Confirmation Number: 334093 Event Started: 3/1/2005

(SACGHS meeting March 1, 2005)

I think we're getting close to being able to have the slides ready for the presentation. So, can I call the committee to order? Thank everyone for being here on day two. Webcast, are we okay? We'll have to go ahead and -- we'll go ahead without the webcast for the moment and you'll catch up with us as we go. That's okay?

Let me thank everybody for a very intense day yesterday. Very hard work. There are a couple of things we want to let you know that are gear main. The discussion on coverage and reimbursement there have been some subcommittee work last night and this morning and at lunchtime, we will have a working lunch and we will present to you a scheme AT&Tic for, we hope, an organized and very precise discussion that will get us to some conclusion at the end of the lunch session. It will take everybody really paying attention and working hard to get there but we believe that we can accomplish what we need to accomplish during the lunch hour. To facilitate a working lunch, you have at your desk the lunch menu.So if you need to fill that out and we'll pick them up at the break. By 10:00 we have to have all the food ordered so you can get your food and come back here and work. So, this is a critical small ingredient we want you to attend to.

With that, let me also let you know that at the break, by the way, we were telling people to go away from the food cart and it turns out that we don't need to tell you to go. You're not supposed to bring bags with you, but that's actually available for everybody at the little food area out there. So it's okay. Our people in the audience, you can get coffee out there and so forth. And we're not going to make you leave if you don't bring your lunch pail.

Today, from 8:30 to 2:45, we'll talk about large population studies, the opportunities and challenges. The human gentlemen nome, and the challenge of translating the wealth of information into improved health, the environmental and genetic components of common complex diseases and genetic and environmental factor and the interplay of those factors. They have been an important and necessary way to translate the human genome see consequence into useful clinical and public health strategies. While many different approaches can be taken, all intend to build on the information provided by the see consequencing of genome . These studies are complex and they raise a number of scientific, logistical and ethical and legal and social concerns. We decided during our priority process that it was important to understand the opportunities and the challenges posed by these large population studies and that these questions required in-depth study. NIH has also asked us to provide feedback on the need for such a study. As such, the large population Force is appointed in June of '04 to begin work on this issue. I'd like to thank the Force members for organizing this session. Hunt, Ed McCabe, Ellen fox, and all the members of the committee, we want to thank you. We want to thank the staff, particularly Amanda, as well as holly, Campbell row send for their work and developing the backgrounder that we've been supplied. By the end of that session we hope to have gained a deeper understanding of what the large population studies are and why they're under consideration this time. The goals of the first three presentations are to inform us about different approaches to large population studies and provide us with a broad introduction to this topic. We're very pleased to David Goldstein will discuss the Conceptual basis. And Gilbert Omenn will present the public health perspective and Teri Manolio will present an overview of national and international large population studies. I would urge you to turn to tab one of your briefing book and you'll see the biographies of each of these three distinguished people and so, I'm not going to go through those right now. So, to begin, let me just thank David for coming and we're very interested in the next half hour to hear you talk to us about the Conceptual basis for large population studies of Variation and common disease.David, thank you.

Your welcome.

By the way, I think what we'll do, depending on how long the presentation takes 23 they stick to their half hour alotment, what we may do is you have an urgent, burning question you want to ask the individual speaker, we can probably take one or two of those right after, but then we'll also try to query the panel later.

Thanks very much for the invitation to come here and talk about the Conceptual basis for large population studies. What I'd like to do is in half an hour, try to cover two things. One is why we might want to undertake such an enterprise. And secondly, how we might go about it in terms of what the technical requirements would be. I'm going to kind of balance this back and forth between those two things. Kicking off, why would we want to set up a powerful framework for studies the genetics of common diseases? The basic motivations are indicated there. We would like to be able to predict risk, but importantly, I'm going to come back to this a few times. We would like to not only be able to predict risk but do something about it. Not good enough to predict risk. This is not for insurance companies. It's not good enough to predict. We to be able to intervene. That's something that's going to come up, I think, in a few places.

The other motivation is not about prediction and intervention but object identifying genes and path ways that might help us in the drug development process. And finally, the aim would be to identify genetic determinates of treatment response. That's traditionally thought of in terms of pharmacogenomics which I'll talk about the genetic determine ats of what drugs are safest and work best. You can also think about the genetic determine ats of other treatment responses like when there are options for surgical procedures, nonsurgical procedures and so on. So, in general, the genetics of treatment response.So the first thing that we need to be clear about is what kind of genetic variation we're talking about. The first thing that needs to be said is we're not talking about the kind of genetic differences indicated on this slide where you have a mutation that's a segregated in a family that causes a disease. So, in that simple case, there is a one-to-one correspondence, often between a genetic difference and the disease that we're interested in and that's actually quite straight forward to work with, genetically and the community is now extremely good at finding those kind of causes of disease. Now, unfortunately, common diseases aren't like that. The genetic contributed to common disease don't have that kind of one-to-one correspondence. The kind of genetic variation that we're talking about here is illustrated with this cartoon so the idea is that our genome is a big place. There are many places in genome where individuals tend to differ one the next. In fact, there are now estimated to be more then 10 million common polyM morphisms and a site where the rare form has a frequency of more then 1%. More then 10 million of those different places in the human genome and if you allow for rarer variance there's many more then that. And these variance, the different forms that many of these sites, we know, often have very subtle effects so they change fizz yule give in some subtle way. That's very difficult to measure. And then, these variance influence the types that we're interested in. The kind of diseases people get. In some kind of complicated interaction, both with other genetic differences in our genetic makeup and with the environment. That's what really creates the challenge. A large number of variable sites in our genetic make up. They interact with one another and the environment and ultimately, they have some kind of influence on what we're interested in looking at and that is the health of the individual. And I really just want to walk you through to emphasize at the end of the day what we're talking about is the probability of certain conditions, being influenced by these variance, the variance don't determine the condition. For that reason, I think it really isn't appropriate to talk about genes for diseases. We're not doing the same thing as we did with the disease. We're not finding the gene for diabetes and the gene for asthma and so on. We're understanding how genetic differences influence these conditions. It's a different kind of thing.

Okay. So that's what we're -- what our aim is to understand how all those genetic differences we have influence our health. That's the aim. And it looks like it's going to be difficult. There is now really no question about that. But what I'll now turn to is some of the technical requirements that we're going to need in order to be able to make progress. I'll spend the most time talking about the requirements to efficiently represent genetic variation. Two reasons for that. One, I was explicitly asked to do that. The other reason is that's where we're fartherest along. When you hear people talk about the genetics of common disease, nine times out of ten, people talk about how good we're getting at see consequencing and gene type and how much we know about genetic variation, we've gotten good at that side of it. That's the easiest side. The difficult side is where we haven't made much progress, which is knowing exactly how to measure in patients what we need to measure. And knowing how to relate that to the genetic variation, that's the harder bit. I'll spend more time talking about what we're better at and telegraph what we're not good at and ideas of how we might improve on that.

First, kicking off, the genome is a big place with a lot of genetic variation, as good as we are at sequencing and gene typing we can't get very, very large numbers of individuals that suffer from a certain condition, individuals that don't. And exhaustively compare them genetically. We're not capable of doing that. We might at some ., that kind of capacity has been promised to be around the corner but it never quite arrives. What people think about are more efficient ways to make the comparisons more economic cal ways. And something that's getting a lot of attention right now is called the -- tagging. I'll spend a few minutes talking about. The basic idea here is to find a framework for efficiently representing the genetic variation either in a region of the genetic make up you're interested in, or in the entire genome . don't know how well you can see this, but what's shown here is a cartoon representing a stretch of genome . You can consider that a gene. And indicated are each of the sites in that stretch of genome that differ. Where there's a polymorvism. 12 sites indicated there. Just . here. This group, those are three, four, polymorvisms that are indicated the gene and you see the first row is one chrome some you might sample from the population N that chrome some that first site has a -- and then, the fifth chrome some you might sample has the -- and then the next site which has -- and so on. The . here is members of the green group are all associated with one another. In this case, if you know the aleal present at the first site it tells you the aleal that's present at the second site in the green group and the third and the fourth. Okay? Those associations among variable sites in our genome are due to a whole raft of population genetic forces which I won't go into. But they do exist. There are these associations. Usually not perfect. I'll say something about that in a minute. They do exist. Because of that, if you were interested in looking to see if any of those sites associated with a trait you were interested in, you wouldn't have to directly asay all of them. You could asay one member of the green group and tell you about the others. You could asay one member of the pink group or whatever color, and it will tell you about the others and so on. They're -- another name is linkage to equilibrium mapping. These associations do K3*EUS. If you understand the nature of these associations you know how to select out a subset of the variable site that is tell you about the others. And in this particular case, obviously, the subset that you can use is one member of each color group. There is no loss of information at all because each member is telling you about the others. So, if one of the ones that you didn't asay was influencing the fine type you would see it through the one you did look at. That is at its Conceptual core, the entirety of the mapping or linkage to equilibrium mapping and it is, in fact, the primary motivation, I think as far as I'm concerned and most people are concerned. The primary motivation for happen map project, an effort to characterize these patterns of association among variable sites so that you can select out a subset that efficiently represents the variation in our genetic makeup. So that is an extremely important tool currently because we can't look at variation exre hencebly and that's the Conceptual core. In fact, the associations -- because we're doing Biology here. These associations are never perfect. You have to use a bunch of statistics to go through the step of choosing one member of each color group. That's a technical detail. This is the basic aim.

What I'd now like to do is take a couple of minutes addressing the issue of how well we expect this to work. So, can we feel comfortable that we really do have a good framework in hand for efficiently representing variation? And I'm going to try to give i a "yes or no" answer to that question. I'll illustrate that with some work that we did on a data set that we collected together with glax okay Smith Cline where we look at the patterns of association among 55 genes that contain the me tab lyzingenzymes. And there were a bunch of these sites that were asayed in a number of individuals both of European an zestry and Japanese an zestry. That's the data set. This indicates the way this sort of analysis is carried out. This is a stretch of see consequence indicated and there's genes indicated and there are all the polymorvisms indicated that were looked at as thin lines and that's -- there's about 60 plus of them spread through four genes that are contiguous. And what you do is do a statistical version of selecting one member of each color group and you identify nine out of those 60-plus polymorvisms that you assess are able to represent the other variation that's there. And then the question you want to answer is "how well is that really going to work in representing variation" that, A., you don't know about and B, variation in a somewhat different population from the one that you looked at originally. That's important. You have to remember the way this works, for example, the way we're all going to use the hap map data. The hap map looks at a number of individuals, for example, from the depostory. And selects these special tagging and goes and applies them in a different group. For example N. our case, patients with epilepsy and so on. You have to ask the question "how well do they represent variance that is you may not knowable initially and in a somewhat different population"? So you need an answer. In this case we find the nine to represent all these others. What you want to know about is how well they represent the ones you don't know about in a somewhat different population.

