of the poplation, IE, the public's he. all the issues that were presented today, this morning and this afternoon are going to be so important in shaping that translation of research agenda. I call this translation because it's taking it from the bench to the trench pass somebody said earlier. Now one of the -- the question of the group is that the apiecement of anxiety and 25 years ago left to the funding of the lc program and the creation of large scientific body of information that led to sort of improvement in the way we think about genetic research, genetic identity, race, ethnicity, all kind of things, and the answers to this question may come from what you already presented but I'd like you to think about it proactively. If we were to think about the next project, next resource or next initiative, not only as a resource recruitment effort to get a half a million people but more of a tran signaturesal population based evident to take the genes from the benefit of to the trench, and if you were to carve out 5%, 10%, 20%, whatever the number is that would allow such an initiative to move forward, how would you spend that money?

Anybody want to -- Tony?

I'll take a stab at it. I think the whole process of engagement is a costly project. We, are engaging 200 people. This is much more intense than one would contemplate here, I think, but we spent $1 million in engaging 200 people in these dialogues. This is a national project. You can't do it quite that way, but it seems to me a good share of this money ought to be sent in this process coupled with education. A number of networks can play a role here. You talked about the role of the public health community and the public health agencies in the project and presumably they would have a role in the study itself, but public health ideally is a convener of groups and the ability of public health connected with some of these national networks of organizations that we have been talking about, convening sessions that come bienl education and discussion could be a valuable network in order to achieve this kind of continuing engagement and that costs mun nirks the specifics of how it's carried out would have to be worked out. But it combines the role that these community organizations play. If they're going to be part terse, partners ought to be compensated the same way as researchers. That's part of what this would take. Those are just a few.

Joan?

There are some pieces of it, being creative about material that can be used broadly is one way of getting more bang for your buck, utilizing the existing networks as Toby said, is another way. But starting early in the process I think will be critical for overall success, so having that money right up there at beginning has got to be part of it.

I'm struck by the way you approached this in terms of thinking about it in translation and developing the alphabet. I think if I would take it a step further -- I was trying to figure out how to put this in terms of dollars and cents. From the alphabet we build a glossary. From a glossary we build a disc fairy. Talking about LC to get some sense of comfort. If are we're going to translate we need a common language and how we have to aloe chat those dollars to ensure that people go from understanding their alphabet and how to make wordses. People go from understanding there's a DNA sequence. I think someone said it earlier, really understanding what these concepts mean and how that then in the future will translate to us in having a dictionary that helps us go to a place to understand what all of these things mean. So from that perspective we think what's it going to take to build that

Joseph? Oh, I'm sorry into miss Lewis spoke about the media. Some are very costly. Media, not looked at as PR, media as a way to simulate dialogue or have a proxy dialogue, these are ways in which one can start simulating national attention and hopefully national buy-in to the project

A comment. I think one of the least costly ways to assure more public engagement faster, which I take to be a goal, whether it's for the research we're talking about here or research generally is for the science community to start actively valuing public engagement instead of dismissing it as something that is either unworthy or too time consuming. It need not be too time consuming. Everyone can benefit from every day engagement starting with one's own family I might add or much more likely to be critical than many others in our society and we can find out right there at the thanksgiving table that maybe we're not communicating as well with nonsigns audiences as we might be by just trying it out on Susan or daughter Nora, son George

Thank you. Joseph? You're first

I actual will you want to thank the panel for clarifying a number of things. One of the things whenever a group gets together and have this sort of dialogue last it relates to a perspective which is engagement and engagement at an equal level, a lot of terms get thrown out. I'm glad that you clarify thrapd community is not a physical place. It's not a group of people. So I think that's important because one of the challenges is to engage people who do not readily understand or take this perspective. That's the real challenge. I think because my colleague keeps bringing it up and I appreciate it a lot the point, who are you talking to. Who do we also have to get involved in the project. Those in a position of making decisions on this. It's not necessarily a lot of people but who already have a way of thinking about how this is supposed to work, so I would actually suggest that we also think of a broader way of defining the question of who should actually be involved and not limit it to just discussion of particular groups of people in terms of race or ethnicity but looking at those -- those are the kind of folks. That cuts across to me ethnic bounds, racial bounds and it gets into other issues that we really talked about, which are issues of poverty those sort of things which by and large there are common things that are shared. So I would say look for things that are now common, commonality and be able to have a dialogue with those who make a decision. Also, I would suggest that given everything that we heard today there needs to be some effort of making a level of comfort for those in the decision making process to feel comfortable with this whole idea of community engagement. I think it's one thing to say scientists should aappreciate community engagement or public engagement but it's another thing to bring scientists to that place where there is a comfort discussion. That's also the challenge, so I would recommend that as something that we as hatch committee thinks and I'd be open to thinking what the panel think. That's something that us or engaged in are constantly struggling with

If I could make a quick response. It's quite an important statement that you made. When I looked at the power points for Dr. Willard, this was quite clear, at least, that this is not labeled as a genetics project. The goal of such studies, large populated studies include determining the mechanisms underlying common complex diseases or looking at the earlier bullet, learning more about the relationship between genes, the environment and common diseases. I think that's a how areful clause. I did not hear Dr. fink's labeling. If this project is design -- it really is a project for everyone, particularly a project for people who are experiencing those complex diseases which leads us to the issue of health disparate. I part company not in what Dr. Kardia said but in terms of the sequence, that the study itself can start building bridges across the social sciences by looking at all of the determinants of these diseases at the same time. It can build bridges to the community by doing the same. Do understand the view which embraces genetics in the middle bulls eye and runs all the way out to social, family and structural determinants. If the project is seen that way it could be exordinarily connective project which can lead to by the community as well as policy makers.

I'd like to add one addition ham comment and framing it more in the context Toby was talking about. There's much, particularly amongst the scientific community about the deplorable level of knowledge of science within the public. I don't know how my car works. But I'm a pretty good driver and I can make it work. And I'm a good driver. I'm really less concerned that the pub plik understands what a polymorphism is or whatever. But the public is capable of understanding complex about technical issues, social issues and ethical issues and putting tell in the context of what they already know. People can get it. So I think education, yes, is a very important component of it, but I'm less concerned that people understand we have 46 crow mow sewns in every cell

Please?

I'm also hearing that if another community that needs to be engaged in dialogue from a different -- from a different perspective, the science community needs to be engaged in understanding the language of both or not in the science community. Toby mentioned earlier bidirectinal. We talk about bidirectinal. We also talk about cross fertilization, which is to say we talked amongst each other to begin to understand what we mean. When you're all in a room with the people you work with and you all think a like and you discuss a lot of things when you walk out of the room you still all think a like. The ged how do we get people who think differentfully a room to have a conversation about a complex issue land get some understanding of how they think differently and come out with a common way to address the issue. That gets into how you translate. So if we were to take this room as an example and have a dialogue, this would be a conversation based on a scientific perspective and sharing what does that mean to me from a community perspective and how do we come out with language that helps us both know we understand what we're talking about. So I think that element might be a part of the process that not only are we thinking about going out into the community out there wherever that is in the world of the United States of America and identifying 500,000 or a million people and saying let's also figure out how we bring the geneticist and researches and the community together in a discussion that helps us figure out what steps to take next.

We have time for hunt

My question is going to be a little bit different in the sense that both the NIH working group and then this committee have identified public engagement as a major issue. Our job, other than just enjoying this exchange is to make specific recommendations to the secretary to guide him and his thought process for how to consider proceeding with the project such as this. So I would ask each of you for some specifics in terms of what would be concrete specific steps that you would suggest in order to take the pulse of the public and or to have them engaged in a project like this because we've all identified that it's important and you each have your own experiences on how you have done this in specific settings but in the context of this setting and this potential magnitude what specifically would you have us or him do in order to bring the public into this partnership. . Pause to switch captioners.

