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., ca