So you think of some statistical ways to do that which I won't talk about. And evaluate how well they do. We went through a few of those exercises. As I said I'll skip. What I'll do, instead, is show a direct evaluation of or not they work. And that is taking these snips you identify out to a brand new population sample and assessing or not they predict variable sites that we know are functional. So there are, in these particular genes, lots of sites that we know change the activities of the enzymes, for example. Those are exactly the kind of differences we're looking for and we can ask "do these tagging snips work? " and this shows the result shown here is the minor aleal frequency of the snips we're trying to predict. Proposing not to type. And here is a measure of how well we can predict them. And without -- it doesn't really matter how that measure works. What does matter is if you're up here at the top in this performance measure that is exactly the situation. You can show this formally. It's exactly the situation of the cartoon. If you're up here at one, in this performance measure, it's exactly like taking one member of each color group that exactly predicts the other. No loss of power have so ever. If you're in this range you do very well. If you're down here you do very badly. Which is to say, if there was a snip down here you didn't type and it was influencing the condition, you wouldn't see it. Okay? So how do you do it? Here's the minor frequency of what you're trying to predict. Once you above 5% you do great. It's fair to say, the short nontechnical version is that, out here, if any of this stuff was influencing the fee know type and we only typed the tagging snips, not these things directly, we would still see it. That's really encouraging. This is the very discouraging note, small sample so far. These rare things may not be predicted at all. Sometimes you predict them. And sometimes you don't. We've gone on and done a bit more of that kind of thing and our impression is that this is a fairly general outcome. That in this framework you just can't reliably pick up the variants that are rare in the population where rare is something between 3 and 5% as a cut-off. More work needs to be done but that's how it looks to us at the moment.

What's the conclusion from that? What I'd like to emphasize is that we're talking about a truly dramatic economy. In the 55 genes that we looked at, we estimated that there are 4,000 common polymorvisms. What we show is about 200 of these specially selected snips can represent the other 4,000. Now, you can select these in different ways and some people would use methods that would result in a number slightly larger then 200. But it is some really dramatic economy that you can achieve this way. And I would assert that it is now not controversial, or not you can represent common variation in this framework. It's still discussed a little bit in the literature but I think that debate really now has gone out of date. I think it should be viewed as demonstrated, that this can officially represent common variation. Issued say that I have no association with the hap map project so I don't feel any need to support the necessity of the hap map project. So it's just a technical evaluation. That framework really does seem -- has been demonstrated to work well in representing common variations. So I think that's encouraging. Of course, these data we have are by no means the only data that make this case.

So common variation can be efficiently represented. We should view that as noncontroversial. It seems unlikely rare variation can be efficiently represented. So for that we don't have an economic cal approach. If we want to also identify the rare variance that influence both common diseases and responses to treatment, we're going to to do more difficult and expensive things. And we should because without a doubt, rare variance will also contribute. I'm not going to go into that whole debate. But I think it's quite clear to most people that both common variance and rare variance contribute to common diseases. The relative importance of those two things we don't know but they'll both make some contribution. We have a good very economic cal method for representing common variation. We don't for representing rarer variation. I don't expect tagging will serve the purpose but if you find more clever methods to do it, perhaps. We probably need to think about alternatives. So, I think in terms of representing common variation, the genetic side, we really are, now, in pretty good shape, even though we've got a challenge for rarer variation it's terrific that we can now start asking questions about those 10 million genetic differences among us all. That's terrific. That's a real tool. We'll, no doubt, lead to advances. But p what is much much more complicated is deciding about how to look at individuals that are being studied genetically, both individuals with diseases and individuals that don't have diseases. For example, if you're thinking about prospective studies and many have been making arguments for the advantages of prospective studies and that is where you enroll people, random samples from the population, for example, in one design, and monitor them over time and as they become affected by different common diseases, you can then carry out genetic studies, knowing about the background of the individual because they've been in your study for a while. So, as we move to carry out those kinds of studies which do have a lot of advantage, we need to think about exactly what information we need about individuals the time of enrollment and don't have time to go into details here. But I would say that that's something we really don't have a very good idea about. For example, if you're interested in cardiovascular disease, exactly how much information do you need the time of enrollment for a large population sample in order to understand the state the person when they're 50 well enough, that it really tells you extra things about why they had a heart attack when they were 66. We don't know exactly what we should be looking at when we enroll individuals for cardiovascular disease or other things, we really don't know. If we move towards very large perspective population studies that's something we'll have to figure out. Obviously, lots of people have ideas but it's not like the genetic side where we really know what we're doing. Definitely an area of active work.

The other things I'd like to raise as an issue is the question of what types of information are the most important. So, for example, we've been carrying out a variety of studies in epilepsy and a common way people think of doing epilepsy work is the sort of thing that people usually do. Which is you get a lot of individuals with epilepsy and compare them to individuals that don't have epilepsy. And, yet, epilepsy has quite a striking potential in that in cases where patients don't respond to pharmacogenomics treatment, surgery is carried out and the actual affected tissue is available for study so you can at the seizure-focused tissue in those patients that have to undergo surgery. That is basically not being done in epilepsy research. You can actually write out a long list of striking opportunities like that if we look at the right place. And interface correctly with the actual care, clinical care, of patients where we might really figure new things out if we actually look at the right kind of information. And sometimes that right kind of information doesn't come from simply enrolling a million people in a study. I'm not disparaging that. I'm saying there are other kinds of data that are available that emerge from clinical care that we're not making system AT&Tic use from in the area I'm familiar with, is certainly the case, and in a variety of other areas. We have to think very carefully how we interface genetic's work with healthcare to make sure we really do capitolize on the most important types of information, as, for example, we're most certainly not doing in epilepsy and we're trying to change that.

Another . I'd like to raise in that context is the overwhelming detailed information about how patients respond to treatment. I'm not going to have a lot of time to talk about this but I'll talk a little bit about it. I think it's very, very clear that genetics plays a major roll role in influencing treatment response, in particular, responses to medicine. In order to make progress in identifying the genetic differences among patients that influence how they respond to medicine, it's essential to have very detailed information about what medicine they were given, in what doses, in what combinations and exactly how they responded. We're not going to be able to make progress unless we have that available and that's very, very difficult to get.And in that context I'll mention one opportunity forgetting that kind of information may, in fact, be through managed healthcare providers where the patient records have been made electronic may be a framework forgetting exactly the kind of information about drug response that you need. In thinking about large population studies, I would say that it is absolutely essential to make sure you do the best job you can do in representing how patients respond to medicine. .

So I'd like to just end in the last four or five minutes with a couple of thoughts. A, about what we're trying to do. And B, about the case for more serious attention to pharmacogenomics. And first, on the . of of on the matter of what we're trying to do, I'd like to raise the issue that in academic genetics research there's been a real focus on a final and accurate determination of whether a given polymorvism really is a risk factor for a given disease. And in some context, that's something you would like to know. For example, in prediction, you would like to know whether polymorvism really is a risk factor. One thing I think is not so well appreciated is there are contexts where you don't need to know with certainty whether a polymorvism really is a risk factor. It's good enough to have an educated guess and I'd like to make that by reference to a project that glax okay Smith Cline, but I've not been involved with but I report this with permission. They've done a gentlemen genetic study compared individuals with and without type two diabetes and they tried to identify polymorvisms that are associated with diabetes. And what they did is look at 400 individuals with diabetes first and 400 individuals without and had a follow-up. And the size of those studies -- and we know this already from calculations you can do in advance -- are not sufficiently powered to reach a final determination with any degree of statistical confidence, that a given polymorvism really is a risk fact for diabetes. In fact, reaching that final . of confidence is hugely expensive in diabetes. We know the effect sizes are small. However, what they did come up with is a set -- when they went through the exercise -- of 21 gene variance, genetic differences that appear to be associated. None of those 21 clearly, with statistical confidence S., in fact, a risk factor. But you can ask the request in a somewhat different way. You can say "I don't care about any single one of those, I care about the set of 21". What is the probability that at least five or six out of the 21, even though don't know which one it is, what's the probability that at least five or six really are disease-associated? That's a completely different calculation. And, in fact, in this case -- and I won't go through the details in this case what you find, probably, with fairly good confidence, five out of the 20 are real but you don't know which. Okay? That's actually still very useful because in the context of drug development, that means you can take all 20 and start working on them. You don't have to know which one it is. You can ask the question if it's going to cost you another $250 million to get really precise assessments for each of those 21, maybe it's actually better to spend $100 million and start screening some of them. So what I'd like to say is when we're thinking of drug development it's not necessarily always just a matter of reaching a final conclusion, no matter what the cost is, of whether given polymorvism is, in fact, a risk factor.

And the ending two minutes is the case for pharmacogenomics. I think that in academic research, far as I'm concerned there is a slightly inappropriate overemphasis of studies predisposition directly as opposed to treatment response. It's starting to change I think it hadn't changed enough. I want to make the case that variable responses to medicines is, A, hugely important. And B, easier to do then directly studies disease predisposition. So these numbers, the study they're based on, has many method issues and they are highly debated but nonetheless, however you look at it's quite clear variable responses to medicine is hiewnlly important and it's estimated that adverse reaction to medicines cause over 100,000 deaths in the U.S. alone ranking as the fourth or fifth leading cause of death. And in terms of variable efficacy as, in fact, a senior Vice-President for glass okay Smith Cline pointed out, medicines typically onn't work. The average rate at which a given medicine does what it's supposed to do is about 50%. And it varies across therapeutic areas. A lot of the variation is genetic. We know it but we haven't found it. I'll close by saying that when you actually start looking in detail, the genetic to determine a drug response what you find out is it's usually quite a bit simpler then the genetic basis of common disease. And that has -- sorry about this -- that has two components. One is that you often know where in the genome to look for possible genetic determinates of drug response. And, two, the genetic determinates of variable drug response often are common, so they're not the rare things that are hard to find. And the final thing is that when you find a genetic determinate of variable drug response, there's often the possibility of doing something about it clinically. The possibility. It's not immediate but you often, for example, have the possibility of suggesting you use drug A instead of drug B or you change the dose. And that is the final thing I want to say in sharp contrast to predisposition studies of common disease where, sometimes, you find things that really are risk factors and there's nothing whatsoever you can do about it. So, maybe we shouldn't do common disease predisposition but it certainly means that in thinkingbility these large population based studies we have to take the drug response side and treatment response side more generally, very, very seriously. I'd like to end there and issued mention the people that work on some of the stuff I talked about. Thanks.

Thank you very much. Very well done.

Is there one hot, burning question? If not we'll come back and do it with the panel. Terrific. David, thank you very much.

Gill Omenn, terrific to have you with us. And we're looking forward to your perspectives on public health . of view on large population studies of Variation . The environment and common disease. Of course, speakers, by the way, so you know there's a timer sitting be side Sarah and it's sort of, you want to guage where you are it's there with the usual -- right there, with the usual yellow light and so forth.

Thank you.

Okay, thank you very much. Great pleasure to join you. The scenario in which I've been intensely interested in for decades. At least 35 years in pharmacogenomics and echo genetics so the chance to share with you how I think about this and how I think many people in public sciences and Public Health think about the opportunities to really make a difference as we expand our knowledge base from genetics and other fields is a special welcome and thank you for having me.

So, here's a vision which is actually a short term vision. But we'll carry on for decades of work. As you just heard from Goldstein we already have begings of an large of genomec genetic information, valueated snips and validations of hap map. Genes and aleals and especially, many kind of the genes for particular disease risks. The second bullet has been very much less addressed. And this is improvement of our environmental and behavioral data sets and most importantly, their linkage with genetic information. In fact, we have many proposed statutes and regulations that would make this impossible. I'll come back to that at the end. The third is to carry ows both of the first two items with well-established and in the public mind and the legal mind, credible, privacy and confidentiality protections. Both for genetic and nongenetic information. And finally, I think we can be quite confident the technologies we have in hand and concepts being developed will yede break-through tests, vaccines, drugs, behavior your change seemed and regulatory actions, all of which would be aimed at reducing health risks and treating patients cost effectively in this country and globally. You know, in medicine we say we save one life at the time. School public health and Johns Hopkins adopted this "we save lives millions at a time." That's the public health perspective.