Despite the power point I am not Pilar Ossorio and in fact, I'm not using power point at all. I'm not sure whether this is an eccentric affectation or laziness or an actual desire for you to actually watch me and not the power point slide, I like to think that as a lawyer I very rarely have data and if you don't have data there's much less power to using power point. What I'd like to do is talk about two big ethical issues in large population resources. Before doing that, I'd like to say that I think the overall issues about whether this project should go forward are quite fascinating and id'd like to pick up on something the members of the last panel said. I think having a big goal, having an audacious idea is really an important thing. It has significant externalities not just in terms of public relations. It's not just bo know and people not going to sleep. But it inspires researchers, students, it inspires people to go into the science. I think moon shots have externalities that are sometimes overlooked. I say that without having any opinion on whether this has -- this particular moon shot has a scientific value to justify its financial costs. I'm not competent to know the answer to that. But I think I am competent to say that if this does go forward it will face a host of ethical, legal, social and perhaps most difficult and used in a broad sense, political problems and I say that as a battle scarred veteran of about a decade of the human genome diversity project which met many of these difficulties and ultimately failed to surmount them. So I do think if one decides to go forward with this a similar study of past projects will be very useful in letting you know not just what methods may or may not solve some of these problems, but what problems you're going to hit. Because the one thing that was overwhelmingly clear to us in the HGDP was that there were far more land mines in that project than we had any idea about going into it. We've discovered a few of them, with the cost of many body parts. There will be more that a project like this will hit, but looking at the land mines that have been exploded in the past or that have been diffused in the past will be very helpful if this goes forward. Now, what I was asked to talk about or to specify three particular ethical issues that I thought were especially important. The three that came to mind were first issues of control of the uses of these materials and data, secondly, issues of the return of information to the participants in the research and third issues of confidentiality. The issues of return of information to the participants in the research, my colleague Pilar is going to speak about next, so I won't say anything more about it other than to say it's really important and listen very carefully to what she has to say because I think this may be one of the most dangerous of the land mines a project like this will have. Instead I'll focus entirely on the issues of control and the issues of confidentiality starting with control. By control, what I'm talking about is the research participant's ability to control how the data and the personal materials, the personal biological materials that person has given to the project end up getting used. And I want to start this discussion with a story about some litigation that's currently in progress in the state courts in Arizona involving members of and the nation of the HAVASUPI, a federally recognized native American triebl government nation that lives in the lower grand canyon. It started in 1989. Researchers from Arizona state university started a genetic research project with them, aimed according to the allegations of the complaint, solely at a study of noninsulin dependent diabetes mall tis, an issue of great interest to many native American groups and certainly to the HAVASUPI as well. The facts that I'm going to tell you about are not yet proven facts. They're allegations in a complaint and as a former lit gator I know exactly how much suspicion one should view unproven allegations with. In this case it's a little bit modified because most of the allegations of the complaint are taken from a report written at the request of the defendant, Arizona state who had an independent investigation of the situation done and that entire report is attached to the complaint. So in 1989, the diabetes study started, bloods were taken, family histories were taken, clinical information was taken and only over a decade later did they learn that the researchers involved were not just studying diabetes among them, but studying schizophrenia and also studying issues of historical origin. They were outraged, they were particularly outraged since they had been specifically reassured that only diabetes research was going to be done and had specifically made that a condition of their initial approval of the research. They further were outraged when they discovered that the samples weren't just sitting at Arizona state with the researcher who had come down to SUPI village and talked to them and met them and who they knew, but that the samples were distributed all over the country and all over the world to researchers they had never met, had no relationship with, and had no appropriately or misplaced sense of trust in. The result has been litigation, bad feelings, and I suspect a very long time before the HAVASUPI are willing to participate in genetics research again no matter how the litigation comes out. This is a particularly powerful example, I think, of the fact that people's interest in the research that is done with their material and their data are not limited to things that affect their -- their physical health, their personal economic well being, their insurance status, but people sometimes care about what you do with their data because they don't want to be come police sit in certain sorts of research. They did not want to be studied for schizophrenia. They felt that it was going to be a stigmatizing study no matter how it came out and it wasn't an issue they wanted examined. Some of it they did not give permission to and did not want to be part of a study of the history of their population because they believed they know where their population came from and had no interest in abetting other theories including the sometimes referred to as BS hypothesis the berian strait hypothesis about where their population came from. Personally I would be outraged if I discovered that the material I had given for one reserge project was used by English researchers to study the intelligence and genetics of the I wish. I simply have a fair idea of how that might come out in the hands of English researchers. More generally, any sort of research into race and intelligence using material that I had given, I would feel was a betrayal and had made me a part of research I did not want to take part of. Other people will have other sensitivities. They may not want their data or information about their family members to be used in research in mental illness, in research in sexual origin -- of sexual orientation and genetics, in research in alcoholism or addictive personalities or a variety of other things, but people will feel betrayed if their research is used for purposes that they think are bad purposes without their knowledge or consent. Similarly, although I think this is a lesser issue, but not a -- not a trivial one, people often should at least traditionally take part in research because in part they trust the researchers who come to them. They trust that Dr. Collins is really going to look after their interests and be interested in cystic fibrosis and they've met him, they've shaken his hand, they've looked him in the eye and they trust him. I think very few subjects, very few research participants or research partners have any idea regardless of what the informed consent form says of how broadly their samples and data might get distributed by people whose eyes they haven't looked into and for whom they do not have that level of trust. Now, in the context of large resources, the creation of libraries, resources like this would be, what I once tried unsuccessfully to get termed gene type phenotype resources this produces a real dilemma because you can't successfully ask people about each and every research project that's happened throughout the history of the data bank, throughout the history of the research and get their full informed consent about each and every use. It seems highly impractical because there will be hundreds of uses if not thousands spread over time. And even if you were able to have the budget to go back and individually reconsent people on each one of those, I think you'd quickly find that people were sick and tired of seeing you and didn't want to be reconsented after a while on each additional molecule involved in pancreatic cancer or involved in asthma. On the other hand, I do think that there's something phony about the idea of informed consent for these kinds of resources. The idea of informed consent both in general and as laid out in the common rule is consent in which the research participants trying to avoid the word subjects which I agree is a bad word. The research participants are informed about the specific risks and benefits about the particular research that's going to be done with them or with their data and how can you do that with a resource like this? No one has any idea what specific research will be done, what particular diseases or genes or environmental effects will be examined. The whole idea of the resource is to make it available for people to do everything that seems important and useful over time. So even calling it informed consent is a misnomer. Now I'm not going to take the position that none of this should be allowed by the IRBs under the common rule but it is a real problem with the issues of consent around participation and resources like this. The consent is not truly informed, cannot be truly informed and yet on the other hand for practical reasons when we know enough about the specific projects it really doesn't make sense for us to be able to go back and reconsent everybody on every specific detail. It's a dilemma. Possible solutions? Well, the first thing to say is they're certainly not perfect. This is a real problem and there are no perfect solutions to it. But there are ways I think where some of these can be mitigated voovling two steps. First at the beginning of the process, try to find out if there are specific issues that the research participant does not want his material or her data used about. You could do that as an open-ended affirmative way, is there any research you don't want done with your material, I think that's unlikely to be very successful or very realistic. One might often opt in, give somebody a 12-page list of different research topics and ask them to check all the ones they're interested in. That doesn't seem very meaningful to me either. A shorter more targeted opt out might actually be meaningful, listing things that you have some reason to believe might be sensitive, might be issues that some of your research participants might not want their materials used for and ask them to check yes or no in advance. Even that, I think, is only a moderate step in protecting the interests of people who might not even know what interests -- know that they've got interests in these issues until something comes up. Another alternative and one that a veteran's department project that I've been involved in has endorsed is to have continual monitoring of the subjects of the research topics that are involved. Either or I think better of both by an IRB and by a group drawn by the research participants themselves and have them discuss the new protocols that are proposed and see if they think there's anything in here that's particularly sensitive and if they think that there's something that is of significant number, weez l word, how do they know if it's a significant number but if there's something that a significant number might object to then they might reconsider the power of the consent. That I strongly suspect would happen in a very small number of these projects. I suspect that no one in can trunly is going to be personally involved or e emotionally attached to issues of pancreoya tie tis or issues of asthma, the farm joemics of different asthma drugs. But when we get into behavioral genetics issues, the likelihood is much greater and the alternative is to have a situation where you've got a research participant who years after signing up for this good noble thing discovers that his DNA or his family history or his health records were used for something that he finds abhorrent in which case I put it to you that he feels cheated, betrayed, unhappy and he has some grounds to do that. Or putting it broadly -- even more broadly on the web, you would need some sort of check, at least a listing to make sure that data and DNA from -- data and materials from people who have said they didn't want to be involved in this particular research topic wasn't involved in that topic and I think you should also for sensitive issues put it before a participants board as well as an IRB so it rules out one alternative. If that alternative is really important. If that's what you need to do so make this successful or to make it as successful as you hope that it will be. So be it, but make sure that the informed consent for it warns people up front that there is -- you have no control over what your data and your materials are used for, they may be used for things that you disagree with and if that happens and you find out about it, don't complain to us. And put that in English, not in confirmed consentESE. Don't hide it at the back of a 20-page consent form. Second issue, confidentiality. Here's another issue where there's an enormous problem. Americans are enamored of privacy, e that mored especially of health privacy and economic and technical reality that is in the words of one silicon valley mowing l, privacy is dead, get over it. The push, which I think is inevitable for more computerization of data, inevitable, I think, because of all the advantages that come from that computerization of networking and ak shesing of data invariably undercuts the possibility of promising people complete or even very full confidentiality. In terms of confidentiality, most research goes forward in sort of a key system where the specific researchers may not know the identities. It's hidden behind a code. There is a key holder someplace that has of course possibilities of abuse if the key holder somehow cheats decides to use this information for bad purposes. Personally I think the odds of that are extraordinarily low and can be made lower with appropriate sanctions, but they cannot be taken to zero. And people who take part in this research cannot be promised confidentiality. They can be promised the best confidentiality we can offer them. Despite what I've heard occasionally from the computer folks, it doesn't look like there's a technical fix for this. I've heard a lot about one-way encryption or hashing encryption followed by a lot of movement of hands that comes to be explained and as far as I can tell from cross examining some computer scientists in some of my classes, it's not going to be a useful technique particularly for a project like this where additional data will be added longitudinally. One sort works all right if you're only putting data in once and there's no way to decrypt who that is. But if you've got data from me and you've put it into the database and later you want to add more data from me, there's got to be a key somewhere. Somebody somehow has to know that file 14678 G is hank Greely. And once you've got that, this one-way encryption idea will no longer provide the technical fix that people hoped for. But there's a more fundamental confidentiality problem. Useful data sets or rich data sets rich data sets or identifying data sets. Swee knee has published some nice work on this. I was born on June 25th, 1952 in Columbus, Ohio. I actually should go back and look sometime, but my guess is Gwynn the demographics of the era there were probably 7 kids born that day of whom I'm guessing there were four males, three white, one black, three females. If you know that information about me, that I was born then and there, you're already down to -- and you know my sex and my race, you're down to three people in the world. If you're really interested, you can find out which one of them is me. I happen to know that one of them is my cousin Mike. We were born on the same day, the first children of my grandparents. He will never let me forget that I'm 20 hours older. He's 5, 6, 130 pounds. It wouldn't take much more data to distinguish which one of us was me and which one of us was him. If you're born in a small town, the side fieblt becomes even easier. If you're a famous person your side fieblt becomes easier. If you live at the ZIP code for the white house it's not going to be all that hard to identify you with just a little bit of data. Now, as the world becomes more and more wired, this becomes a bigger problem because more of this data is put online. Interestingly, I think the thing you've got to worry about for a lot of this place and date of birth is the genealogists who are by si as beavers online putting all sorts of databases on line. Genology is second apparently only to sex or pornography in terms of its interest level on the web and they're constantly putting new data sets on line. So right now you'd have to go to the Franklin county records to look up my birthday but that's not going to be true for very much longer. And once that becomes possible, the ability to identify people with identified data sets becomes much stronger. You can fuzz the data sets. You can say not born on June 25th, 1952 but born in 195. Every time you do that, you lose something of potential scientific value and the real harm there, the real problem is you don't know how much value you're necessarily losing. And there are seasonal variations in disease incidents based on what season somebody is born in there are some things like schizophrenia that have a higher or lower rate depending on what season you're born in. I went to my ophthalmologist who looked at my retinas and said were you born in the Ohio river valley? I said, well, close. He said, well you've got hip to plasmosis scarring on your retina which is very common in people from the Ohio river valley. You can try fuzzing the data. As you fuzz the data you lose some medical and scientific value and you don't know how much you lose. So the dilemma is you lose the wide breathed of people that are able to get it, the less you can promise confidentiality and an no, ma'am anymorety. There is no key anywhere. You can't successfully do it. Is there a solution? Not much of one. The only solution that I can recommend is complete and total honesty. But that will be expensive. People are leery enough about their privacy that if you tell them, now, you know we can't promise you confidentiality and even if it's anonymous somebody who cared enough might be able to look at all this data and figure out who you are. We don't think anybody's likely to do that, but in good conscience, we have to mention that that's a possibility. You will lose some research subjects and probably not a trivial number of them. The alternative though, is to not tell them that, let them sign up based on their understanding that there's broad confidentiality protections and then feel betrayed when they discover that their identity has somehow been blown and that their confidentiality is not there. As I say, I think this is a much bigger problem than just a problem for large population research resources. It's a problem all of American health care has to deal with that stems from a mismatch between our public expectations of privacy and the realities of the society we live in with respect to privacy. Well, there are a number of other important issues, but I suspect I've gone over my time. Let me just close though by saying that I think this is really important. I think it's really important to line up the ethics of projects like this so that people do not feel betrayed, do not feel that they've been lied to or mistreated and I think it's important for two reasons. One is because it's the right thing to do. You know, if you've got subjects who feel that you've mistreated them, lied to them, bebetrayed them, then at the very least you've probably done something wrong. At the very least you didn't communicate as well as you could have and that's an unethical result. Secondly more pragmatically it's bad for science. Any research subject who feels betrayed and mistreated is not a subject who's likely to sign up for more research. They're also not subjects likely in their role as citizens to lobby a vote for support by medical research. Treating research subjects well is ethically important for science and for scientists. Treating research subjects well is politically and pragmatically important as well.

Thank you very much Mr. Greely and we'll hear from you again once the full panel has spoken. Our next speaker is Dr. Pilar Ossorio. She's an assistant professor of law and medical ethics at the University of Wisconsin law school. She is also an associate director in the city of race and ethnicity in medicine at the University of Wisconsin law school. So thank you very much for being with us.