Okay. The new world in which we live is well known to all of you here, we're excited about the new Biology. Most of us roig the developments in Biology have been made conceivable by new technologies. You know, there's this notion to go from science to technology to application. There's a huge feedback loop from technologies. It's reflected in the protein economics which I'm working on and bioand on the medical side, an increasing community health services, public health preventive services side, we talk and evidence based medicine. Many of you heard that phrase, evidence-based medicine. When you use it in a rotary club or someplace else you can see mouths up open and jaws drop and finally someone asks "if this is exciting and new, what have you folks been doing up until now? " we're doing better. We're trying harder and of course sometimes the hardest sell is with our own clinical colleagues. The vision from all this is kind of healthcare and community-based services that would be personal, predicktive, andly preventive.And this takes people prepared to carry out such programs, through medicine two or three years ago we issued this report in which they stated with the arrival of the era in which we'll have the ability to understand gene environmental interactions comes not only the era of genome medicine but of genomecs based health this. Is essential for effective public health work-force and the CDC is particularly well represented here today, appropriately so.Here are our centers that CDC establishes several years ago including the one we're proud to have at the University of Michigan and another, pleased to help get started at the University of Washington. And the third in north Carolina. And they collaborate effectively to have a website you can check. The mission is exactly the mission of this discussion.

Now, just so we're on the the same wave length and especially those who are likely to be aware of this meeting and not actually particularly involved, definitions do matter. There is a something of a struggle over which is the broader term "genetics" or genomes" and in recent reports we've tried to help the public and ourselves understand genetics is the broader, historical, Browarder scientific approaching the roles and helping disease, luges. Genomes being the set of powerful new tools from Molecular Biology and science that is permit us, when we choose, to examine the entire complement of genes and their gene products all together of those you just heard, generalizing across all the genes as a formidable task and we end up focusing pretty quickly.

These global analysis do permit us, in fact require us, very usefully, to go beyond what we sometimes speak of as looking under the lamp post where we know aboutity gene of fee know type we're interested in or a desired affect of a drug and ignore the off target actions of the same drug that lead to nasty complications. Same thing on the protein side. Individual proteins or proteins as a class. Proteinics and looking globally as as many as possible of the very much larger number of protein and proten forms coded by those genes.

So we already had a good instruction to that about the genomec information from the global analysis. The international hap map consortium and the direct associations of the individual snip aleals with dairs disease types and the very substantial database we heard is over 10 million, and the hap type structure work which is really still emerging with a lot of clever efforts to use tagging snips and variable linkage equilibrium, a combination of hot spots and other details of structure.

Where can we get information about environmental variables to put together with the genomec information? Well, I'll give you a few examples and you'll hear from Dr. Teri Manolio and this is morning, the centers for disease control, national center for health statistics, conducted for 40 years, surveys of the American population. And increasing numbers of laboratory analysis. Now we're going to hear later, I will come to a slide about what is really the set of categories called environmental or nongenetickic in the U.K. biobank but here I want to focus particularly on chemical and environmental exposures complementary to behavioral traits and history and what you hear more about from others. The thisains proud of May jor impacts and major contributing factor in the removal of lead from gas. One of the public health try umms of the last century. Collaboration of pediatric growth charts. Preve lense estimates for cholesterol. Blood pressure, Hepatitis-C and other important variables. These are the environmental exposure that are asayed currently. And this is ongoing. So lead and a lead-biomarketer. Cad up, Mercury, arrests knick, and also, organic chemicals, Acrylamide, and metals, IGE antibodies showing lay tex allergy. The hydrocarbons. Estrogens, die objection sins and a whole bunch of markers for these exposures. And also, the smokes history or if a nonsmoker, environmental tobacco smoke exposure and a lot of other types of measure in laboratory. This is a rich data resource. Over the years, the tool which concluded in the 80s had 14,000 people. In haynes three, 34,000 people. I couldn't find in the very extensive website of NCHS the number of the current ongoing study. They told me there would be about 7,000, 6 or 7,000 so far who have DNA samples taken. I think that might be about a 10% sample of the total.NIHS is interested in environmental and genetickic interactions. I served on an advisory committee on personalized exposure assessment. The approaches we highlighted in our report, which will be out shortly in environmental health prospectives where the use of geographic information systems and the example there is the NIEHS set of children's health studies where they combined GIS and wireless devices to track exposures. Pesticides to validate dietary -- diary entries. These are diary entries not just of diet but potential fivities that would be tied to those exposures including children who might be exposed as migrant worker families or children who would be exposed with information about pesticides in the house and garden. They are developing spacial models for households at risk for lead poisoning and a variety of other exposures.

The second comes from the technology side of the biocenters and the devices that permit feasible measurement in the individual of exposures and relate, then, to actual bioburden measures of the sort that haynes does.

Third category is molecular signatures of exposure, early affect and variation sus Septemberability. The Conceptual strategy here of really building a program which would fit nicely with what was just described and what will be described in the biobank and some other large studies, may be applied in proper settings to retrospective or in case control studies, as well, of course. You have to be able to identify what your priority diseases are and the plausible or hypothesized environmental factors. This is nontrivial. We basically punted in this study for later work to be done on this. Identify potential genetic determinates and model systems for explores the genetic environmental interactions. Identify target study populations for feasible measurement. Define the genetic determinates to cu Septemberability. Conduct targeted exposure assessments. Identify and validate biomarkers and bring it all together with genetic environmental interactions. One thing that should be emphasized is the era of fighting as to whether things are nature or nurture, genetic or environmental is behind us, we're now all thinking about contributing genetic and nongenetic factors and specific ways they interact and even I would say I cringed a little at the comment in the last talk from dealing with disorders we know what the gene type pattern is. It's a lot more direct then for multi-factor Al disease. The variation can be quite stunning for the single gene disorders the most dramatic being over the last decade from Saudi Arabia of people with hemoglobin and -- with no apparent clinical fine type for biochemical fine type and many other examples.

Technologies and approaches. Some are listed here. I think I've already basically mentioned them. This is a natural process language to try to search the best literature. Very good tools now becoming available for doing this in an automated way to assist us limited humans. GIS I mentioned. Mapping and systems. One of the questions I asked was the extent to which the haynes findings sampled through the American population are actually being mapped. As EPA trying to do for other purposes, to states, locations, neighborhoods, maybe all the way to individuals. And so forth. This is one of the most important things for the laboratory sciences which is to link perspective sensors and molecular biomarkers in animals and in humans with invee to and studies to try to make the bridge between tox cooling and Epidemiology which has been needed for so long. .

EPA, EPA, of course, regulates the air, water, soil and together with FDA, foods for contaminants. The EPA has many measurement and modeling programs which this may be the most relevant for our purposes today. It's called the musty my yeah integrated modeling systems. MIMMS. The primary application is to simulate airborne substances in urban settings and the spacial scales they look at range from 10 I can lome teres down to less then one I can lome ter which kill METERs which gets to be interesting.

They're working on prototypes and successive generations of support tools and this is for air pollution and for Homeland^Security. You can easily imagine that. These tools bridge gas between two quite previousesly quite different approaches. One is the chemical grid modeling. The other is the disburstion model common tore water and air pollution. These models capture -- ground level concentration of air tox ins and hazardous releases from stationary sites and may reveal enough hot spots to be quite interesting in terms of human studies. .

There's a sort of progression to make measurements in the air wherever there is a monitoring station and where the stations are placed, of course, is highly irregular and never been systemized around the country. There are personal monitors. We're familiar with these in the work place in industrial high gene but available for community sampling studies there. 's biomonitoring as shown here for several examples. Of course, with pie you monitoring and in isolation, as with hains or the biomonitoring or the studies done under these genetickic population, there's little information about the source of the agent measured and that needs to be thought about in advance. And finally, the national scale. Sort of the summation of all this. And the CDC2003 data had 116 environmental chemicals including the ones I listed for you a moment ago.

Here, John, is my take from the web and I was at a planning meeting in Dublin four years ago. I wasn't aware when I prepared my slides that we were going to have an expert talk about this from the people who are actually doing it so I'll be very quick. Maybe it would be interesting to see perspective of someone across the ocean so we know what's going on. This is a genetic data bank to be developed from blood samples from half a million people. I understand the studies will be based on proposals from researchers. The -- general practices, many of them, in regional combines. With a ten-year follow-up. The age at recruitment, 45 to 69, and their expected to be substantial numbers of deaths over that period of time from common diseases. So that would be of great interest here.

There will be a questionnaire or risks, lifestyle, diet. A blood sample taken. Not too much said yet about what the blood sample will be used for. Maybe we'll hear today.

Statistical power estimates, very important in planning studies. They expect over 5,000 cases per year for diabetes, heart disease, Colorectal cancer and breast cancer and you see the projected relative risks and interaction ratios they would be able to detect with these numbers and that power and notice that should be that should be 1% significance. Isn't that right?

And at a lower incidents, there would be arthritis, Parkinson's disease, bladder cancer, and others, with, again, power estimates. And they have a very high expectation that 40050% of the patients in each practice would actually enroll. This would be astop knishing in America. Maybe they can do it in U.K. They chosen for the the blood sample, a very interesting question as to what form of serum or to be used and the separate, big, collaboration that I lead about this in the plasma and serum. We have similarly given high graisd to EDTA and higher to the plasma. There will be a case control and cross-sectional studies including a variety of family-based studies.

There have been some criticisms of a design, naturally. One is, even half a million people, that's too small to analyze complex diseases. And within these disease diagnostic carghts is extreme. When I was in Ireland, there which is big discussion about a proposal to actually enroll pairs which would be particularly informative for genetickic studies. I'm curious about the status of that. I couldn't find any mention on the website. The age of 45 to 69, of course, is a late time to be gathering information about crucial determinates of early stages of latent diseases, long guess todaying diseases. And, of course, relying on medical records while maybe they're better then here, I still limitation.

There's some comment that might be an overemphasis on genetic factors because of reliance on medical record and back of the lack of much collection about other kind of environmental factors and there have been vigilant consumer and patient groups looking out for confidentity and opposing any kind of genetic behavior studies and some other concerns.These are the exposure carghts as I understand it. You can see them all listed here. And no categories and no specific mention of environmental chemicals which, in this country, would be the top of the public's list.

An example of the kinds of studies that can be undertaken you see here. All of them are interesting. But they are of a subset of the variety that I've indicated would be a broader genetic environmental interaction.Now, other large-scale studies are underway in various places and in the biobank site they mention the much-publicized studies in iceland and much publicized in the development in Canada. A big European collaborative study called "epic" and others which Teri Manolio will, I guess, is providing you have received the materials for this meeting. In this country, the most remarkable study of the last decade has been the women's health initiative with 160,000 women participating. Both obs variable and randomized studies and as you know the outcomes have been front-page news for months. Let me bring this into a broader perspective from the public health view.

This is about genetics and environment and how we share a lot of interests. We both bring together the digital -- aim to bring together the digital code of information with the environmental could yous some people call them from knew trirks metabolism, pharmaceuticals and don't forget the knew tray suit cals and the chemical exposures. The broadway to think of this is a system's Biology approach to look at the inputs and then, the genomec ep pi genomec, protein -- levels of integrating the molecular information. Echo genetics has been the focus of my talk. I'll carry on about environmental and occupational exposures and variations to cu Septemberability. It can be looked at from infectious diseases, chronic diseases, nutrition, unhealthful behaviors and it means we should include genetics prominently in the case of disease prevention and these would include most interactions well as drug and vaccine development. I've already mentioned the training need.

Put all that together and should be, in the next decade or two, a golden age for public health sciences. We need these kind of population-based disciplines in order to make sense of a genetic variation. It would be a tragedy, in my view, if we had extensive genetic variation and couldn't make the relationship or answer people's questions about what you could do with the information to reduce your health risks.