Thank you and I do have some slides so it's okay. I'll just say next slide. And we can go to the next two. There we go. So I'm going to talk about reporting results back to participants and I should say that professor Greely and I are both involved in a project at Stanford University at their center for excellence in ethics where we have a working group that has been discussing this particular set of issues very intensively. We will be coming out with a white paper soon and I suspect that you will all eventually get that white paper. Some of the things I'm going to say today I will actually highlight them as the results of those discussions and where we come seemingly to a consensus and others are my personal analysis and I'll try and highlight that. So I wanted to start by emphasizing background conditions and assumptions. Some things that I understand about the proposed project here. Importantly that it's going to measure a lot of environmental exposures. It's going to measure environmental exposures probably ultimately some people will have a lot of gene expression work, epigenetics done so there will be at least for some participants at some point almost something like total cellular characterization that will be associated with lots and lots of not just medical data but other data. So you will have people who have biological material in a repository along with more data than most people would have in their medical record. This means that inevitably you will find out medically, clinically important things about people as you go through this project. Next slide, please. I also want to think about this somewhat separating the issues in terms of building the resource that is collecting specimens and data initially and then follow-on studies. That would be studies done by people who are using the resource. And the reason to do that is because I think there might be in general, some differences in those two categories, differences that are ethically important and that have a pragmatic sort of impact on what you might do. And those differences involve the proximity of researchers to participants both in space and time, so people doing follow-on studies somebody might develop clinically relevant information but they might be crunching data five years after the material and the data were collected. The fact that it's five years later that you found something clinically relevant and that you may not have any interpersonal relationship, the follow-on researcher may never have met any of these participants, was not the person who collected biological specimens from any of them, that may influence the ethical obligations or the per missability even of reporting back any of this information. Follow-on studies may be more likely to generate information that's not yet validated and they may also be subject to the regulatory regime in slightly different ways which would affect how difficult it is to go back and report information. So I think we need to be -- we need to realize that there's a lot of complexity here because there's a whole set of issues around reporting back information when you're first building the resource and there is a separate set, somewhat separate set of issues about reporting back information from people who are doing follow-on studies. Next slide, please. So the first thing I want to say is Frances mentioned earlier this morning that there are lots of -- lots of people have thought about this issue, there are lots of papers, a number of different policy reports including one that secretary of advisory committee on genetics testing, I think, put out. A number of policy committees that have studied this and made recommendations. There's not much consensus actually and I think that some of the issues that this proposed project raises are issues that really haven't been addressed fully or not addressed at all by the proposals that are out there. I guess -- next slide, please. So there's the obvious spectrum of practices and proposals. One -- at one end of that is not returning any individualized result and I should say that right now I'm very much focusing on the return of individualized results to individual participants as opposed to aggregate results to community of people or even aggregate results returned to participants individually. I'm assuming that there will be some self-obligation to return to make publicly known and available the aggregate result of research done with such a project, so that's one of my background -- so we're really talking about individual results and in fact, the practice of most genetic studies up until now has been not to return individual results and that's partially because a lot of these studies we weren't yet collecting any information that had been validated that was viewed as clinically useful and the practice of not returning results was initiated in that context, but now things have changed. And so people's views about the per -- per missability is beginning to change and in this project you aren't just going to have genetic information. You may have lots of other clinically relevant information. That is the clinical utility of it might be very well known. But at that end of the spectrum don't return results, that's where a lot of IRBs have been, so a lot of IRBs are very reluctant to approve protocols where individual genetic results are going to be returned. Of course beyond that end of the spectrum you have everything from sort of very limited set of clinically relevant results. Might be returned to almost any clinically relevant information. One big battle that we're having is where does reproductive information fit in. Individuals may think that this is very -- it may be very important to people in their lives, their reproductive choices might be as important as their personal life or death medical decisions but a lot of the ethics guidelines that are out there to the extent that they discuss returning results, either don't treat reproductive information as the kind of results that are very important or that must be returned or they just don't talk about them separately at all. Next slide, please. So I thought I would take one moment to say there are good reasons not to return a result. If there's any anonanymorety -- that is unless first of all unless they have been analytically validated but also that we know something about the relationship of having a particular medical outcome and there's good reason. The balance of harm and benefit is likely to tilt towards not returning results when you don't really know the meaning of those results. The cost of sharing results when they're am by gutous when you don't know the -- a lot more difficulty in interpreting the results, so for -- so I think there are good reasons for not returning clinically validated results. Also by not returning results you're increasing opportunities to maintain confidentiality and privacy protections to the extent you return results you have to have linking information back to individuals and you have potentially a number of people getting in contact with them from research projects. And again, this issue of sort of the relationship between the researchers and the partis pants. In cases where there's no direct personal contact of any sort, the value of reciprocity of some kind of mutual obligation, mutual sharing is not -- tends not to be weighed as strongly by probably -- certainly by researchers, but I would suspect by participants as well. And secondly, the -- the information may be already outdated in some way, the person may have already discovered it. If you don't find it out until five years after they gave material and information, they may already have found this out, for instance. So some people would say that if it's not -- if it's distant in time and space, that there is less of an incentive ethically or otherwise to provide the information. And I think the final thing and this is important, is that not returning back results helps to maintain the kind of cognitive and legal distinction between research and the provision of medical care. And when we're -- what we've been talking about this morning I think in some ways for some of the researchers is going to very much blur that line between the provision of clinical care and the doing of research and sometimes that's an almost -- it creates conflicting obligations that are very, very hard to reconcile for the researcher him or herself and a lot of confusion for the participant about what it is that they are going to get out of this project. I think there are lots of ethically permissible possibilities in there, but we need to get really clear. You need to get really clear about where you see the lines drawn in terms of what the projects would provide to people and what it wouldn't and then be able to very clearly communicate them because -- be able to clearly communicate those boundaries because we already know that participants in research have a lot of confusion about the distinction between research and medicine. Next slide, please. So it's pretty clear to say that a project of this sort will almost certainly have to return some results. Then you get into the really interesting questions, which are which results? To whom? How? What is the process of returning them? And when would you do it? So next slide, please. I would reiterate that there's a pretty wide agreement among researchers, among ethicists, among all the policy recommendations that results shouldn't be returned unless there is some analytic and clinical validity. For sure analytic validity there would have to be at some point in returning of results has to go through an approved lab, although I am very aware that many researchers believe that their lab does a much better job than the approved labs to which they sometimes send their specimens but nonetheless, legally that would have to come in there somewhere. But clinical validity as well. Again, most -- I would say there's fairly wide agreement that we don't return results when we don't really know what they mean. There are lots of reasons in favor and I tend to think about this set of issues as there's going to be a very, very small do main of research results, if any, do main of research results where it is obligatory to return those results. There will be a much wider do main where it will be permissible to return those results, we have reasons in favor, perhaps reasons against, both ethical, pragmatic and so it's going to be a weighing and balancing. Right? But if you look at all the recommendations and the kinds of things we were coming to agreement on in this working group at Stanford would be when the results have very serious medical implications for the participant directly, when those implications are -- when there's an urgency about knowing these results, when the results would change, the medical management in some way. So there is certain debate. What if you find something very serious but there's nothing that can be done about it? Are those the kinds of results that ought to be reported back? I think there are reasons in favor, but there are more reasons in favor of reporting back results where it's both serious and you could do something about it. Right? Where there's a more robust relationship like a face to face relationship between the participant and the researcher and the value of reciprocity is greater, their expectations of what you will do on their behalf is greater and it won't come as a surprise if some complete stranger drops in on them and saying oh, by the way, I found this out about you and it's really important for your medical care. And then as a matter of respect for participants. There's not a lot of research on what participants want in terms of getting results back, but there are some surveys and a few interviews and mostly they show that participants have a fair amount -- a fairly high degree of interest in getting results back. And also in the few instances where results are at least genetic results are being given back, mostly we haven't seen real harm coming from that. Although anecdotely there are certainly anecdotes and individual instances, not so much from genetics but from other areas of medicine and clinical research where people have gotten back clinically relevant results and found it to be at least -- found it to be very burdensome and maybe something that they wished they hadn't learned. So participants are going to have a range of views about what results they might want back and a range of experiences if they do get results back and there's not a lot of data out there on 24 right now but I do think that the data we have suggests that many participants would like at least some results back. Next slide, please. All right. So going on, which results would we give back? There are a number of interesting questions that are raised. One of them is whether the nature of the research gives ethical or other kinds of reasons for returning back results. So for instance, does it matter whether you're doing a study do look for a particular gene environment interaction like you're doing a study looking at prostate cancer and you find something clinically relevant about prostate cancer that a person probably doesn't know? Or what if you're doing a study about prostate cancer and you find genetic information suggesting that the person is likely to have onning genic BRCA 1 mutation? When you're doing these big studies, there will be people who have a significant portion of their genome sequence and you will find something in their genome that is clinically relevant and it may not be anything that was the particular study of the research initially. So if you're going to report back results does it matter whether it was an incidental finding in the context of these very, very large studies? What does incidental even mean if you're doing a nonhypothesis driven research? In the working group, my -- my belief is based on recent phone calls that we've had that there is at least a category of research for which it wouldn't matter or a category of results that are seemingly so important for a person clinically that it wouldn't matter whether they were incidental findings or findings that were the direct focus of your research that they might need to be reported back. Does it matter that in these very large studies it's forseebl that you will find something or if this is something that nobody ever foresaw? Right? Those might be different categories to which you would attach different degrees of per misabilities or obligation to report. And also do researchers ever have a duty to look around for clinically relevant information? So if we've got sequence data that was just turned out by a machine, does somebody have an obligation to look at what your BRCA allele are and there wasn't agreement about that. In current, you know, the way we currently do research it wouldn't be hard to put a query into the computer to look for all of these things but you're going to find clin di different relevant thing tsd and we couldn't come to an agreement about whether or not there's a duty to go search for clinical information. My own personal feeling is that we ought not to put that on researchers. Also, is there a right not to know? So almost all of the ethics guidelines would say that there is a right not to know, but interestingly, many clinical researchers say huh-uh and I can tell you that in front of our IRB we get people who say I would not have someone in my study who said don't give me back clinically relevant information. People who are clinicians and who in the course of their research have contact with participants or are doing a clinical exam, their feeling is, if I find something incidental or something I was looking for that's clinically relevant, it's my obligation to tell this person. And partly that's -- they're in a context where their duties as a physician and their duties as a researcher are both coming to the fore. Where as many of the people doing sequencing or other kind of cellular analyses are not physicians, they're not having direct personal contact and they're feeling that I feel something in these data but I don't really relate them to a person. I don't have any connection to that person, diminishes their belief that they ought to report back clinically relevant results no matter what. Whether that relationship should make this much of a difference is a matter of debate. Some people think it should not. I think as a practical matter it does. All right. Next slide. so our working group is going to end up proposing three categories of results that would have different degrees of obligation or per missability with respect to reporting back and that's not so different from a couple of previously published papers. Other groups have come up with some similar kinds of recommendations, so category 1 would be results whether they're genetic or other kinds of results that you would be obliged to report back. And it wouldn't matter what the focus of the research was and it wouldn't matter who was doing the research whether they were doing follow-on research or what that these results wouldn't per xiphoas so important that you would report them back. And there was really as I said no agreement on whether there's an obligation to go searching for that kind of information but I think many people felt there was not. Category 2 which would be a broad category would be things that might be permissible to report back but it's discretionary. To the extent you're going to do it, we felt and many other groups have felt you have to plan for it up front, have it in the protocol, have the IRB see it. Have it in the consent form to delineate what they might get back, what kind of future contacts they might have from researchers if they choose to participate and so forth. And category 3, information that is not permissible to report back. Category 1 might only include really very, very few things. Next slide, please. All right. So we had the 3 categories and that addresses the question of what kind of information should you report back. And in category 1 are things that are so important to someone's health and their health care decision-making now that you would report them back. Everything else is either discretionary or impermissible to report. And the question is how? And the method would depend somewhat on the category, so we felt that for all categories, if it's going to be reported back has to be approved by an IRB, included in consent and has to be reported back by a person with relevant expertise. And that in a project like this could be quite complicated because different genes, different people will have different alleles that might be medically relevant. It won't just be one person or two or three or four people associated with the project who would have the expertise and that's just the genetics. What if you have some other findings? Think about it. What if you find that some group of people is having a very toxic exposure to some chemical in their neighborhood or in their work environment? You might find that in such a project where you're collecting a lot of environmental information. How would you report that back and to whom and would it be just to the participants? There are going to be a lot of issues there and you need people with relevant expertise to do it and figuring out who those people are when a lot of different kinds of expertise may be relevant is going to be difficult and, you know, we didn't go so far as to figure out the nitty-gritty details of this but one of the things it suggests is the more you want to report back, the more extensive it's going to be, the more personnel you would need dedicated to this process in one way or another, maybe not full-time. And of course for genetics has to at some point be evaluated in a lab. We didn't agree exactly on when and with what specimens so we actually came to agreement that there are a range of possibilities about when in the project it would go to an approved lab. Next slide, please. There's also the question of how. What kinds of contact? We figured for category 1, the initial contact might be by phone or letter. However it happened it ought to invite people to contact you and have a discussion about a clinically relevant finding and it ought to be formulated in such a way that they knew there was something serious. And that it had to be followed up. So if you make some initial contact and people don't call or write in or make any attempt to follow up and find out about the clinically relevant information, that there is a fairly strong obligation on the researchers to follow up, try a second contact, make sure they really got the letter or received the phone call and it was a person and not just a phone machine. Every effort must be made to have face to face delivery of the information when the discussion takes place. And that there's no obligation to provide follow-up medical services, but that at the -- at a minimum, should be able to provide referral information. Next slide, please.

Can we perhaps in thefection few minutes wrap up please?

Sure.