Go out to the chemical exposures specifically, there is a discipline of risk assessment, risk management. Risk communication, that I've developed over the last 25 years, it's all addressed at this observation. Scientists disagree. This is extremely bewildering and disconcerting to a lot of people. In the current debate of faith-based ways of thinking and scientific ways of thinking, the characterization of scientific ways of thinking is based on fact and certainty is a huge failure of our communication. We are typically most interested in what we don't know what is uncertain and how we could learn more and make it useful.There's a framework for this kind of thing with regard to regulatory decision making on chemicals and other factors, especially chemicals to identify if there's a potential for hazard with all these methods which is what I'm talking about to, characterize the risk, characterize, not just to quantify, but to describe, have a useful narrative about to nature of the types. And how reversible they are. How serious they are. Related to potency, exposure analysis which, until recently was very underexplored and, our saying of variation cu Septemberability. To do something about it. Very often, information long before there's a regulatory action, has a powerful affect.

The tox koel genome , I mentioned at the national tox cooling program. A framework which says we need to Putney tox koel give. An environmental scare of scientific finding into broader health context and have anorederly process to develop the assessment of the risk, reasonable options, make decisions and carry them out and evaluate what we accomplished, if we did. All of this, from the beginning with proactive information of the stakeholders as the they've been doing. Context means in the environmental world, going beyond the statutory have one chemical, one environmental medium, one health the time. about the total public health of or any group. This requires multiple molecular markers and specially public health comprehensive view. Context means multiple sources of the same agent. Multiple path ways of exposure. Multiple risk the of one agent or multiple agents causing the same effect.

Data, surveillance, interaction with the environment and crucial issues about health disparities, environmental injustice, social and cultural traditions and differences in perception about risks and should be done about them. Finally, I want to . out some good work from an organization called "partnership for prevention: Endaging with the states" and CDC is very active with that. A lot of action at the state level. And a pending Federal Legislature on protecting people from insurance or employment discrimination for genetic diagnosis some 38 states, at least, have passed their own patchwork of Legislature. .

The aim for states are shown here. Monitor what's happening to assure that we have applications not just for treatment of people with specific diseases, but for health promotion and disease prevention. These are the two key findings. The first we've already covered. A lot of opportunity in this genomec era. The second is a hot policy debate. And it was the position of the partnership for prevention that genetics and genome , should be integrated into existing health, social and enviernmental policy rather then stand-alone genetics program. This is a quote from that report citing a very highly-regarded report which I was not personally involved in at the state of Michigan, the governor's commission on the state of policy and progress. At a time when many state policies were based on exceptionalism, taking genetics out from the mainstream of medicine and public health -- Michigan adopted an integracious perspective and recommended genetics issues be dealt with in the overall values and principals. All health conditions have some degree of genetic basis. It's very hard to dry a line between what is genetic and what is not. Most common diseases we're emphasizing result from gene environment interactions so the genetic advances are likely to extend and expand and not to is your plant the environmental protection. Some genetickic variations are associated with greater health risks then others covering the huge range with a one-size-fits-all policy is inappropriate. Issues about ethics , costs, societial issues. Medical cal care decisions should be links with research, insurance, and broader health policies. The intersection between public policy is immediate and longterm, warranting close monitoring. I added this line on the bottom which is that in this era where in the clinic where I'll be all day tomorrow, we have to tell patients that would be wise to make sure your insurance is complete and adequate before you have any tests done. That prohibiting discrimination based on test results or genetic diagnosis is necessary. .

The kinds of research we want to stimulate in populations and communities requires certain principals. Albert Johnson prominent bioest cyst observed in a seminar in Seattle that while we had developed widely accepted concepts and tools for ethics in medicine, namely, the informed consent principal, and the principal of autonomy of the individual participant, that we had no corresponding highlighted principals for public health or community-based research. So he, I and others developed and published this scream about engaging community partners early in the planning process. Keeping them posted. Seeking their input in the analysis and interpretation. Building productive partnerships that last and empowering people to propose studies. There are sources of information shown here and final comment six year ago from Frances Collins that what we're engaged in collectively, mapping the human genetic terrain may rank with the great expeditions. It's clear to get maximum value and meet our public responsibilities that we need to understand that progression from genes to proteins and from molecular and laboratory interests and, of course, clinical translation. And more broadly, to address the issue of this meeting which is to link genetic variation with the many kinds of nongenetic variables.

Thank you very much.

Terrific, thank you very much, Joe. Again, any one particular pressing question? Great. Thank you, we'll come back to you in just a bit.

Now, Teri Manolio will give us a sense of the overview of this issue from the international and national perspective. Thank you so much, Teri.

Great, thank you very much.I appreciate being invited to comment on international and national studies. There are a large number of them and we won't be able to do them all justice, several will be discussed in more detail. I was asked to review the studies and then talk somewhat more about design as well. Design of perspective studies of case controlled study. I probably won't have a chance to get to the last one. Use of existing okay hooters and new existing okay hooters. But if we have have time we will.

New ones are cropping up every day. Very few of them have gotten into the field and gotten going. The population -- the public population in the U.K. biobank you'll hear from subsequent speakers so I won't focus as much on them. Biobank Japan, I can talk about. This one I can go into in a little more detail because it's the one furtherest along and generating results. I'll comment on the marshfield project and the national children's study and a variety of other clinical samples I won't go into.

A broad overview of several international ones, the biobank Japan, obviously, in Japan, is anticipated to be 3020,000 people ages 20 and above that focuses on, at present. 47, common complex diseases which as we heard before, were diseases that don't seem to have the pattern of inheritance that are related to a single gene but probably to multiple genes. Access to those data and sample at present is limited to Japan and Japanese researchers. The genetics in iceland. They anticipate having most likely, the entire population if they keep going, of at least all of those that consent be at least 200,000 of all ages. 50 common diseases and access is possible with collaboration.

The genome project in astone yeah is varying estimates to have total size of the country is 1.3 million and they initially talked about trying to get a million of those, now they're scaling back closer to 100,000. The age I'm not sure of. I assume all adults but don't know. Common diseases and with dlab ration.

And you heard much about the U.K. biobank and we'll hear much more about that.

The cart gene is a Canadian study in Quebec anticipated to be about 50,000 people, age 25 to 74, focusing on common diseases and they -- whose flight was cancelled, will tell you more about that. The twins, similarly, is part of that collaboration. It has seven European countries with 800,000 twin pairs. Twin pairs are a very interesting genetic model. Great strengths well as weaknesses. I'm sure you'll hear about that. Focusing on seven key outcomes at present and are available with collaboration.

The marshfield penalized medicine project relying on the marshfield clinic. Anticipated 40,000 people. 18 and above. A large focus on adverse drug reactions and David Goldstein spoke to you early about the importance of adverse drug reactions and I would think you could find really exciting information about this.

The national children's study we'll talk about later to, include 100,000 infants and mothers to follow them for 21 years.

Just briefly to comment on the biobank Japan. The goal of the study is to clarify on a large basis, the causes of diseases and medication side affects in relation to genetic variation and ultimately, to develop new drugs and dying nos. The goal of many of the large biobanks focusing towards dug drugs and diagnostics to to the field, but to help support the biobank itself. Samples and data will be collected by a network of collaborating organizations and private universities, public universities are not involved. And that has raised some eyebrows outside of Japan but the Japanese are quite happy with it and it's their study. These are some of the universities involved.They hope that their project will stimulate the development of lodge slags in Japan to predict personal research information. Not only genetic information but research information in general, which is an interesting sideline of a biobank. Begun in 2003. 90,000 samples have been collected to date and that's 120,000 disease cases because each person they collected has more then one disease. This is unlikely to be a random population sample. More patient-based because it's working with hospitals and, so, it's relevance to a general population is a little more questionable.And distribution of DNA and serum to Japanese researchers has already begun.

The astonian project has a similar goal to find links between genes and enviern American factors and common diseases to apply it to improved healthcare. Maybe as many as a million persons but scaling down to, perhaps, 100,000 begun in October of 2000 with about 10,000 recruited in an initial pilot as of 2004, in three astonian counties. Written-informed consent. 6 to to 90 minute questionnaire including information back two or three generations, simple measures, height, weight, balance sheet, heart rete and a blood sample. Personalized information is intended to be provided back to participants with their consent and interest, and to their physicians with their consent. People who participate in that are called gene donors and actually, participants can go on to their website in astone yeah and ask a series of questions about their involvement and what it means.

There's a nonprofit astonian genome product foundation in public-private partnership with egene, ink, which just recently dissolved their arrangement with egene in 2004 and they are now looking for other sources of funding.

The marshfield project, as I said, is based out of the marshfield clinic in Wisconsin, a very large private set of clinics. Intended, also, to translate genetic data to knowledge that will enhance patient care. It utilizes the marshfield Epidemiology study area in central Wisconsin which has a long-standing electronic medical record and utilizes the strength of having ongoing electronic record. I would comment the CLINICIANs are still CLINICIANs in Wisconsin and don't ules record things in a standard way. Just because it's electronic doesn't mean it's reliable.

They intend to recruit up to 40,000 people. Age 18 and older. In September of 2002 and they have 17,000 recruited so far. Response rate is fairly respectable for a study of this size and scope of 45%. In the Epidemiology studies we like it to be much higher but for a variety of this is quite good. Written informed consent. Questionnaires, dap extract and blood. Data is encrypted which means there is no one with access to the identifiable clinic information has also, access to the genetic information and there's a link that can be broken by a third party.

Decode genetics is the icelandic group, a biopharmaceutical group that is studies the development of drugs for common disease. They yiewt lies the unique resources of iceland. It's relatively isolated. There are founder affects there which means they were settled by a relatively small number of people, probably still in the tens of thousands in the early 10th century and have remained isolated since then. Also gone through a series of population bottlenecks, fa minimum, disease and volcano eruptions and things. They also have an extensive gene logical database going back to the settlement of the Long Island in 900A.D. and good record systems. They currently has DNA data on 110,000 consent icelanders and 20,000 nonicelanders from various parts of Europe they have collaborations with begun in 19 98. There was tremendous controversy generated by this project because of their proposal for an opt-out consent for access to medical records. A proposal to have what was called a health sector database accessed in everyone unless --

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Well, what can I say?the Lord has spoken. But I'll try to have a little more activity here. Okay? As I was saying. This opt-out consent caused a big problem and that, eventually was abandoned. The plans. Whether they're revisited or not in iceland is not clear. But there's written informed consent for all the genetic studies and third-party encription as well. In the interest of full disclosure mention I am collaborating with this group and that's why I know a little bit more about it so take my comments in that context. The uniqueness of this population, founded by settlers of mixed European descent of norway and swee den. The British aisles and picked up passengers, sometimes willing and sometimes not. And went to iceland from there. The current population is about 285,000, which is almost exactly 1/1000th of the U.S. And another tremendous resource is their careful geneic records. This is almost an obsession, they all know who they are related to. When two icelander's meet they'll say you're so and so's grandson and my cousin went to school with your aunt and they can all relate each other to various relatives. And it's an interesting -- without, you know, any -- it's not like there's feuds and that sort of thing. But clearly something they're very interested in and have kept very good records. Given the relatively small founder population, relatively similar genetic background and isolation following that means fewer variances to study. What has been done with the records which any family, if you visited an icelandic home, after dinner they'll show you the books. These have been computerized and every icelander has a password. This is the gene yule give of the founder of this and he can go into this as can any icelander and trace his gene yolg back to six generations to this person and then, click on this next button. She was born in 1776 and trace her back another six generations and then the next one, born in the 16th century and in the 14th century and in the 12th century and, finally, back into the 10th century. Back to their original Norwegian founders and of them can do it. It's really quite remarkable. They can also, when they meet someone, go home and look them up in this database and find out who they're related to and find out how closely they're related to each other. Married couples were very interested and they were like, oh, gee, we're related back five or six generations. Maybe that's why our son, Charlie, is so strange. More often it's just an interesting how pi they have. They're very interested. They'll say, I can go home and check and see who I'm related to. This is a big deal for them.

Also a big deal for science, what one can do is take two people that happen to have the same disease and see how they're related to each other and pull out groups of cases that actually are related in very large ped agrees and that's done in a project. This is a ped agree with 69 patients. Not the largest one they had. One was 700, but this one fit on the page. All these people in these little black boxes and circles which are a tremendous resource for finding genes. The purpose of this study is to identify genes related to common diseases.And what we did with this, then, recognizing the common diseases don't show the inheritance patterns and very often you don't have relateded effected siblingses which is the model most often used in this country, but you often have people with more distant relatives. So you can look at the degree of relatives you have a person with a disease, his or her first degree relative are 77% more likely to have the problem, too, then people without a relative with the disease.If you exclude the first degree relatives which are mothers, fathers, sisters, brothers, daughters and sons, the relative risk is still 36% higher. 18% higher if you look at third-degree relatives. 10%, 5%, and very few populations can go to this level of detail in relationships. And what's interesting about this particular example is that decline by halves, in the degree of relative risks parallels the decline in sharing of genetic variance through generations. So it's very strong suggestion that there's something genetic here that's related to this disease. Usually this approach to map diseases which means finding areas of chrome somes that are likely to be related to par for all of these diseases shown in white, for those shown in blue, sorry, we actually identified what looks to be a variance within a gene and a possibility of a variant related to it. And then the purple ones are ones they developed drugs for and in clinical trialing to try to reduce. So, again, a very pow everful way for finding genetic variance.

One of the challenges in identifying genes to actually understand, as gill was alluding to earlier, the population impact of these, I would Squibble a little bit with Dr. Goldstein's comment that just because you know a gene doesn't mean you can do anything about it. Sometimes they -- it may be that one would want to really reduce those other risk factors as a way of, perhaps, reducing the risk before. That's a reasonable research question that needs to be pursued. If you consider genes to be risk factors passed from parents to children, the Epidemiologies know what to do. You look at association and preve lense that are identified in family studies or other studies, assess their magnitude and independence, recognizing the common risk factors are generally not strong ones, strong risk factors are generally not common, if they were, we'd all have them and get sick. Those get weeded out and we end up with the smaller affect of much more common. One can define associations with I is variety of types, but perhaps related to other diseases as well. And identify factors particularly enviernmental factors because these are the things we can change. They've've changed in the past 30 years to us the incredible epidemic of obesity. If we can identify those things and have impact on them we may particularly want to do that within the genetically susceptible individual. This shows just three of the variance that they've identifieded. There are a little bit known on the frequency and risk associated with these in the icelandic population, for a variety of reasons very different from the U.S. population and one would want to know not only the frequency in risk but what other types of associations are there with this particular variance and particularly, what modifies them. Very little of that work has been done and that's what needs to be done in these larger biobanks.

Frances Collins published a paper earlier this year talking about the need for large studies and we'll have comments later.-- the actual quantitative contribution of the environment and genetic factors, the interactions Monday them and other disorders that may share common risk factors F you get heart disease, does that affect your risk for asthma or cancer? It probably does. Rerecognized and pointed out that replications of associations and estimating their magnitude and consistency and time relationship is best done through the perspective studies.

Just briefly, the studies that are prospective, before the time the disease develops into the the future of investigation of a representative sample. Representative meaning you can relate that to the population from which it was drawn. You're not just studying truck drivers who may be different from the of the population. Not just studying air force pilots, a sample that's representative of the entire group. Follow them for development of specified end times. Identify things and look for them actively so they don't just happen to be picked up but are surveyed and 3EUBGed up system AT&Tally. The purpose mentioned before is to identify the risk factors predisposing the disease of the general population. Particularly, you want the design, when you're looking for risk factors effected by disease so you can't measure them after the disease occurred are things that are affected by treatment or lifestyle changes, when people are sick, they think they need to help do something to prevent myself from disease. This can have an impact. Joe you larly want to look at those difficult to recall and which there is buy yos recall. Once somebody develops a disease and we'll talk about that. Something that has an impact early on and later on may not have much of an effect at all, you're likely on to pick those up in prospective studies rather then waiting until the disease occurs. .

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Thank you all very much. Our next three presentations will explore the low link cal, legal, aspects of large population studies. We're very please d that that Marlene has been able to join us on very short notice. It turns out that Barbara moppers is in Canada and there's something like a snowstorm up that way and she couldn't get In Somar lean was very, very kind to come in and help us out here. She will present an overview of the Elsie issues followed by Charles that will explore the dichotomy between social identity and the ancestry and the issues raised by this die -- dichotomy and John Newton in an effort to develop the biobank. Let's turn to Marlene of large population studies. Thank you so much. There's a little timer there in case you need to time yourself.

Good morning, and thank you for the opportunities to talk to biobanks. I learn yesterday that I would be giving this presentation by March that's plane was cancelled so I hope I will be able to convey her ideas because this is her presentation. The presentation is divided in three parts. I will first talk about the legal and ethical framework and I think we're still in search of an adequate one so I will comment on these. I will kind of skip the second part because I think engineer Teri Manolio talk about these existing aspects and I will focus on the thuvrd time challenging and the issues of population biobanks and I'll talk to you lastly about p G3 at the end of my presentation. Let's start with a small brief introduction. I think it's clear now that we, the way we do research has changed in the recent year. We first looked into more single gene disorders and now we're in more complex diseases. We're really now focused too international and international collaboration and, in fact, they're pivotal to ref and complex diseases. And we went from what we call research on traditional biobanks, the ones that, you know, the small and researchers lab to towards human genetic research database per se. Finally it's interesting to notice that tissues were at some point interested almost waste and now they're kind of to the level of almost equivalent to the person from whom they came and there's been some recent bureaucratic review. I don't think the process was sfwended to be as complex and bureaucrat advertised as it was right now but there is -- it's certainly an element we need to take into effect. Was it the biobank. For the purpose of this presentation we're focusing on collection of information that is organized, that is searchable, it's not just a large bulk of samples. You need to have a way to search through it. It's interesting to note that in the legal ethical literature, oftentimes biobanks collection courts, these are works that are used as if they were all synonyms and we need to make sure we use the appropriate wording and I'll focus on this presentation of the reality meaning this large population database including at least 10,000 individuals. What are the legal and ethical framework and what struggles do we have in those? I can see two things. First there's really a trend toward a proliferation and specialization of international and national policies, and I'll tell you about this in a minute and through this we see that this demonstrates a need of urbanization of some of the principles but most importantly of the terminology and I will tell you more about this too in a second but talking about the proliferation and specialization of policy. Here you see at the international level within the past three years, some of the international guidelines, legislation or declarations, I should say that has been adopted by various organizations like uc Oor the world helicopter organization, if you look now at National levels and the title says it all, it's very uneven playing field, you see a great disparite between all jurisdictions. Here you have a few countries, legislation that specifically regulates human genetic research database and these are interestingly enough they come from the examples we have here, all come from northern part of Europe. If you look at other jurisdictions, some of them just rely on the current data legislation, public health legislation, traditional content legislation and this creates some confusion and conflicts and overlap, and some areas are sometimes left even unregulated. I think this code says several systems co-exist so there's different angles that ignore each other. You try to regulate by pieces that are not well, a dapted to human research databases. You can see an increase interest in debate including the database and these are examples of very recent documents that are issued by advisory committees or law reform commission in various countries. And the Canadian biotechnology advisory committee being the most recent one that we have here so we see that there's an interest and some discomfort at least in the countries with respect to the current situations. If we go to the second part, the challenge of urbanization, the international level, it's very clear that there's an increased need for urbanization, sorry. I think the lack of internationally agreed upon rules but most importantly common taxnommi is really detriment to research collaboration, it's an impediment to be able to exchange your sample to other countries or to transfer information so we need to acknowledge this problem and it's already being acknowledged by various organizations such as the wh O. Here you have the bible towers, really I think that's how researchers of out of their field and this secretary general Ewan quote, says it all. It says despite the existence of codes dealing with jet Nick tick data the changing call for the establishments of an international instrument that would enable states to agree on agreeable principle to transpose into their legislation. This is a wish. But it's a tool that we really need right now for the type of genetic research that we need to do. At the international level now there's a need to recognize the specificity of human genetic research database. These are no longer research projects but research resources that will be used for put multiple future uses so it's quite the different thing. There's limits to the traditional concept and privacy legislation. These legislation often time were created in the context of research for candidate gene for diseases and are not really appropriate in the case of database like the one that we're talking about here. There's also a need in personal data and privacy legislation, there's a need to have a more common language. We know that there's a huge problem with the vocabulary that's being used right now for coded deno, ma'am nized, d link, deidentified and one country and another country the same word will mean something different. And so when you want to respect participants and make sure the concept that follows the sample will really show your partners how they should use the sample it's a problem because we're not even sure how it's understood at each -- between each partners. So there's also a cause for the implementation of a more comprehensive regulatory framework so that we'll be more easy I would say to conduct these types of research. There are some consensus on what shall we should be working on. The first thing is certainly to work on the tailoring of traditional concepts of research databases. We can no longer use the traditional consents models. I don't think it's appropriate neither for participants nor for the needs of researchers. We immediate to have a better correlation between the data I'd fiblt and the obligations that comes with it. It's more interesting, of course, to have data that are coded and we can link to a part pants but it comes with obligation and what are we going to do in 20 years from now? Will we have the obligation to bring results to these participants. That's something that we need to clarify. The need for ethical oversight from the inception of a database as well as monitoring mechanism. That's something certainly we need to work on as fast as we can. Initiating and promoting and strengthening the professional and public dialogue. This is fundamental to the type of enterprise we're talking about and we certainly need to work on it. And it's kind of reted to the last point either, the need to give up a benefit sharing policy. We need to do I think a better job at really being able to identify what are the benefits and it's difficult because we know the benefits are long term but for the participants and the funders and be able to justify such an important investment, we need to to be to have better communication with the public about this. Sole controversial issues, funding. If I think -- this is a very sensitive issue. If we want these human genetic database to stay in the public domain, the way they will be if youed has a tremendous impact. This issue about original concept form and secondary use of sample is also one that's controversial. Are we going to go into this banquet concept. We have very big doubts that something that's going to be accepted in the legal system but it could be possible. There's suggestions about the authorization model, maybe it's a new way we should explore but certainly what's the appropriate type of consent we need here is something we need to further discuss and it's really something that he is a sensitive he should because it will have an impact on genetic research and any other research. Protecting privacy. Again, the choice of word is very important. Personal feedback as I said or what are we going to do in large-scale setting, it's recent to think we will bring back results, individual results. Is this something that's reasonable and feasible. The status of genetic material, ownership, who owns these database and the tissue and certain jurisdictions, the mere fact that you would own tissue is counter intuitive I would say and against most of most of basing fundamental principles. Looks into checks and balances is something I will talk a little bit more in the second, and ethical review for multicenter research project is also quite challenging these days. I will skip this part and go right through now to the challenges.