I guess on category 2 we thought there might be the need for something like a DSMB or a similar kind of committee to help researchers decide in that permissible category when at least some results were actually at the level of significance that they ought to be reported back.

What is a DSMB?

A data safety monitoring board. So -- yeah. I'm sorry. Next slide, please. There are also questions about when. Again, this comes back to, you know, what happens if you have data sitting around somewhere and then years later somebody finds out oh, that allele has some really medical significance attached to a particular allele. Do you have to go back and continue to review the data that you have to see how new information affects the significance of the existing data? There are lots of questions about that that we didn't come to agreement on, but I just am going to highlight them now to say they are actually important questions and you need to come to some agreement on them. Next slide, please. I'm going to skip that one and go to the very last slide, I think. This is not the last slide, but there was an agreement that you ought to give participants options and the options ought to include reporting back to the participant and/or reporting back to the doctor, primary care provider or somebody like that. They also ought to have the option of not getting information back. And although some clinicians didn't like that, at least our working group thought and most ethicists believe that there is something like a right not to know. With respect to families, there pretty strong agreement that there is no obligation to give this information to families, but that it ought to be spelled out for participants that this information is of -- is important to family members and that ought to be part of the discussion in the follow-up. Next slide, which I believe is the last -- yes. So I just wanted to sum up in my last slide that a lot of this is about what will be permissible rather than what will be obligatory so you're going to have tradeoffs because reporting back is going to add a lot of costs. The more you report back, the more cost it's going to add. And so there are tradeoffs between your desire to report back and to create benefit for people by doing that and the amount of data you can collect, the number of participants you can have in a study, etc. It also, the issues of reporting back intersect with questions about who you include. If you include people who are not in short or have very little access to medical care, does it ever provide a benefit? There's debate about that. Perhaps it could, for instance, you might end up creating more constituencies who are pushing for more things to be covered by medicaid or medicare, for instance. On the other hand, you might report back something of real clinical relevance to somebody when they couldn't do anything about it and they would view that maybe more as much more of a harm than a benefit. So -- and finally I would say also, this is where your consultations and interactions with communities, your community engagements could help formulate the project with respect to in that -- within those bounds of permissible reporting back, what kind of information might people most want under what conditions and things like that. It actually gives a lot of opportunity for ethics experimentation as well as scientific experimentation. And I will stop.

Thank you, Dr. Ossorio. Our final speaker for the day is Troy Duster. He's professor of sociology at NYU and also holds a position of chancellor's professor at the University of California Berkeley.

Well, first of all some truth in advertising. I do have a drinks with bioethicists and I've been on committees with them, but I'm not a bioethicist. I'm a sociologist. I sat for three years on the LC working group and just to give you an example of the kind of issues which occur and recur, I would say over those three years the most con ten somehows topic that we dealt with was access to stored tissue samples. We had disagreements about many issues but we often came to some kind of consensus. On access to stored samples we had no capacity to come to consensus. Sews logically, I put that other hat on right away and what I was seeing was interest groups people in the biological field or pharmaceuticals anthropologists had different angles of vision on this topics about access to stored samples and buy ethicists took the extreme position, no ak shes unless there's consent before. The people in the research committee thought this was crazy because we're talking about delivering health to people so how could you be against looking at a data set that if you really examined it with some care you could actually bring health to people. So that's by way of prologue. Prologue is that I'm a sociologist by training. I'm not a bioethicist and I'm going to step back from the project and make some rather broad statements and then become more specific in the short time I have. I can collapse this presentation or expand it based upon the time allotted. I think I'll collapse it. Okay. I found it useful to think about this kind of a project using a metaphor of the Chinese game of go. At the very beginning of the game, infinite number of possible moves, but when you make the first two or three moves in the game, it limits almost dramatically what's possible. Now, the same is true for a large research project. When you first start off, you've got a whole field of possible categories of inquiry, but the -- when you begin to use in that first cut what the categories are, like in the game of go, you limit what's possible from there on. Now let me start with a question that was asked of me, what might be one of the major concerns. Let's take the topic of does the research represent the population. Depending upon how a society is organized, the very categories of who is represented is vital to stage 1 of the study. That's -- let's take a case where you have a society that's divided into Hindus, Muslims and Christians. Those are the major dividing lines between the categories of people. Access to resources, who has power and so on. In that situation you would say we have to use that as the -- that's plain representation. Well, let's be specific. Let's go to India. Now Lynn dos have the most power there. There are Muslims and there are Christians and so one looks at the population and one would raise the question, well, what would be the representation of this huge amount of Hindus that makes the most sense? Cast? 1949 the castE system officially ended but the last 50 years those of us who know a little bit about India know that it has residuals, the castE system isn't over. So when you do a large population study of India, and you want to talk about representativeness of the population, would you use braman, sue tra, would you use those categories and if you did, is there not some danger that you'd find little frequencies in those categories which coincided with those castE system categories? Whoa! Now, the question comes up right away, is the research reassigned with hexnomic system that you thought you destroyed in 1949? And people will raise the question, are you going to use race? Coming back home to the topic here for a moment. As a hexnomic system when in fact we know race as a cot goir has all kind of fluidity. We know that. So once you use the notion of race then you're going to use genes, like the bra mans of India, are we not as researchers in danger of providing a kind of reethic Asian of the economic system. So that's the concern. Surely after 3,000 years of a cast system where you only could marry inside of a particular cast, you'd find a little frequency variations which were pretty common in certain groups and not in others. But when you interpreted those results, would you conclude that this was about genetics or rules of monogamy heterogamy, anthropological rules, because the rules of engagement around sex in India are not so much about biology, but about those cultural rules. The cultural rules produce frequencies in casts A, B, and C which turn out to maybe have outcomes for health. I'm going back and forth between India and our -- for obvious reasons we are clear when it comes to India. But this might be problematic. We get a little bit foggy in our own country about this taxonomic system. I'll say how this might be addressed in relevance to the U.S. will become obvious. What does it mean to have a population study that's representative in the U.S.? We obviously want white and blacks, we want Asians, we care less about Christians, Jews Muslims and Hindus. Why? Because it's not part of the stratification system in our own conception of what's deeply embedded in the structure. That's not about biology, that's about social categories. We can say, let's have a study which represents Christians, Muslims, Jews, we'd be laughed off the block here. Not in other places. One half of all cancers occur among people living in industrialized parts of the world. One-half of all cancers. This group constitutes one-fifth of the world's population. World health organization collected data on cancer rates from 70 countries. And here's a direct quote from the WHO's study. 80% of all cancers are attributable to environmental influences. So step back for a moment. Look at those two figures. Half of all cancers that we know about occurring in one-fifth of the world's population, mainly in the industrialized world. Now migrant studies are among the most powerfully persuasive ones. Jewish women, who migrate from north Africa where breast cancer is rare to Israel, the nation with high incidents, initially the breast cancer risk is one-half of that of the Israeli counter parts. African born and Israeli born Jews show identical cancer rates. One of the most compelling studies of cancer ever conducted researchers found an association which was significant between the use of agricultural chemicals and cancer and mortality in 1,497 rural communities. Okay. A study that represents the population. Could we not have a study of -- which represents those who live around toxic waste dumps and those who don't? A study that looks at those who are handling chemicals and those who don't? That is, it may not be that race or other kinds of social taxonomic differentiations is -- to bear, it may be what these data are showing is that the representativeness of the population that's relevant to a health study on cancer could be what someone said earlier in the earlier session maybe has nothing to do with race unless race puts you around a toxic waste dump, the work of Julie in New York City. What she found was that there were four important waste sites and it turns out that the African American Latin population was living much more around those waste sites than were upper middle class white people. No big surprise but it does have some bearing on how you would design a study. If you're looking about genes and environment, that's the way this is being framed, it sounds kind of good, and it sounds like we're going to look at genes and environment, but this table is not set evenly. The ones doing the research on the genetics of these kinds of problems whether it's hyper tension or cancer or, you name it, it tends to be the notion that they're doing the really hard science. They're doing the closeup impir Cal work and those doing work around toxic waste dumps that's kind of epideem logical, soft humanistic, not very focused, not hard data and yet the data that would seem to me to be the most compelling, the ones that I just gave you, where is the cancer rate in this country? It's around these various sites. So my concern, if you haven't quite figured this out, is that the framing of the study has genes and environment assuming that there's already some kind of interaction here that's more or less equal. In fact, and I think empirically one can say we've got good data that the environment is going to play a role in many of these kinds of diseases, that genes will play some role but that when we put it together, it will sound like the real science is on the genetics side. What's the bearing of this? Well, I'll give you an example. I told you I could expand or collapse. I'm going to collapse here in a few minutes and open this up for a conversation. The example is one that most of you are already familiar with, the fact that we now have a particular market for hyper tension, the drug for African Americans. I'm not going to belabor the point. It's just going to make the point in the following way. It's about how one thinks about the problem. If you -- if you find that a population of African Americans or any ethnic group has a higher rate of something and then you find that there's some kind of a shift or a shift in the body of those people you say well it must be about their ethnic or racial category. Well, the work of some epidemiologists suggests that it does depend on whether or not you can do migrant or cross cultural studies so hyper tension in the black community is high in this country but if you go across and look at the work of Richard Cooper looking at eight different countries three different continents looking at hyper tension among blacks and whites of these different countries he finds that the differences certainly go aaway, certainly not clear that it's racial. In this country, looking at a national study, seeing high rates of hyper tension among black people we might say little frequencies we may say it's more common over here and we might make this huge mistake inside our own boundaries. If we look at the Caribbean as Cooper has done and we show that these differences begin to shift around, then the whole enterprise looks very, very different. Prostate cancer, I'm in with that. The black prostate cancer rate in this country is double that of the white prostate cancer rate. Let's say you do a national study and you find more data indicating that's the case. And you might find that using computer technology that you would see little frequencies in the black population that were different than the white population. You might find that. It wouldn't surprise me at all. However, to leap to the conclusion that prostate cancer rates are a function of these differences in the genetic structure is a huge leap unless you have functional genomics. We're some part away from that. So the question is going to be what do you make of this data? Because back to the game of go. If at stage 1 you've decided that the taxonomic system that you're going to deploy is using race, then how are these data are reported out as you just heard becomes vital. As a social scientist, what deeply concerns me is that the table is set so that the genetic interpretation is more powerful when the data set might indicate if you went cross cultural you might have a different conclusion. So my advice is, expand this always to talk about migrant studies and cross cultural and include that in in kind of attempt to talk about a national study. Otherwise you've set in state and the motion at stage 1 in the game of go and you'll see where you'll wind up with the earth kags of race.

Thank you, Dr. Duster and thank all three of you. We'll now open it up to a round table discussion and I'm going to turn it over to Ellen Fox who's going to be leading this part of the session.

Thank you. I'd like to add my thanks to the three panelists. You've certainly given us a lot to think about and talk about so let's begin the conversation. Yes, Kevin?

Just to throw something out to you all three. Thank you, too, for your comments. There we go. I'd like to throw something out to all three. Thank you very much for your presentations, but I'd like to start with professor Duster first of all because it's so rare that somebody uses go as a metaphor. So I'd like to build on that a little bit and draw it out just a little further because even after you have chosen the first few moves that you're going to make to sort of set the pattern that you want to pursue, then comes in this constant tension between continuing to make the bold, broad move or having to consolidate at some point to either attack or defend a smaller territory. And I'm wondering, would that decision, though not normally done in the game, be better made in this case by committee or say, community than by an individual? Or say a small group? And so to use what we've heard before, if we were to follow a sort of community engagement model as a first step, take the issues that you have raised, all of you, and put it in that particular context, what would you see would be the advantages or disadvantages to addressing those issues within that community engagement model?

Well, as -- as you heard in the previous session, community engagement is a very foggy and vague idea, what's the relevant community for African Americans so what would be the community and engagement for prostate cancer. Well we're going to talk about black males age 40 to 70. That's going to be the relevant community. I think it is possible for some of these kinds of things to be understood situationally and impir cli. I don't think you can say okay, we're going to have the community, to be the community. To determine a kind of research. That's my first answer to the question. I don't think community engagement is the answer. Is the beginning of a probe, a wedge, an entry into the relevance of the research and then the question is, well, is the community quote, sufficiently informed to pursue? Now, this is an old horse. People will say things like does the community know enough, the community of 40 to 70-year-old black males to know of prostate cancer. Huge variation. One of the things I'm drawing on my experience of the LC working group, we had this discussion earlier in the session. One version was you educate people -- one version was because they don't know genetics and I thought Joan Scott was quite good good about that. You educate people about the issues. You don't teach them about molecular genetics you teach them about the process of genetics. So what would you begin to teach them about prostate cancer. The possible migratory foe churs the way in which the environment is playing a huge role. Nutrition and diet is playing a huge role. You're going to bring the community into kind of a fog and the scientists could say, well, we have good data indicating that prostate cancer has a frequency X, Y and Z and what's the community going to say? I think the frame here is vital and I'm not sure a community engagement is going to get us very far. But I'll leave it to Laura and hank if they want to --

I'm not sure this is community engagement exactly that I'm going to respond to your question with. And the only times I've tried to play go, the computer has crushed me on the simplest setting. But I do think that there is a role in the creation of appropriate informed consent protocols and methods for preliminary discussions with communities and other research subjects, other potential research participants to try to figure out, try to make sure that they understand the full meaning of what you're saying and part of that is in a sense community consultation or community discussion to make sure that, you know, when you say these could be used by other researchers that they understand how far that means or if you say you won't have any control over subsequent uses that they understand with some specific examples of what kinds of subsequent uses those might be. So I guess I see it both of the possibility for discussing some of these consent issues with communities, but also using that as a way to hone your consent process to make sure subsequently when you put the consent process into play that -- that people undergoing a truly as best as you can guarantee, which of course is certainly less than 100% but truly understand what you're telling them.

Just a quick response. It occurs to me that maybe a better way of thinking about this is community engagement, maybe the community engagement that's relevant are those that live around toxic waste dumps, not blacks.

That -- that is what I was going to say, actually, that I think that Troy's comment went to the question of exactly who are you going to engage, right, and I was a little concerned when I saw the kind of background paper that people were conceptualizing this project in kind of a -- an old model. And not thinking about the possibilities of gathering a lot of environmental information, gathering a lot of exposure information and how that actually cross cuts a lot of these kind of simple minded notions of race and genetic causation of disease. So I agree with Troy, that when you think about whom to engage, just thinking about -- I wouldn't -- I think it would be a failure if the engagements were just sort of done along the lines of racial -- racially organized communities.

Next I have jewel owe, Nguyen, jo testify and Jim.

I'd like to thank the panel for a really wonderful discussion and I have two considerations that I'd like to bring particularly to -- it's usually that and I really appreciate all the comments about how we contain -- there may be many compounding factors that may not lead to a clear association between a specific genetic allele and a disease, but let's say that association is found. Then how do you handle this in the process of informing people and one is that most likely, almost certainly what you're going to find is a percentage of research attributed to that allele and then how you tell somebody that they have a percentage risk for something? For example, if they have a 90% risk of having a fatal disease for which there is a cure for treatment, there's not much to think about. But what about if they have a 50% risk for which there is no clear cut treatment or that they have a 10% risk or given the enormousness of the study you could have 1% or you know, half percent so where do you go around telling people you have a 1% risk of having this, what does it mean? And where is the cutoff and who determines that cutoff? Over what time span? So that's kind of one line of questions. And the other is that I was in a very thought-provoking -- on genetics exactly your area. So the thing that I don't think it's being deflt with very much here is the genetic by proxy. So it's basically obtaining genetic information about somebody by not testing that person but testing a relative. So a match between the DNA found in one of his victims and the DNA of his daughter who did not give consent for the DNA testing which led to a criminal type of investigation but her DNA happened to be in a database, so what about this issue applies to the -- it should be very farfetched and removed but if a member of the protocol is missing and you have a body found, do you use the DNA from the project to identify that person or what if it's a terrorist attack on a building and you have a charred body. And then if you check, let's say and it's not the person but there's a match and the search continues and found that the person's DNA is actually in a crime scene so you know the yiem was committed by a sibling of that person and where do you start? It sounds almost cruel, if a member of the study goes missing, but if you don't do it I think it's problem malmatic and then if you do it, and if something, you know, usually something that seems unpredictable do happen and if something like this happens can put the credibility of the study at large at risk so how can we address these two issues?

Wow. Okay. The issue of finding alleles for which there's a fairly low -- it looks valid and you have the statistics to say there is a 5% probabilities that if you have this allele that you'll develop X outcome, first of all, that would definitely not fall into the category of information that -- probably that anybody would think is obligatory to report that back. So you would be in a range of per missability and perhaps fairly low if you're talking about a range that is trying to be attentive to the seriousness of the condition, the importance of this information, managing somebody's medical care, knowing that you have an allele that puts you at just a slightly increased risk for a common complex disease probably is not going to be the kind of thing that you put very high on your priority list for reporting back information. So one of the things that I'm assuming is that -- and some people have said well, you should report back anything that's clinically rel vanlt. I think it would be incredibly difficult to do a study where you involve 500,000 or a million people and have that kind of a regime where you're reporting back anything that's medically relevant. The economic burden of doing that would be so high, just for one thing. So number one, I think that there's a range of per missability and some of these things that have only a slight predictive value would be the things that you'd put in the category of not reporting back. How you make that decision could -- you know, there are a lot of different ways to make it. One of my suggestions is that that is the kind of decision that you might make at least in part in some kind of community engagement because it might be that -- and I think for instance, the reproductive things that sort of have carrier status, I suspect that if we did engagements we would find out that for a lot of people that is very important information and if we can give it to them they would like to get it from us. And if we say there's going to be a limited set of things that we'll report back and we have some choices to make, participants can help us make those choices. Also, we can give participants a range of choices, some people won't want any of it back and certainly wouldn't want back sort of things that don't really affect clinical management or something like that. But I agree, there are lots of choices like that that will have to be made. Also something I didn't talk about is that there will still be unexpected things that come up and for instance, if you're a researcher doing follow-on research and you don't have the linking information which will probably apply to a lot of people and you find something that it turns out is very significant and wasn't really anticipated by you when you started the project and you didn't go back and get additional informed consent and now you feel, oh, gosh, this probably really should -- it does fall into that category of things that we said should be reported back, those are the unusual situations that should go back to the IRB to develop a process for contacting a person in doing that. So there will always be some adjustments that you have to make on the fly. And you know, the second question of the nonmedical uses of this kind of a data base, I mean, part of this has to do with the data access policy and what kind of policy you have upfront, the idea that, you know, you would give out data to parties who have IRB approval might rule out, you know, on the face would rule out a lot of these nonmedical uses or law enforcement uses, but, you know, if they wanted to subpoena or they wanted to get a court order to open up your data base or get access to your data in some cases they certainly might be able to do it. I don't know to what extent their certificate of confidentiality would really work in this kind of a case, but it might. And you know, what I wanted to say though was what Kathleen said to you early on was very true. In those communities that are -- and you know this. The communities that are disproportionately targeted in stops and arrests by the police, there is an incredible concern about law enforcement having access to these kinds of things and I both think and I -- and I think Troy as well had been working at various times in -- as part of a project at the Kennedy school where they're looking at law enforcement uses of genetics and the things that the FBI wants to do with genetic testing, you know, they're way out there. Woi would love to be able to get all kinds of genetic information from people. And you know, it's interesting that there are provisions in the law to use law enforcement databases to do identifications in situations like another terrorist attack, right? Some state laws would perhaps protect a research database against being used for other purposes in many cases, but not all state laws would. So there certainly is a legal area where it would have to be a policy, some kind of policy of the project and of the NIH or of HHS that would set those limits.

That would have to be set up priorly and also to set in our engagement project in Los Angeles in Hispanic community, the first issue raised was is this going to be used in law enforcement. So we completely don't know who it is that issue is not applicable but it is here. And the last comment is that if you really have this possibility that the sample could be court ordered which was the case in the example that I gave, should you put that in the consent form up front, that you know, it's anonymous but these records could be obtained by court order and we cannot stop this from happening.

You have to, I think. You've got to be honest. And there's no way, even with a certificate of confidentiality that you can necessarily guarantee that a court order won't be issued, the specific example that I think is most likely to breach a certificate of confidentiality is when a criminal defendant can make an argument that this information is crucial to his defense and he has a constitutional right to it and the constitution trumps a mere statute or a regulation. So if, for example, a criminal defendant has -- there's other DNA found at the crime scene and he can show that it matches an anonymous sequence in this database, I think he has a very good argument that he has the right to get that identity whether or not it has a certificate of confidentiality. In those cases you've got to tell people up front we cannot provide you complete confidentiality and here are some of the ways in which that confidentiality might be breached beyond our control.

I have six people on my lifth list. Your next one.

I'd like to thank the speakers this afternoon. It may be the lateness of the hour or sort of my own fog here but I'm looking a little bit for more clarity around a couple of areas and I think Dr. Duster sort of challenged my mind to think harder than usual around two areas. The first area is around the presentiveness and how you cut such a study by religion group, ethnicity, et cetera and the other area is genes and environment and I'd like to throw back these things at you so it can help me with more clarity. But as a signment to the public health professions I spend all my time collecting data on populations from a public health perspective and ideally if you want a population temperature l that represents the whole U.S. population and assume we have 300 million people and you want a 1 million person sample you have a line listing and you pick every person, every 300th person and you will have a totally representative sample of the U.S. population completely random. And then you can post hock study which religion, which group live in toxic dump sites whether they live in state X, Y or Z. That's sort of the completely random approach to public health research that we've used. Unfortunately because minority groups complete random savrp l doesn't do us a service so we've done a lot of tricks on public health to do what we call the strat fi the samples. We go enrich the sampling scheme with sort of the minority groups but there is no limit to how much you can do that cutting. Right now we do it by race and ethnicity because of the health disparities around that area. But when you start doing it by state, by county, you have 50 states, 3,000 counties, rural versus urban. ZIP codes, toxic dump sites, et cetera, migrant versus nonmigrant, it gets more difficult. The other issue is around genes and environment. I think it should be obvious to everyone that a study like this, if it was only based on genes we -- it's not worth doing, because using appropriately collected case control studies, you can look at the genetic contributions of all diseases because genetic variants don't change and you measure them once and that's it and you don't need to do a cold study and I would say the major impo fews for such a resource or a national project would be to look at genes and the environment. We all know the complexity of measuring the environment, although we're making major progress in measuring toxic chemicals in the serum and the blood and the urine and all of these things and some of it is -- is tough, I mean, like measuring social environment, so -- and you know, this reminded me, when you -- at some point you said that 80% of cancer is environmental. No me it doesn't imply that the other 20% is genetic because one famous epidemiologist many years said we can easily show that 100% of disease is environmental and the same 100% is due to environment as well. So if it is anything to be gained by a resource like this, you will have to get that sort of the balanced view of measuring genes and measuring the environment. And doing the appropriate scamp ling scheme that would allow us to get the most pragmatic sample of the U.S. population to allow generalized ability of results. So given what I just said maybe you can repackage what you said earlier and help me see how what you said can change my way of thinking, because I think there are some gems there that I'd like to get at the table and anybody else who wants to respond is welcome.

No I don't think I have any gems. I think the message that I want to deliver is that this early stage framing of the project is so vital that we need around the table some understanding not just of the genes' environment, but how the genes' environment interaction is going to be reported out. How the data are going to be collected. And that's -- that can't be done by a group like this. That's simply a cautionary tale. And what I was suggesting is one way to think about it is the kind of work that Cooper does. We're talking about race and genetics, that's -- boy, that's already volatile. So let's talk about race in four or five different countries and see whether or not the rate of hyper tension or prostate cancer or breast cancer among groups A, B and C changes. That's a different kind of study than a national study. So the national study in some ways, I think, reduces your capacity to tease out the genes environment issue. I mean, that's an old argument and we shouldn't go down that road. You know, one should never say genes and environment. We're always going to parcel them out.