So if you were to establish a human genetic research database right now what would you consider? What are the fundamental elements you need to think about? And we think there are at least three elements you'd like to go through. The first one is ensuring legitimate of your database of you'd like to look into the adequate protection, building trust, making sure that it's well protected and you'd like to make sure that there's appropriate checks and balances and let me go into more details into all these three levels. If we're looking into legitimate things. You need justify putting so much research, money resources into these huge human genetic research database. What are the benefits? And how, we need to explain these benefits. So this is key into the funding and the support of the community and we need to work on this I think. Legitimacy can come into different ways, in some countries they've chosen the democratic forum through parliament and legislation to start these human genetic research. You have his Tonia and ice lands where in these countries they've created the genetic database. Is parliament the most appropriate way or is appropriate forum by which you could engage the public and make sure that there's legitimacy there. And question that we had is if there's not enough public consultation, public communication prior to this parliament enactment of the legislation, we might have questions with respect to the process. But nevertheless in many countries, it has at least -- it least it's very clear, whenever there's a legislation, you know what the rules and being done. In other project, the initiative instead of going through parent is a project that started by scientists themselves and they are adapting the science to communities's needs and the population's desire and through discussion and again in this case, it's more I would say in the way self-regulated. But the participants have really again here to discuss about the regulatory framework that's being built. So these are two different ways in which you could approach it. Now for transnational enterprise it's a little bit more complex like general no. These are transinternational international collaboration and it depends on trust and communication between members and based on common understanding of the issues issues and agreements on the scientific ethical legal social issues and common philosophy so this is quite challenging but at the same time the benefits are I think incredible. Now the second part is about building trust. Building trust at different levels. First ensuring public representation, and ideally inclusion of all the groups that could be representing the sample population but we know that there are financial constraints and it's not always possible. Building trust with the community realize on -- depends on your communication strategy and we cannot emphasize enough how important it is really to create a communication strategy that really include the community from the start, and that will really enable bilateral communication if I should say so. Ensuring that a collector's participation and expertise, making sure that the people that were collect data are properly trained. That the researchers are sensitive to all these ethical legal, social issues. That's something you will with a to think about. Privacy again, prices cyst often times the think that worries I would say communities. That's the first thing that will come and it's -- in a way it's legitimate because you're in these genetic database you're putting in sensitive information and really concentrating in one spot. So it's legit Nat that they have -- legitimate but we have to be able to answer with appropriate tools, choosing an appropriate concept process, looking into our security mechanism and looking into the type of identifyability of the samples that you're going to look into. Individual feedback and general results, again that's something that the research team will have to make a decision about. You see here different options in his Tonia, they chose to respect the rights to know in a way and in other projects, there will be no or research results except for the medical examination from the start. So that's another element you'll need to consider, but is it possible, that's the question we're consistent derg is it possible to get the appropriate genetic counseling to make sure that you don't fall into the potential problems in genetic discrimination or mis interpretation of results. Finally, stig tides sayings or discrimination are issues you want to consider and commercial aspect. This is a very tough one making sure that you get free public access, yet at the same time, we need to respect all these intellectual property rights that are involved and the involvement of the industry I think there's -- the resource, the financial resource needed for these type of projects often, we will for sure need the involvement of the industry but how to do it, at what level and how to appropriately make it, that's the question.

And finally checks and balance. Thinking about checks and balance, you need to think about it from the start to get profile not approval not only of the protocols but you need to lock into the framework itself and stamp of approval. We wrote from the authorities it could be anybody from the ethics knew to other types of authorities making sure that the public is recognized again as a true partner and will have the say in the establishment and the creation of the framework itself and need to built in mechanism for the review procedure will will it needs to be there from the start. If you look into the research project review and monitoring, this is really I think a quite challenging area because we want to set mechanism to really make sure that there will be appropriate ongoing monitoring not only of the research project, but, again, of these public resources and how it will set. There are very innovative, biodid something interesting. I think there are very innovative -- innovative solutions out there but we need to work on those. And finally the management structures. In each these projects, they've built interesting charts on how the project would be managed appropriately balanced, et cetera, et cetera, so we need to ensure for transparency and independence and integrity but to create and conceive, consistent accept lies these -- conceptual lies these management structure is quite challenging for researchers as well. I want to talk to you a little bit about the ptg project because I've been talking about some of the challenges, the problems of having different taxno, ma'ami to designate similar things. And public populating projects in gentlemen note -- genomics as none for profit organization that is currently building an international consortium to promote the type of discussion that we need in the field of genetic research. We want to foster this international urbanization at all level. At scientific to be able, for instance, to have common words to designate the type of research, common ways to collect data, and also at the ethical-legal-social level to make sure that people are provided with the types of tools and that we can benefit from the experience also of other population genetic research database that are already out there. And we want ultimately to create a body of knowledge that will be publicly available so that all the human genetic research data bays that are out there will have opportunity to really be able to communicate with each other, to be able to compare data if it's interesting, to be able to exchange data because they will have a chance talk about this urbanization of taxKnomei talk about the doubt of some of theegs issues of making sure we have a common roach and common vocabulary. The true pasters in of pg projects and I'll go back to the slides of the website. Transpartners are genome u twin,. The his tonian, genome project, and cimgr, is which is a Manchester project. We have other partners that are coming up in the project right now. And the chair of the board for this project is bartek monopoliers, I invite you basically to go see our website. So just in conclusion, I think, I think we're building really unprecedented, very interesting research tools that will be used for generations to come. But I think the legal and ethical tools right now might not be -- might not deal appropriately with all the issues that are raised. I think often times they were created as I mentioned earlier, for drug research or mandalYan research and if we want these biobanks to really span the test of time we need to look at these three things. We he need to probably revisit the currents ethical legal framework and make sure that participants are on board and on board in communities are on board very early on in these types of projects. Because I think ultimately the success of these types of human genetic research database will rely on their trust in these types of tools. And we had the common goal here. It's really to benefit the health of everybody. I think we then should have common vocabulary and we still don't have this yet so we need to work on. This thank you very much.

Thank you very much, Mary. That was terrific on its own merit but even more terrific for having stepped in at the last second. I'm looking forward to Hance opportunities to lead the rounds table with all of our participants and the opportunity to query eave of you at that time. Let's turn now to Charles rotin suz heny who will chair is his thoughts on the dichotomy between social identity and ancestry and large population studies. And, Charles, thank you. Again Charles is acting director of national genome center at Howard university.

Thank you. . Thanks for inviting me. What I thought I'd do today is to share with you some of my thoughts, some of my biases and how I think about some of these issues in relation to how we do large population studies and how we try to represent different groups or not represent different groups for various reasons. One of the first comments I want to make is depending on what we're doing, we desire different level of resolution. For example, F. we are trying to identify how common layers, at least five percent or higher impact on disease, we will define our study in such a way that we have a level of resolution to get at that. For example,. If we want to identify people who eat beef, that's one level of resolution. And if we want to identify people who not only eat beef but eat it in a certain way, cook it in a certain way that's our level of resolution and you may have to go to some part of the world and not go to other parts of the world. So again, depending on how we are defining ourselves and our identify, we do stop at different parts of this. If you really look at only in terms of our history, one can say that we are, indeed, Africans and we started somewhere in terms of the roots and trunk of evolutionary history of somewhere in Africa, but, of course, time has -- did not stop and we -- migrate to different parts of the world and depending on your socialization and what you wereling to accept how you want to define yourself and the question of survival, the identity you want to put forward, your level of resolution do differ and we have to always bring that to bear and that is why it's extremely important when we are defining large-scale studies like what we are planning here, that is capable of impact our health for a very long time, we need to be extremely careful who is at the table and who is making decisions not just in terms of science but in terms of how is this representing the people especially if you're using taxpayers's money so it's extremely important for us to appreciate all of that and scientists were socialized before they became scientists, we bring all of our baggage to these issues.

Also I want to again make some distinction here and that is in terms of when we are talking about understanding geology and eliminating here disparity. Sometimes we say these things are the same and overlap. I want to make over lap a little Bicker but I couldn't figure out in the power point. It is a little bigger than that but they're not complete overlap. For example, if you are interested in Elim nature her disparity, you may be interested in how people get access to care. That means they have nothing to do in terms of etiology, we need to be clear as to what is it that we want to do. a Strategy to look at the disparity may, indeed, may have more involving strategy at a social level. Again, typically we look at a die gram like this or we usually use this to represent a disparity and sometimes to point out etiology. One of the things I want to point out here is when you look at, a 50 percent prevalence of type II diabetes among Pima indians one has to wonder as to the same United States as to what is going on and the gene hasn't canninged that much. It doesn't mean genetics isn't involved but it hasn't changed much over years. One of the things we do know certain characteristics has changed the looking at the eatling and disparity and maybe addressing both, now this is looking at populations of the African population. This is where I used to stay when I was working at Louisville medical center in Chicago. It's 34 African-American and this cohort is over 10,000 people from different parts of the people. What you see again is this is clearly a disparity issue but on more people who are recent African ancestry. About 50 percent here, about 34 percent here and you do see a dramatic increase in body mass index so clearly how heavy you are and the environment you find yourself has serious implication for hypertension. There's a new study that is extremely important in terms of how we address some of these issues, what are we calling disparity, how plentiful groups in different parts of continuum in terms of the experience with the problem of hypertension. This was done with Richard Cooper and colleagues recently and what did you see again. Clearly depending on where you are, you do have very different rate. What I want to point out here, when you look at whites, a group we call whites within the United States, in relation to our group, typically we say there's a huge disparity. There is a huge here disparity but if you place all of this populations and look at it together. You see that it is truly a human experience. And when you are in Germany your rate of hypertension is really, really high. The U.S. tends white -- white tends to be quite health any in terms of European population and there for exaggerate to a large stents who gets hyper Texas and who does not. This is is really important that we have to bring to bear, cross culture experiences, bringing to bear international experiences so when we're defining variables, and we're defining strategy that we take those into consideration. This is the same set of studies. Now if you your group is Europeans, the populations in all African populations, do you see that Europeans have a much higher level of systolic blood pressure you but you don't hear this when you hear people talking about their experiences of blood pressure and hypertension. So again, cross culture comparisons is extremely important international, and extremely important when we're doing these large-scale studies. Also what we want this large-scale study to answer. We want to define this to the study. Do we want to give us the level of who gets diabetes, yes, no. Who is reacting to drug, yes, no or also want us to tell us some stories about who we are, where are we from, how we are represent thed. May be use thul this type of activity. It, indeed, it is, we need to bring to bear a design strategy that will help us to say this in a way that we are not reinforcing notions about who we are. So in that regard, ancestry in my opinion becomes a very critical thing for us to consider. I like this slide a lot because every time people talk about this whole issue of race ethnicity, I'm getting so tired of the whole issue, but I always ask myself where do we draw boundaries, and how do we draw boundaries. Again it really depend on where you grow up, how you were socialized, the things that you are afraid of and the things that up like. Who is black? This is the whole spectrum of who is black and this spectrum is limited. Husband pan panics, there's no -- hispanics, one of the pictures I've seen on a PBS website where they actually show that you can see all the variations of complexion right there in Africa, all of it the, the skin complexion you can see, and I'll show you some of the of my experiences in Brazil. But do you see that these could be considered black. But there again, radically different ancestral history through Ethiopia and different parts of the world. I put a slide here to tell a story in terms of what we're doing in the type II diabetes in the Africa Astoria.