You know, when I try to think about this and in great detail like what would be the best sampling strategy I just get myself really confused. And I think part of it is that those questions would be easier to answer if there was some particular medical focus so that understanding how to do the stratification might -- it might matter whether you want to first look more at cancers or first look more at heart disease that might actually change the optimal way to do the stratification and I -- you know, I'm now way outside of my area of expertise, but I know that in discussions with NCI a few years back, one of the issues that came up was that people, you know, different collections of tissues and information are better suited to answering particular questions and so that -- there are reasons and in that case they were talking about there are reasons to go ahead and do new large studies, right, make new large collections. And you know, I mean, again, there are some choices to be made about how much in resource is going to be very broadly applicable and how much it might, if you focused towards a particular set of conditions that might influence the stratification scheme that you would use. And I also think, you know, we had some discussions this morning about interdisciplinary work and stuff like that. In my own sort of discussions with people about how to develop a project that could really measure interaction better, I'm constantly struck by the fact that there are, for instance, out there data sets that are lo*ng Tuesdayal that go back decades about air quality and certain pollutants in the air that go across the United States, ZIP code by ZIP code that could be married to medical information and genetic data. There actually are a lot of sort of environmental data sets already out there that it's worth trying to figure out what they are and how they've been collected because that might actually, if we really want to be serious about collecting environmental information, that might help guide some kinds of -- of sampling schemes.

Yeah, this is a great panel. I've learned a lot. One of the the things that's worthwhile being reminded of as a geneticist is that it is definitely true that most of the mallties are more environmental than they were genetic and I think if we are going to look at genetic and environment interactions we have to be as diligent in our methods for looking at environmental influences as we are about genetics. My -- my question is -- is for professor Greely. I think you -- you pointed out something really important which is that truly informed consent in this situation are impossible. In fact, there are those that would argue that truly informed consent is really almost neither in a clinical situation and that what makes the interaction work say in a clinical situation or perhaps in a more abstract situation is one of trust. That -- that if there is trust between the practitioner and the patient or the researcher and the participant, then those issues are much easier to -- to get around. And I think that underscores everything we've been talking about about openness and -- and having some degree of trust. My question for you is if -- it seemed like you were talking mostly in the issue of opting out, you know, what kind of control a participant has. In trying to decide those things up front, isn't there a huge role, if you can maintain contact, which you would have to do anyway, if you can maintain contact, if you can continue to inform participants in aggregate about the research projects that are going on, do you think that it's a viable kind of solution to much of that problem to allow people to give very general consent initially, which I think we all agree at some level is necessary for such studies, but then to -- to opt out if they see that, okay, there's a -- there's a project plan that raises problems in my mind, etc. Would that be a way of addressing?

It would be a way and it would be a way that's better than the current system. I don't think it would be the way I would most recommend. And first, I do think we should talk about this initial -- initial interaction of the he search participant as more -- in this context as more permission than consent. And it's useful to use a different word, to separate it entirely from the concept of informed consent which though it can never be done perfectly can almost always be done better than it can be in the context of one of these multiuse multidecadeL resources. The idea of maintaining communication is I think an excellent one and making and trying to inform the subjects, the partis pants of what things might be done with their DNA and their data is a useful one. And I think that will help you with sort of intermediate ones, intermediate issues where, you know, you wouldn't really think that anybody's going to be all that concerned about it, but it turns out you've got four research participants who really are quite troubled by research into pancreoya tie tis and you had no reason to suspect that was the case but by golly they are and they read it in the newsletter and they objected and the newsletter told them if you object to any of this please let us know, et cetera, etc. If you get into ones that are clearly more controversial where people are more likely to object, the difficulties of maintaining real contact with people are so great. You know, recontacting people six months later, you lose a large chunk of people. A year later you lose a bigger chunk of people and then -- and here I'm speaking from anecdotal personal and empirical experience. The odds of any piece of mail getting into the trash can without getting read are fairly high in most households I think. So if it's something that you've got significant to believe a significant church of your population might be concerned about, I don't think the information plus opt out is sufficient. Because some of the people won't get the information or won't read it, won't realize it, won'ts take the opportunity to opt out and if you later tell them, hey, we told you about it, you had an opportunity, they're still going to feel misused.

I think we have time for the last three I have on my list. Cindy?

I just think I would like to make one more point for clarification for lay people like myself. And it's directed to Dr. Duster. Am I correct in assuming that the dangers that you are speaking of are not so much in the fact of collecting data and including representative sample of individuals throughout the country, I mean, we obvious -- I mean, we always hear in our meetings that it's important to include women, it's important to include different racial groups and have a good mix because it does nobody any good if we just have, you know, a bunch of 20 to 40-year-old white males, what good is that. You know, we have to have everybody represented, but the real danger is really more in the interpretation of the data once it's been collected and the types of studies that are embarked upon using that data? Because I don't know that just having a lot of different people from urban areas and rural areas and different racial groups in and of itself is problematic. It's more what people do with it and the jump -- the jump to conclusion type of results. Am I correct in assuming that or are you saying that at the very beginning --

I think both things are true. How it's reported out is vitally important. How one interprets these things on prostate cancer and race, that's -- that's the reporting out problem. But having shaped the study and framed it in terms of these categories, is itself the problem of go. That once you separate people based upon race and come at them with the different analytic frequency patterns, it's essential to believe that those frequency patterns are within that group whether they are or not. One could say that empirically that would be sorted out. Over the next 30, 40 years that will be found out. But there tends to be a reporting out which says, let's take the example I used earlier. Blacks actually may have a different kind of frequency than whites who have prostate cancer, but we don't know if it's functional outcome. We just know that that's the pattern. In the interim, the reporting out it's going to sound like, must be genetic.

But isn't it more in the prostate cancer study or the person who's trying to reach those conclusions as opposed to just if facts of getting people to participate in the large population studies?

Well, if we leave and go to the cast system I think it becomes clear. Right? We say, why would you think that people from different casts would have different genetic makeups? Well, because they marry each other over 3,000 years. Right? That's why you might think that. So would you think that therefore had an impact on their prostate cancer rate? That is having to collect data by cast, you've already prefigured the capacity to report out certain things. That's why the two are related. It's not just collecting data. It's collecting data by certain social categories and society is being stratified. It's inevitable that it's going to reflect that as well. So the genetic interpretation is going to be genetic stratification interpretation.

But is there something wrong inherently, are you saying, with including all of these different groups and factors for example race, gender, ethnicity, all of those things? To me it just seems that the danger is in what you do with that and the conclusions you reach.

I think that's right. I agree with you completely. It's in the conclusions and the reporting out. What I was pointing out was something at the very outset of the study which is why I went with the cast system to make the case. It becomes clear in the cast system that there's a rel danger. If you begin to the genetic studies in that system people would say we're recreating the system we thought we got rid of in 1949. And as you give reality to lilic frequencies, there's going to be certain patterns there. But what are you going to do with it in terms of health concerns?

If I could add a little bit to that. I think part of the problem -- the -- one thing that needs to be really clear about why -- what your notion of representation is and why it's important. And I frankly think that part of the reason is important to have broad representation with respect to race and generaled r and so forth is not necessarily to achieve a particular scientific goal, but because this is a huge project potentially in which millions and millions and millions of federal dollars will be spent and those categories are politically important and there are disparities of all kinds including health disparities that map on to those categories and that participation is a political way of saying to people, you are important, you matter, your needs matter, and it might perfectly well be that if you did a study with only -- say only white people looking at the ones that live right near toxic waste dumps and the ones that lived out in pristine wherever you might find a gene environment interaction that's absolutely generalizable to anybody that has a specific set of alleles and a specific set of exposures over their lifetime. It might be a very important one. Even if that were true, I still think it's very important to have representation in the political sense. Right? And then there are also scientific reasons to have different people with different exposures to -- and different life experiences and of -- sort of the greatest amount of genetic variation that you can. And to the extent that you're using things like race and ethnicity to try and expand the amount of variations that you've got in there to study, you know, there's a scientific justification for that. But part of what happens is that we sort of collapse every reason for inclusion into some kind of notion that's very deep in our culture that, you know, races are genetically distinct groups and when you see differences between races and ethnic groups that in some cases there's a genetic cause and we don't get much beyond that. I think this project has the opportunity or some project of this sort has the opportunity to break down some of these kind of simple minded ideas, but you know, part of that is thinking what -- what kinds of data would you collect about people, not just are we going to go rural, urban, whatever, but what other kinds of information are you going to collect about them that will help you understand the gene environment interaction so that you're not just left at the end with analyzing your data, based on race and gender.

We have only three minutes left in our scheduled session so if I can ask folks to keep your questions and answers brief.

I realize that we're going to be having a general discussion about this and my question is more relevant to the members than the panel, so I'll hold.

Okay.

Office for human research protections. Some of the comments I've heard seem to presume that the research studies that are going to use this data base that's going to be created are all going to have IRB review and I presume that's on the assumption that the regulations are going to require such review and I think it's important to note that some guidance has come out of our office involving use of coded private information or coded biologic specimens actually can be done in a way in which recipients can't ready ascertain the identity of the individual as to whom that data and specimens pertain and therefore under the regulations that research doesn't involve human subjects and therefore that research doesn't need further IRB review or any more informed consent process or exchange of information with the subjects. And so I just think that group needs to be clear about that. It doesn't mean you couldn't impose some ethical review or some other review for any uses of it and that's probably a reasonable ethical consideration but it may not be based upon a regulatory requirement and I just wondered if the group had any reaction to our guidance on this project and if they find it problematic given the type of research being proposed.

I would hope that such a resource would include as a condition, Katrina chul or otherwise for use of its data IRB or IRB like review. I would also hope that IRBs, the recognizing that it might not technically be human research and might not technically be something they'd be required to review would be required to review it. The broader question about your guidance I do find is a much longer story than we have time for. But I do find it somewhat problematic particularly because of the limitations on confidentiality and anonymity that I talked about earlier.

Thanks to all the panelists and that ends our round table discussion.

Thank you, Ellen, and thank you all three of the panelists and by extension, of the whole day's worth of speakers. It's Ben educational for all of us and we appreciate your contributions and your being here. So we now have I guess 45 minutes for the committee to have a discussion to address next steps to digest what we've heard today, hopefully distill that down into what we've learned today and how that impacts the kind of issues we would like to tackle in a report which would be transmitted eventually to the secretary. So I have some thoughts but I think I'll hold those for the time being and simply ask -- see if other committee members want to start off a conversation. Debra?

I'll start off being a little controversial. In listening to the last -- all the sessions we've had on large population studies, it seems to me that this project is much bigger than NHGRI or the NIH, that right now it's coming from a science, everyone a genetics perspective and could get into a lot of trouble and I'm concerned that NHGRA is not engaging the expertise or resources of the other agencies CDCA, EPA, other agencies that I don't even know the initials of who may be relevant to this project. And I think that these other agencies have a lot to contribute if not being essential to the success of the project. So I -- I was wondering if the other members of SACGHS were feeling the same way and maybe what we need to request is first something from the agencies as a group to come to us with a plan of how to better work together rather than this having to be a solely NHGRI driven initiative.

Just to correct Debra and I'm sure Frances will -- will add to this. There have been several contributions from members of CDC for this that -- that report that you see. I -- I think the way I look at this is that -- that right now if we think about this as a research study that's going to involve 500,000 people to be collected on genes and environmental factors and be followed up over time, that's sort of one issue and I think there has been a lot of thoughtful xhebts and discussion that the group that Frances assembled which involves multiple agency representatives as well as a scientific community at large, I think the implementation of where we want to go next, if we think of it as a national resource, then I think the advice that this group can give to the department is about a study that's in the context of the general translation of genome science into population benefits because this is the first time that we are embarking on a study that's beyond the test tube, beyond gene sequencing and trying to figure out what genes mean for the health of people who live in Michigan or Hawaii or wherever and then figure out how to use that information for prevention and treatment and medicine in general, so I think as you all deliberate in your discussion here, think about the context. Think about not only a study in a particular time, but -- but as part of an initiative that the various HHS agencies can rally around because we all have slightly different missions but we're all -- other than NIH we're all in one shape or form or some it ration into the process of translation -- translating the basic science that NIH sponsors and produces into population health benefits so we've heard for example throughout the day a lot of issues around the community engagement, the education of the public, the public policy issues, the -- the LCs and the larger context, the -- the involvement of state health department and the convening power of public health because at the end of the day, this is a public health research endeavor because it -- it purports to generalize the finding of series of studies under a big banner into what it means to the health of communities. I mean, the whole human genome project was done with the blood of one or two people or under ten. I mean, here we're talking about basically a lot of people coming together so there are all these issues that will have to be weighed in and discussed by the committee as you produce your final report. As you said earlier on the study is not -- I mean, the report is not going to reflect the scientific minute of the study but the broad policy and public implication of a study like this in the context of a -- of the current health system as we know it today. And one thing that I'm sure the committee does not want to end up with is by widening the gap between the research enterprise and genomics and the application enterprise and genomics because right now the gap is large in the sense that there is a lot of public and private resources going to discovering genes, both from NIH and the private sector but very little in the context of translation and if you want to make a real impact, I think that view is -- should be a little bit more balanced than providing advice on one study in one given point in time.

I'm going to go to Frances just because it specifically deals with NIH. So --

Yeah, briefly I'd like to reassure Debra that there is no expectation at all that if a project of this sort were ever to actually get off the ground that it would be run by NHGRI. This was sort of a difficult circumstance this morning. I found myself talking too much and defending the project in part because we didn't have in the room a lot of the people that were involved in that year long study that had generated a lot of the study design considerations, most of whom were actually not from the government. Scientists of various expertise in the extramural community. NHGRI's role has been sort of to be a convener to try and get people to think about this in the sients tifk opportunity kinds of questions that come out of it but if this were to get underway it would no*efr succeed without the full participation and a partnership of many of the government agencies that are represented around this table and some that are not like EPA, for instance. And further more, I think need to be cig partnership explored with the private sector because it's the kind of data that they'll be interested in and might be able to cor part of the cost. Would it be at NIH, would it be somewhere else, if it was at NIH would it be at one of the institutes that are being used to doing the large studies? I have no idea. We're nowhere near beginning to think about those issues.

Kevin?

Thank Frances for this. You are absolutely right. I think if there's one thing that we heard that was at least clear to me today, if this goes anywhere, it has to have the public engagement. It has no traction without the public. It is a public health issue. The public has to be on board. I mean, we can leave it up to somebody else, we can leave it up to the secretary to bring in more experts to decide exactly how to go about that, but I think if there's anything we suggestion along with this, the one thing we did clearly not only does the public have to be engaged, it to be ingauged immediately and be involved all the way through. One of the points that the bioethicists brought up, at least hank and Pilar, is that this feedback question. Well, if there's continual conversation with the public, think think in many ways that at least mitigates a significant extent. If we have structures to continually get feedback from this constructive engagement that certainly helps address a lot of those issues.

Other comments?

Yeah. I was just thinking that it would be helpful to get some data or get some expert opinion on the -- the feasibility in the broadest sense given the fact that we're talking about a prospective study of a huge number of people in a -- in an environment in which I think jo an Bachmann put it nicely we have a very frak chows health care system. I know from personal experience that in trying to keep up with people in a large study much smaller than this is extraordinarily problematic and if we're in New Zealand, I think the question would be different and the question would be much easier and I think that it might be worth getting some expert advice about just a simple feasibility in a broad sense of this kind of thing in this country with our health care system. And it.

You could ask the IRS. They have experience.

Yeah, they can track people down pretty well.

Yeah.

Jim and I were talking at one of the breaks and it does seem astounding how many things, issues would be addressed and so much easier if there were national health care policy -- plan. That doesn't seem to be in our purview to make comment on, but it's something that having sat on this committee long enough and listened to ASGT also it just keeps raising its head and can we just ignore it or can we not ignore it I guess is my question.

Well, we can certainly put anything in the report we wish to point out what may be obvious already to the secretary that that makes it more difficult to mount a study like that in this country than in other countries. I don't think we can recommend to him that he change it suddenly but we can certainly point that out.

In that spirit I'd like to ask Frances what's the different although obviously it's like talking to a different country but in terms of what we're supposed to do between this and the cold with the xher shlg issues aside?

Well, the commercial issue is a pretty significant one to set aside. Well, sob rows sli it's a very different population. What you learn about the role of genes and environment in Iceland may or may not map nicely across to somebody living in L.A. I think we really want to understand those interactions, you need to apply them across a broader and more heterogeneous group from what you're going to get from that somewhat exceptional part of the world. The other obvious one is the whole idea of data access, the intention of a U.S. study as I think most of us have talked about it today would be that this would be a data set that lots of people with ideas would have access to and they could intersex what you learn from environmental and clinical and genetic exposures with other kinds of data that are coming out of our advances of biology and that just empowers a much greater opportunity for things to be developed that are going to be useful and exciting. Let me just say in -- I was a little worried about Jim's comment that we don't know how to do. This I'm not an epidemiologist but I've gotten to know a lot of them over the course of the last year. Look at the ethnic study of atherocler row sis following not anywhere near this number of people but having all of those same problems and having pretty good success in terms of enrollment and being able to do the followups. Look at Jackson Hart. There are lots of experiences at NIH that make one believe that it is possible to do this although it's going to be hard.

What's the scale difference, Frances just for everyone's benefit?

About a factor of 20.

Just to respond to what Debra was saying before too, earlier in the day, Frances pointed out that, you know, you might -- we might have some infrastructure challenges, but that pursuing a project like this could help one get the inertia to surmount some of those infrastructure challenges. Similarly engagement of the public even just initially to just even think about the possibility of doing this could also give you some inertia to address certain other particular infrastructure challenges such as the lack of a nonfractured public health care system. So many things could come out of this that would be good, not necessarily the specific ones that we're targeting. But that's -- again, that's the beauty of engaging the public. As I pointed out too in that one question that I asked, I wanted everybody to be sure, also disappointments could come out of this. The public could say no. That's certainly a possibility. So that's all part of the beauty of that kind of engagement.

Sort of an observation and a question, if we look at the report that you did earlier about where we on a commit he, the subcommit tee agreed to stop and we look at where it was today, there was -- that's kind of where we kind of took off in discussion, which that's just an observation so that means that we go back then and reconsider those -- that information in terms of, you know, do we -- should we start talk more in detail about those things? Should we find another way to kind of move forward with the things to stop? I think in terms of next steps as work plan since that is what our charge is right now to do. But I'm just observing that we did a lot of work up to -- I mean, as you said the committee did because I came in late. I'll have to -- there's truth in advertising but it still seems to me that a lot of what was discussed today is sort of next step stuff. I haven't -- and I have my own theme music to go with this?

I think we have before us the opportunity to do whatever we'd like. I mean, we could within the context of the priorization process we could decide this is the only important issue that we have left before us and that we should spend the next year addressing this issue. At the other extreme we could stop now and simply say that after having spend two meetings or parts of two meetings being brought up to a certain level of knowledge and understanding about incensization around certain issues that we're now ready to sit down and write up a report as we did on the reimbursement issue and share that -- those thoughts that we have with the secretary or anywhere in between. So a good question to ask of the group now is, are there particular issues that we either heard about today or didn't hear about today that we feel are so important that we need to hear about them again in some future meeting or do we feel that we actually have had a fairly good broad discussion of many of the -- many of the policy and process issues sufficient for us to go ahead and -- and say something intelligent or hopefully intelligent to the secretary? Sylvia and then Joseph.

I think I would like to have a report that -- and this is going to be difficult, simply describes the complex di of this -- this project or this proposal. With the recommendation that the only way to do this is with this community consultation process as the starting point to build upon -- to see how the public responds and what they want to do and how they want to do it. So I don't know if we can simply put -- describe this complex project in just simple terms with that strong recommendation. I don't want to bog the report down in too many recommendations. I want the secretary to realize how strongly we feel about community input.

Can I -- okay. I was actually going to say something similar, but actually a little more expanded than that. Because it seemed to me that if you listen to everything that was talked about today that there's a -- there's a taking off point on a lot of these things. It seems to me that more instructive thing to do, not only to talk about the issue of public engagement which is a key issue, but in all the other -- each one of these areas where people presented, they -- everyone had a clear -- to me, there was a lot of commonality in what was being recommended. It seems to me if we take that information and condense it to where we stop and said, you know, here's what we understand about the key issues that we talked about, here are the common things that everyone recommended and here would be the recommended next steps on thousand to address these things and it may be that we as a committee cannot do that in a very short period of time. We may have to go back and do some more computation or instruction on it but in order for this to make it a dynamic document that is actually practical and could see that it has some legs to it I think one of the things would be to really think seriously and seriously review what has been told to us and come up with strong ways to get it done. That seems to me to make the most sense right now. That would be my recommendation. That's kind of in the middle that you're talking about, but I think to me I'm -- I'm the person who's a bridger so I always look for the middle because I think the middle is very, very doable most of the time.

Well, certainly one possibility and either Amanda or Sarah will tell me if I have the words wrong, but one option is to allow a small group, which I think is called a work group, working group, is that what I've heard? Which includes not only members of the committee but allows us to take advantage of some of the expertise from some of our panltists today and do essentially what you said. To assume that our note taking was insufficient in and of itself so we might need some more expertise ongoing to help us draft the report as opposed to simply turning to poor Amanda and saying go to it and let us know when you're done. And Amanda's been great up until now as we all know those of us who are on the task force but this would be slightly more expanded way to drill down on the issues that we've heard today.

It would seem to me that that's something very concrete we can do. That would actually -- I would recommend to the group -- I mean, the committee I'm sorry. If the committee was amenable to that I would recommend that. I put it on the table as a recommendation.

Before opening this up to the full committee let me ask Sarah whether I have that right. Is that something that we have the option of ding and do we have to take any special action norred to do something like that?

No, you can do that. In fact, I'm not sure -- I think your task force could involve other people so we could continue to call it a fas k torrs and -- but that be governed by rules of working groups.

So let me open it up to -- Suzanne?

In listening to the discussion which was very profound and outstanding today we've all acknowledged but what I'm hearing now in the discussion of next steps is the reenforcement of the complexities and the challenges and as I think as part of the discussion as we move forward in next steps is the potential of this and the rewards of this and why it's so significant to the potential health of the country over the next decades and I think that should be part of a framework as the so what and yes we have to deal with all the issues that were so eloquently presented today but I think that's the context that we need as we move forward with this.

I think it might be quite useful before we throw it back to the task force of which I'm a member to try to kind of have a general discussion as we are having right now to get the committee members to say sort of -- I mean, to have a round table to have the two or three top recommendations that if you were to address HHS today what would they be and then the task force would take that in the context of all the stuff that we heard today and digest it into some kind of a document because at the end of the day, I mean, we know the complexities but what we want is something that -- that you guys will take to -- to our boss and tell him HHS should do A, B and C just like the way we took the -- the reimbursement report and, you know, we -- and then we can backtrack. Now, if there are gaps or holes that would not allow us to make these kinds of vast recommendations then we can go back to the committee or the task force and rehash it a couple of times and come up with it. But it would be nice to get the members to say, okay, if I'm in the same room with the HHS secretary today what would I tell him around this issue?

I would actually back up. There's two issues I would like to go around to the committee members and get everyone to comment on and that would be one of them. What are the two or three leading issues that everyone can identify based on what they've heard and read. But I think before I get to that, I think it's necessary to get a sense of the committee on level of enthusiasm. And because there are two ways to approve -- there's actually many, many ways to write the report but there's two sides of it. One is simply to throw the hands up and simply tell the secretary and say, this is the most complex thing I could ever imagine and you're going to have to reinvent the U.S. government system and the health care system and God bless you, but, you know, good luck to you, because this is an incredibly complicated issue and by the way, here are some of the processes and mechanisms you may want to consider. The other is to come at it and again, there's plenty of ground in the middle so I'm overstating both extremes here for the purpose. But the opposite is to frame it the way I believe Suzanne was suggesting which is to make sure that we're pointing out there's a tremendous upside if we could figure a way to do it. If he could figure a way to do it and that we as a committee are very enthusiastic about it or put the very word however -- depending on each of our own feeling in order to give him that sense of recommendation. I don't think we necessarily need to put our stamp of approval on this or not, but we could and that depends in large measure on the sense of the group and on the level of enthusiasm for this. Before we then would necessarily go and identify the issues, I think it would help the -- the writers of the report and bring a report back to this committee which is likely to be representative of the entire group. So I'd like to go around and get a sense and we don't need long speeches here, but we do need some sense of the committee members on -- on a level of enthusiasm and level of feasibility to this whole challenge and whether this is something that we should urge the HHA secretary to take on as a matter of priority or whether this is something we're -- we're a little less enthusiastic about because of its extraordinary complexity and because of the depth of the issues that have already been identified. So I'm looking on both sides but since my body is turned in Joseph's direction we'll start at your end, Joseph, and work our way around.