The real intention, what we're trying to get at why is the high rate of type II diabetes in African-Americans and to get at that we need to go back to the population of Africa American, and we are noting of the history of the middle passage and that our most African-Americans again came from this part of west Africa and again Mozambique. But the story here I really want to put point out when we started writing manuscript, reporting the results of this study, one of the things that I I called to task on is how are you sure that you can combine all of this group to go because there is an effective design and we analyze the cohorts about 400 pairs with type II diabetes, we analyze one cohort as one group but repeatedly, we say how, why do you think you can combine all of this group together. But the point here is that I have done a lot of work in African-Americans and no reviewer has taken me to task why do I think African-Americans are uniform group. You see how the way we are socialized when we reviewed the work what will we find because this cannot work if you're -- anything can be cured for that reason only, that reasoning. But you could he that even the ancestry history of African-American is even broader than what we have here. Nobody takes us to task on it because the assumption is we are dealing with a uniform homogenous group so we need to be very conscious so what we're talking about so the problem I say is group identities confuse with ancestry. Identification is confused with more complex tapestry of ancestry. Now, when I prepare a slide for this talk, if you take the issue of African-American is confusing, talk about history called the Hispanic group, what is the group we call Hispanic. That is completely mind blowing where you think of about who we classify some people under that umbrella. To some unity to me begs the question of what we are doing and it may indicate why we are not getting some consistent results, some work we've been doing because we lump people together and build on some very interesting groupsings. When we look at the census pretty clear. We are the one that confuses it. If we're not doing anything based on biology, we're lookinging at society bails itself and collecting information on that. When we do our studies we I want to impose biology on that, sometimes it works, and sometimes it doesn't work. So Hispanic, you can be of any race, okay. So this is just to oipts out some of the groups we call Hispanic. Mexican, you know, South America, Cuba and Puerto Rican. This is a whole list of people who have radically different ancestry, if you really go into the history and I put a slide here. This is -- picture, my only visit so far to Rio. I wish I extremely informative for me and I enjoyed myself quite a bit. I was flabbergasted when I drove into a major road going to the university in Rio and I saw this junction. It took me to my young elementary school days when I was in Nigeria going to school. We used to put up a school bag, ours was made out of metal box. We put it on here. We're so good -- on our way to school. But what it turns out is this is sacrifice. In Rio, they follow the European tradition and I was extremely surprised by that. You have these chickens and parts and oil and wine, you know, making offerings to the God for protection. This is three years ago in Rio. Now talk about Genome environmental rack. If you're studying this group you better take into consideration the African ancestry and history and why this group have kept this experience offer over the years and what does it mean, therefore, to have Cuba and Mexico, Brazil as Hispanic and studying them as group? This is again to assure again how we lump people and sometimes lose quite a bit of information. If you look at people who are 18, under 18 and 65 plus, you do see that depending on which population, Hispanic population that we are sampling you could be doing yourself a disservice or service again just to show that and the same thing also are here in terms of education. The radically different experiences again, relevant. I think the same story is true when we look at Asians. We do group all of these group and we call it Asian. Now, for example, Chinese, now, how does that represent the experiences of this are report and the ancestral history of this people and if, indeed, there is something that has been selected on over the years and these are the other own experiences, may, indeed, Lumbee were captured, I don't know but for us to be conscious of who we're calling Asians, one of the other extreme in this experience in working and actually I live in the United States is that depending on how you see yourself, and how you related to your environment, you 10 to lose some of the social identity that you have. It's not important any more to be German American. It doesn't offer you any extra advantage. Okay. Whereas maybe extremely important to identify native American or, you know, Hispanic or, however, as you want to do it. , but, again, this shows that depending on the group, who is sitting at the table, the maximum relevance of certain things and not the relevance of others. So we need to again be very careful as to why we're using this labor, how this labor came about and what is the present relevance. Okay. Now to sort of rounds out here, looking at ethnicity, identity in terms of Africa, one of the things that happened over the years, -- and this is just one of the issues I take to apologies, I 10 to single them out" is this whole notion of thinks within that part of the world or remote environment sort of static and they don't change or we don't want them to change so if people have been cooking, in particular, we want them to continue to cook. Whereas in our environment we are creating jets that can carry 1800 people now. We are like the society to evolve and want others to stay static. I don't know the rationale behind it but the point is just like anywhere in the world, identity changes how we look at ourselves changes and these are based on economic, political and whatever else ways for us, especially an issue of survival. Obviously we're extremely efficient in the way we identify differences because I do believe somewhere down the road that we need it to be so. We need to know who is family, who is friends and who's -- so we're very good at seeing differences and it may not be the reality when you're looking at the genes. So the message here really is things need to study. That identity changes, it's multilayer, depending where you're looking genetics may be important, may not be. Making the sacrifices may be more relevant in terms of the issue. So I like to end by just again bringing us to some theory as N terms of who is who is telling the story. Depending on who is telling the story, depending on who is designing the study, depending on who is present, who is funding this study, you can tell stories and history in a very, very different way. Okay. For example,. During the interaction between Europeans and Africans, there was some surprises that were not anticipated. And because of that biases that came or preconceived notions certain things were difficult to accept. By the way, this is where I grew up. Some of the issues we have again we're still trying to get some of the work that went away a long time ago. But the typical message here for this particular slide is we need to take more comprehensively if we are going to design very large studies and especially if we're going to for genetic environmental interactions. Again, this is the same set of points. I'm just going to escape this. But where do we sample, again, because they're relevant. Because very interestingly oriental European Americans, again that's a very broad term. I'm not quite sure who is under that umbrella -- tends to be -- you can sample anywhere in the United States for that group. But if you're interested in American Indians, eskimos, Asians, blacks, his pan he can, you have to go to different parts of the United States. For example, you do see most African-Americans are here. The people we call hispanics are here. So again, it is very, very important, if you want to emphasize efficiency that you go and depending on also who you're putting on that umbrella of Hispanic it may do you better to be in Florida than to be in California. Again, just for us to be conscious of that. And this is something that we did recently at Howard university with gentlemen met ticks. Really and some of the people are here, actually contributed to that effort. It's really to not get at how do we explain the fact that yes, there is variation at a genome level and that variation is to be studied and how do we do it in sufficient a way that we don't bring old notions on it, let it tell its own story so we can really know how we relate. But the point I also want to make with this slide on depending where you draw circles here, here, here or here. The genetic variation will tell you the story. If you move, it would tell you a story. There would be overlap, there might be some differentiated frequency. Usually what happened is that you you don't have uniqueness. So in terms of large-scale, I look at large-scale as this big umbrella. And as we are trying to fit a lot of things you know this big umbrella. Depending on how many thinks we want to fit you know this umbrella, the timing, the level of compromise that we are going to have to make, this could be prostate cancer, heart disease, this could be infectious diseases, HIV or whatever. So depending on what's it is that we want to put you know this umbrella, we are going to compromise, we are going to have to make some compromise and I want to say at this point that the real critical thing here is the type of fen no typing that is going to drive all of this again. This effort. At some.in the very near future, five years or so down the road, we'll probably have genetic variance, and we'll put it around our neck like an id card but the environment is interested because it's ever changing or not, and depending on how we feel today, my blood pressure quarterback high or it can be low, just looking at you, I can be smiling and things happening to my physiology. How do we capture that in a way that we can relate it to genes that are supposed to be based on this environment. I think we need think carefully how many things we want to put you know this umbrella or we want to answer. So as as a final note here is that the whole point I'm trying to make in my presentation, or I'll try to make, was well articulated here. Historical and throw Poe logical thing of pop saigz which are research the correlation, superficial understanding of the present ethnic populating or or how these populations were developed. The future drug therapy will not depending on the emphysema significance of the race ethnicity but individual adaptation and David made this point earlier. It's not to eradicate or diverpdz or redefine or move beyond levels such as race. Thank you very much.

Thank you very much as well. We very much appreciated that. Thank you. Now let me invite John Newton from the U.K. biobank to share his perspectives I'LL TRY TO FILL IN A BIT MORE DETAILWE'RE STARTING WITHFIVE00 THOUSAND PEOPLE. WE'VE CHANGED OUR AGE RANGE AN GONE DOWN TO RAGE 40 TO 69REASON WHICH I COULDTHE ESSENTIAL IDEA IS RELATIVELY SIMPLE. WE IDENTIFY VOLUNTEERS AT BASELINE. WE COLLECTINFORMATION ON ENVIRONMENTALEXPOSURES, WE TAKE CERTAIN MEASUREMENTS FROM THEM. THEN WE TAKE BIOLOGICALSAMPLES: BLOOD AND URINE(PLEASE STANDBY]I'LL TRY WITH THOUSAND AN COULDTHE RELATIVELYWE IDENTIFY COLLECT ON FROMTHEN STANDBY]OFOF OF.

SO IT'S IMPORTANT NOT TO OVERSELL THESE PROJECTS.IT'S ONLYPART OF STRIKE THAT TO ANSWER THESE QUESTIONSTestingSign tfic objectives..