I would agree with Debra that it's very complex proposal and but at the same time it seems to me that we -- we've looked through a lot of the issues around it and I think with a little bit more review, I would be able to make a real decision. I'm highly enthused about looking a little deeper at some of the more complex issues in terms of feasibility. The -- and that's what I would be enthused about is to see that because I think that the study itself has significant merit, but I recognize the limitations so that's where my vote would be.

Jim?

There's -- there's no question in my mind that such a study would be very interesting and give us important information. My biggest hesitation is not that. It's -- it's trying to balance that with the obvious incredible complexities of -- of such a study, especially in the kind of environment we find ourselves in with the -- with the U.S. health system. I would I think that perhaps to me the most interesting question remains, can we get these kinds of data and can we derive most of the benefit of such a study through the types of case controlled studies and the types of population studies Al beit more limited and focused that are currently going on? Talking about kind of doing the whole nine yards with really rich phenotypic data with long prospective followup, I'm -- I'm not sure that the information we get is going to necessarily be orders of magnitude more value than what we can get from smaller studies but we can certainly be assured that the complexity and costs will be various. So to me the big question is not would this turn out important things. It would. It's A, could we get most of that information through the studies that are going now and that are going on in other countries. Right? That's a big question and should we either -- what we have to decide is would we recommend to do this with various recommendations around that or would we recommend a more limited type of focus? That's kind of my -- my thoughts at this time, that I think we need to discuss it.

I'm not as negative about this. I think it's pretty innovative and -- and with the talk from Yvonne Lewis, I was very surprised about how engaged the public is really to accept this. And if we could get the public involved and get that first step to accrue the people and let them understand this, we probably will be able to use that as a -- like a push to form a policy issue to have all the other stuff to put together to get this thing working, so from that point of view, it is a very complex project and it's going to be a very expensive project, but with the help of the public, we probably will be able to work it out somehow.

K*iven?

I actually am reveling in the complexity and the challenge of this project because I think it -- it in and of itself may be and I'm not trying to think of any other examples I can think of but may be right now the best opportunity we have because this is kind of new, so it's not politically entrenched, it's not grid locked anywhere, but it may become that way so you have to ask mour renoand Frances if they want to die in this trench, but here's the possibility of bringing something to the public that is right now not polarized or grid locked so that we could use this to get public engagement going and per hats set a precedent, at least set a precedent that way because this is in one sense no more complex or costly or anything than a lot of the other stuff that's coming down the pike that the U.S. public is going to have to face. And so if we can find a starting point and I don't know -- I'm trying to think if there's a better one. Not in the sense that I think it's necessarily going to work, but I think it's a great starting place for that kind of public engagement and discussion to see if it could.

Ago necessary?

Well, I agree with everyone regarding the complexity of the project, but I fall back on what we were assigned to do in our charter is actually from is secretary add Weissly committee to actually look at the impact of the human genome project on all the aspects of health, society and medicine and I think if we don't support or fail to support a way that we could conduct this large population study we will fail to charter what we were given to do. So I think from that perspective that is one of the main reasons we should move ahead whether we have to look at some of the issues before we put recommendations forward, I think it is well worth and I enthusiastically support moving forward with recommending this to the secretary. You had asked also hunt, regarding some of the other key issues and I think just to reiterate what other people said about the issue of community involvement and maybe community engagement is one of the things that we would need to look at would be actually developing a whole new paradigm for the way research would be conducted with this aspect of community engagement and I know the CDC has a whole network of -- the CDC community partnerships for prevention and maybe some -- we would have to look, at both the national level of engagement of community partners as well as local levels and that maybe that would be one thing that we would need to look at a little further in terms of making recommendations.

In all of the comments that I heard today, I didn't hear that this was not a worthwhile endeavor. I heard that there are some complexities and there are timing issues and cost issues and things that we need to be mindful of so I'm in the category of the enthusiastic supporters for the concept. I mean, it's like going to the moon and I think others have used that example and I see no reason why we can't think big and embrace the idea and regard our job as helping to guide the secretary and helping guide the process so that we're on the right course and I think it's really more a matter of timing and making sure that things are lined up everybody is thoughtful about it so I'm in the category of enthusiastic yeses and I think our report, our job should be in helping to figure out how we get there and over what period of time and addressing all the different issues that were raised.

Okay. Julia?

From my own perspective I see this potential study of both revolutionary and visionary and I think it would give power that does not exist in current status. For example, I have the impression which surprisingly enough like you know, clinically relevant depression has a rate of 15% of the population so if you study 500,000 people you would have 75,000 people with depression that would be general typed and know that they're phenotyped in an environment and that doesn't exist anywhere in the country. For obesity the lowest rate I could think of is 30% so that would be 150,000 people general typed to obesity. 50,000 people with obesity. So the difficulty I think is that given its unprecedented scope, we could talk about ate forever and never get it done. And on the other hand, so we have to decide when do we stop talking about it and begin it? Which I think would be a key issue for the secretary, but on the other hand we do not want to begin the project with built-in structural force that we're not enforcing ahayed of time. So a suggestion that I would make would be to define time allotments for key elements and stick to it and importantly give the secretary kind of a decision that we need to decide what things in priority and address those in a time limit and go ahead and do it. And then also define other issues that could be decided as the project goes along and then set milestones for those maybe every year and then set up new things you know, that we don't predict everything that's going to happen before we do it and then set deadlines for those. But I think we should neither try to, you know U talk about it to death nor starting without, you know, a thoughtful process but it should be -- those things have to be very well balanced.

Debra?

I'm in the yes camp. This is a complex project but U.S. has a unique population and we're behind other countries. And we were a leader in the human genome project so it seems sort of sad that we're lagging behind other initiatives like this. I do think we should emphasize that it will require broad government agency and private sector involvement and participation. I think that there has to be a public man date starting at the beginning now and as soon as possible as feasible. And emphasize that while there are hurdles, the potential benefits for individual and public health are enormous with the additional potential for other nonhealth outcomes that are not the focus of this project like happened with the -- the space initiative. I think there will be other outcomes of interest in science among young people and other kinds of things that will come out of this initiative if the public truly is engaged. Can I add one other comment? Which is, I was struck by Dr. Duster's point about the taxonomy that's being chosen for the representiveness of the cohort and I would ask to consider something like a ZIP code taxonomy or something that, you know, there are billions of ZIP codes but it just seems that you're not -- you're basing a lot on race ethnicity and I think there's a real danger in having heard what Dr. Duster, I think it's overemphasized if it's truly a gene environment study then you need a gene environment to bes onmy that's not in this study currently as the work group proposed it.

And Sylvia?

Oh, I think that I'm very enthusiastic about this project because the rewards will be probably more than going to the moon. I think that this also gives us an extremely great opportunity to show how research can be done right in a large population if we do it right from the beginning. Of course, as I said, I'm really supportive of the community participation from the beginning. I think we have to emphasize that this needs to be new funding. We don't have enough funding right now for the research that's being done. It's being cut all the time. We need to have new funding for this and finally that the participants need protection, protections from discriminations, protection from not receiving the proper health care. I don't want the situation that hul owe was saying about watching people get sick. I mean, that -- that is not acceptable to me. So if you're going to participate in the project, those participants need to have health care.

Great. That was certainly useful to me, I think. My sense is and I'm watching the clock, so whatever we do we're going to do it in the next four minutes so I see Joseph and then I'm going to try to offer some final comments.

Not supposed to give my level of enthusiasm to such a study because I'm the exofficial here but I wanted to act a couple of things. You're the only one who brought the idea of could we do it through some other means and I think it's very important to at least give an advice to the secretary as we move to implement the initiative and again, four people here on what I heard keep saying this is a study and you know, I heard one, two, three, four and it's not a study. It's sort of a big initiative but it's very important to have the sort of what I call the knowledge integration piece, sort of what are we learning from the existing cohorts, what have we learned from the existing case control studies, what are we learning from the bio banks that are moving forward and then figure out a way to integrate that knowledge as we move forward. This is not as trivial as some people think because pooled analysis and META analysis is a very complex things. I think when I presented to the committee about what the genology network, last week we hadst just had a meeting where we brought together 24 networks from around the world that are primarily diseased based so half of them are cancer, osteoporosis, heart disease etc. These are con sovrpgss that have existed for the last anywhere from 24 to 30 years that have cleekted thousands of cases and controls on specific disease topics and they have pooled analysis and DNA and they're working together to integrate their knowledge about genetic variation and that specific disease. There are other cohort studies like eric and farming ham and women's health study and nurse's study and the physician's study so I think it's very important at least from my perspective to put in the advice that as we embark on this new endeavor or new initiative that we need to provide enough resources for that knowledge integration from all the existing studies, whether they're case controlled cohorts or bio banks that are beginning to be launched. Otherwise we may be missing the boat here or be studying things that we don't need to study because I mean some other people have solved that question so knowledge integration is the key.

And Joseph?

Mine is brief. I just -- you can just answer also, your perspective as you ask that too. I'd be curious.

I thought I was going to follow reed and reserve the right not to say anything. No, I'm very enthusiastic about this. I'm full of question marks but I think everyone who's dreamt about this study is full of question marks on how exactly to proceed. I think for me the two issues are public engagement and how you do that and how early do you do it and then two, how one might creatively look at the issue of smaller starting studies because you can't start on day one saying we want 500,000 samples and we're off to the races. So where one can get all the information from a smaller set to teach us how to do this project as we go along, the human genome sequencing project did that. That's why a lot of organisms were down, there was a lot -- there was a learning curve and I would want to think about ways in which that could be built into the process so we could learn from our mistakes and avoid them the second time and see what the gaps are. But I'm quite enthusiastic about this despite the levels of complexity and despite an awful lot of what ifs

Like the one person who probably perceived it as the biggest wet blanket my plea would be that we do exactly what mour renohas suggested. We need to learn as much as possible from the kinds of studies that have gone on and are going on already so we don't reinvent the wheel and so that we do this right.

So with that, my sense of the committee is that we would -- that the committee at large would like the task force to work with Amanda and staff to begin to draft a report, sdraft an outline which the task force can be examining and we can pull in other expertise as we see fit based on what we heard today and then hopefully bring that back to the full committee as a -- as a draft document. Well, it's hard to answer by when without turning this way to -- I think it's impossible to say by when until we actually begin. I don't see how this could happen before the March meeting which is the next one. Right? So we're really looking at --

Yeah. Not beyond that.

Yeah. So that would be -- is there a sense of the committee that that's a reasonable series of steps and then it would come back to the committee norred to both vet the report and identify issues that need to be drilled down more completely and Frances you had a point oar a question.

Just would like to know, would the committee in the meantime encourage further exploration of how to conduct the public engagement? Because it sounded as if that was pretty broadly endorsed and I would hate to lose the time between now and March to begin to try to put something more concrete together along that line if you all believe that that's critical.

Yeah. Are you asking for a -- a sorts of preliminary note to the secretary along those lines

I don't know if you have to turn it into a note to the secretary but just a sense of the committee that would justify perhaps NIH perhaps spending some money on this and not feel as if we're completely out there on a limb.

I think you would have the sense of the committee that this is a high priority item and any efforts to learn more about how to tackle it would be well carried out. With that I would thank everyone for hanging through to the end. We'll reconvene tomorrow at 8:30 in the morning and members of the committee planning to attend the denner this evening you should meet in the lobby at 6:40. And with that, thank you all.