There will be large numbers of people with diseases.If you choose the right diseases for exampleThings like so rise you can do rather nice studiesOn theCases.We can also do the classic studies looking at people with a particularExposure. an environmentalExposure.Perhaps exposures to pestsides orOtherPerhaps smoke orClass or some occupationalClass.And follow them up as a Group.An interesting vair yent on theStudies isDrivenClinicalWe're recruitingHalf million people and there'sExpectation that perhaps within five years it will bePossible to genotype the wholeCohort for at least a limitedNumberSnips. would thenPossible to identify peep wlSnips and invite them so they canVolunteer inFashion to take part in studies looking at the effect ofGenotypes inRepresentative Group of people as opposed to people who have identified because they're ill.This isVery powerful.ItWholeSet of ethical and legalProblemsEven on top of the ones thatMarlene described IBut nevertheless we'veSomeInterestingDiscussionsTheGroups in the U.K.Suggesting thisLikely to be feasibleProvide it's done carefully.TheThird big area of interest of course is in identifying bimarkers as earlyRiskOrNot just as a potential diagnostic tool but as something that helps us to explain the model.The fact that substances raised beforeSomeone's developed the disease may giveClues to the disease mechanism.In general I think the point is that studies like biobank and all o others we've talked about and indeed complimentary studies will help us to understand disease models in a way we've never done before.And of course is really the holy Grail of biomedical research.What we do with thisSeparate question.Scientific justification for prospectors. course you f heard this before. one or two things.HavingInformation on people regards to severity is importantTake coronary heart disease, many people who develop coronary heart disease it arises in suddenDeath and not having samples beforehand can be a problem or indeedRisk factors beforehandAndOf as certaining blood Sames generally for pro tee ai mix isNot just genetics isImportant.Point about genetic study is if you take genes as justRiskFactor it's important thatPerhaps as Charles points out you have to have no preconceptionsWhat the disease risk factor relationships might be.If you start with case control studies you will rarely detect relationships which with diseases that you haven'tThoughtSo if a particular gene causes say parkinson's rather than breast cancer, you are doing a caseControl study of cancer you won't defectThatRelationship.It's importantPick up things you weren't expecting and it's important to be able to study health well as disease. would argue you can only really do that by taking samples of the whole population not just a Group of apparently representative cases and controls.So recap the general benefits of uk biobank lie in public health and look at howFactors work together in populations, clinical medicine, understandingDisease Groups better, particularly k lookingAtCenturyPrognosis is the essence of goodClinical medicine.And biosine, particularly the bio marker disease associations.And the process of doing biobank raises a whole lot of issues that we've had to work through.And we think ha will have inthenfits for others.Particularly our work on ethics and governmentThe whole approach tends to provide better access to resources for scientistsAnd it promotes InternationalCollaboration and in some sensesIs efficient and economicallyBeneficial as well.Moving on to the details of biobank itself.How is U.K. biobank funded?WellFourResearch funders Cale together.Cost is 61 million-pounds about million of which the lion share comesMedical researchCouncil and the welcomeTrust, a large biomedical research charity, well as the governmentDepartment of healthIs that a lot of money?It's approximately the cost of aFilm three cost the same as biobank.Some will argue that terminalThree made a profit.Bio bank may make a profit too.Of course the point is the value statement for biobank is thatThe value of the resources isWorth a lot moreThan the cost ofCollecting it. that becomes increasinglyTrue as time goes on.TheHealth service in the U.K. spends the same amount in eight hoursSo if we canHave some benefit on health care it will seem a small amount ofMoney.Again another comparative cost. cost of biobank is about1 percent of the spend onBiomedical research in the U.K.SoFunding a project like biobank isn't really distorting funding priorities in the U.K.Well that's my bit on the fundingHow have we established biobank? it's important toProperly.It seems like hard work but I'm sureWorthwhile.We haveBoard that biobank itself is a company,Charity withAims.But an independent companyThere is aScience committee which advises biobank on all matters scientificThere is on the other side a separate ethics and government council which is independent chaired by the professor of bioethics which advises biobank on ethics in governments particularly in relation to the interest of participants and will continue to advise biobank and will speak pubically about whether biobank is conforming to its ethics inGovernmentPolicies.WeCollaboratingCenters whichScientificGroups around the country comprising 22 universities in all.Approach is to try to be as efficient as possible this.Is a very large scaleProcess.If we're not efficient we will fail.It's easy to spend 61 million-pounds and not deliverBuy oi bank.I itPossibleTo61million-pounds andBiobank it is an industrial scale process.I would emphasize the need for process planning and project planningEarly on.And we've done a lot of thatA distribute scientific collaboration is think is only way to do but you do have to haveStrongCentralThere is the potentialBuild a tower of babble in producing these big projects and there's a fine line to beCut between having masses and masses of torque and no action and enough torque to make sure that you haveCovered all the bases that needCover.We particularly value theCollaborations and we've had a number of meetingsWithPeopleIn UnitedWhichHelped a lot.Send out our material for comment quite widely and again we very much appreciate the comment that we receive from the years.So we'llParticipantsWe're probably not guying use practices themselves that much.Essential recruiting to biobank is like launchingMobile phone network.You got to try with direct mailing attract half a million people toBuy into our idea and so after considerable thought and planning we are probably guying to take more of that sort of lineSo we will have a increasing we're going to start off relatively small try to get the procedures absolutely right in the first year then roll it out in a massWay. account for thisStudy that you tend to overshoot at the end if you don'tStopHow will participants enter biobank?Well they'll attend the clinic.We set up a dedicatedClinic.Do a data collection and againEfficiency of these processesSo important that weWe think dedicated clinics are the only way to do it.Satch amsTransportedCentral resource along with the data.The question is we hope we'll be on touch screen entry so the data will instantly beAmal gated into theResource.And a big emphasis on archiving and cure ating theSamples and the data for long termUseAnd ofBox five is very important it's always easy to forget this.In the end the resource is only as goodExtent you can distribute and make available the data and Sam for future use.It's important to put resources into that now as well.Data management is a big challenge.Just flick through this relativelyQuickly.A lot of dataAcquired at recruitment to doWith the questionaire, the samples and how the samplesStored.At the end we haveAsFollow people out we have information coming in from the nhs particularly but also research input as well from dedicatedFollow-up procedures.And it had to be gay mated into a intoSecure dataBase.All this isNew, it's got to be developed.There's a lot of interest from commercial suppliers and we're working with some am ofTo develop these systems.Although mostly it's the experience of researchers that really tells you what's going to happen.We also have a big investment in the U.K. InternationalProgram for it.Many millions of pounds beingSpentGrassing together theseData sources which may or may not be useful for us butWe're not dependent on them but they wouldHelp.We've done a lot of work on this.There was anGroup that pondered this.Reviewed theProduced a report which is available on the webFor peer review.And in the end we decided this is what we're going to do.We willGet things rolling but we thinkThe mistakes we've made will bePardonable in the future.Because of the way we've approached itIn essence we'reBlood in various different ways so they can be madeAvailable for the things that scientists want to do so there's going to be plasma and serum we can do baseline -- baseline hematology, baseline biochemistry. the key is storing blood in such a way that people canDoJee net studies well as urine particularly for me ta boletic studies.We'llStore blood so we can immortalize white cells in the future.Just emphasize the volume of work involved at peak we'll be recruiting 750 people a day.That's3,750 bottles arriving in the everyThe storage will generate24million tubes each of which identified withTwo national markers.This is a huge, huge resource.Quite a challenge to manageThe samples will be stored in two ways.Liquid nitrogen.You partly need that for wholeBlood to be able to mortalizeWhite cells at that low temperature.The problem is put k blood into these things is fine.Getting them out is a lot more difficult.Traditionally people have usedLiquidNitroStorage facilities and they are secure.But also used an automatedMinusStorageSo this is a system whereThe tubes you will seeAre stored in racksIn here and these areHeld at minus 80-degreesTheRobot operates at minusThis is a Markup working in aFactory but it's very similar to the one that will be built in our storage facility.The robot thenEssentiallyProcesses theSamples according to protocols which are computerized and uses a laser toRecognize the tube so it knows which tube it's handling all the time.They're used quite widely in the pharmaceuticalIndustry and they're usedEverywhere including restaurants have them for picking bolts from their cellars so if it's good enough for them. of course the huge advantageYouSet the thing runningAccording on the protocolThat the scientist has declined -- defined and it can issue up toSamples a day which can then be made available for analysis.Whereas to extractTubes by hand from liquid nitrogen it can take up to two months to get four to 6,000 samples out. one person working forMonths.Apart from it's extremely unpleasant work.So the health and safe issues.So this is I think the way to go.This is the way to do things in the futureAnd itCostOn the sort of scale we're doing.The cost of the minus 80 storage is about the same asCost of the liquid nitrogenStorage.So there we are.Ethics andThere's a huge amount I could say about this.To sumarize briefly, biobank's base odd fact that people are volunteers mostThat they can with draw any timeThey give broad consent to future use.And this is a huge issue. think I would be more optimistic.And I think broad has been quite widely accepted particularly in Europe asAnSentence approach to prospectiveResearchmentQuestion to what broad consent means and what safeguards you have to put in place to allow broad consent to be reasonable is a big issues and needs carefulConsiderationConfidentiality has to be assured and there's a lt of work that has to be done on this.We've chosen to retain control of the samples.WePeople are wary of their dnA being widely distributed and therefore we have tight controlSamples. other hand we haveFull access to evaluation of the samples andTest on the Sam as and data for appropriate purposes.The word appropriate needs to be defined soInternal and external uses of the science of potential uses of biobank.One of the safeguards that covers a lot of is this our independent ethics and governmentCouncil.We undertook a lot of public consultation before we drew this up and that was of the issues that came out of that public consultation.Felt an independent GroupWho could speak on their behalf was importantWe've also had a lot ofSupportParliamentWe've done a lot ofWork for the house of loords -- Lords the house of commons.In fact there's a veryBig report from the house of Lords on genetic databases which was done as early as 2,001Biobank's a bigStudy.Five00 thousand but it's notBigAnd you quickly run out ofIndividuals for a lot of studies.So it's sentence we can collaborateAnd collaboration means two things.ItEncouraging people to set up similar studies and working with them but alsoMeansNo good if we all set up studies which don't talk to each other.Which is why theWork of btg is important and theWork from cdc look at the outcome of the research studies.There we under the U.K.These population studies lend themselves to countries where you havePopulation registration so there's aNatural tendencies for Canada, U.K. and the Scandinavia countries to think of sit setting up these studies.I was in a meeting at Sweden -- sing apour last -- Singapore last week and we're hoping the U.S.A. will make a contribution.There are already studiesWhich clearly will makeAnd really hope that I will be astonished if the U.S.A. doesn'tReally make an importantContributionTo this world wideOf course you are very welcome to use ourIt would be great if we couldSwap.How far have we got? is the time line.We'rePilot studies.Testing the sample, handling procedures, testing the clinical procedures.We'll start integratedPilot studies which will look very much like the real study in September and we start the main study in January of 2,006.And from then on it's one personFiveMinutes five years. are we doing at the moment? are we all looking so tired.It isHard to work setting up these big studies.There's a lot toWe're doing the piloting.We're setting up the it infrastructure.And tryingThe-- we're planning how we approach the general public.Developing a communicationStrike that to support recruitment.The participants are fundamental to the studies.If you don't have the trust of the participants.If you don't convey the fact that we think they are participants, not subjects, then people will walk away from usSoTakeVeryWe're developing the protocol which was published about two years ago was really a proposal.There is a huge amount ofWork to be put into the protocol.For we've mentioned environmentalExposure measures.That in itself has produced a draft report and there will ab second report.So there's a lot ofWork to be done.The ethics and governmentWill remain draft throughout the project it needs be brought up to date continually and we're thinking we will produce a new version quite soon. put it up for public consultation and we'reImplementing theProcesses.We've commissioned ourRobots.Peep until cambridge are building the robots and we're building the building.This is whereThe storage center is going to be.This is the new headquarters.This is in Manchester U.K. so we thought this might be quite good in terms of putting burglars offSo -- to be so close to them.But the billings will go upQuickly so we hope to have that ready byThisWhat are the ?z a number of challenges.DeliveryThe time linesIt'sSupertanker of projects.It's many, many peopleInvolved.Some of them have a vestedInterest and it's important to try to draw these together behind a common goal.TheApprovalsWe feel secure.We've had a loft discussions.We think we have a lot of support.We've been straight forward about it but it takes time and you-- it's very hard to on you are guying to get the final approval.Whilest you have yourProject plan and the ethics committee can feature quite high in the risk management of that we need to negotiateAccess towards the information sources that we need and we need toInsure continuity of the data chain.By the time people come to use the data we'll be long gone. it needs to be carefully documentedProfessionally I should say long gone.SoWhat is best about U.K. bio bank that perhaps Marks it outThe of theAt the moment I think is the biggest fundedProject.Both in terms of number of people but also in the long termNature of it.The biological resource will be unprecedentedAnd there's a great deal of interest just in the buy market.People would fund bio bank just to get hold of the blood samples.Bio bank is a lot lot more thanThe design of biobank is what makes those blood samples valuable because the inferences that you draw from the analyses we think will be more relook thanInferences drawn from other biological resourcesWeIn terms of ethics and governments we have anElement. can recall the individuals, the participants for intensive pheneo typing and otherInformation. it's continuing relationship with them.We'reRoutineRecords extensively in the nhs and we think that willQuiteWide benefits.I think to emphasizeEthicalApproach one of public participation and we hope byShowing this is an effective approachThat itTo some scebt set new stand stand tareds for this sort of work.Not just in theU.K. but internationally. you very much. Thank you.. you very much.Kevin, you had one quick question then we'll go to theNext Thank you.Just a quick question.You keep talking about thePublic participation and the participants.Do you have outlined aFor how these participants willParticipate in the process

In terms of influencing decision making and the managing of the project.

We have a participants panelment and we've been consulting with them inWhat -- what we wanted to avoid -- we have representatives the publicOnEthicsCouncil.What we have avoided isSort of a token member of the public on the boardForSo I think we're open toIdeas particularly from our panel about that. Okay thank you.

Now let us move to our next panel which will inform us about federal efforts in this area and provide federal perspectives on the need aLarge population study.In this caseOur panelist are under a little morePressureThey only have ten minutesTo do their presentation.So we appreciate though very much their involvementLet us start with Ruth BrennerFrom the national institute of child health and human development toUpdate us on the national children study and thank you so much. Thank you.I'll try to go through this briefly and stick to the time frame.I'll be providing first the background about the national children's study, an update on the current status, and the future time line.The national children's study was authorized in the children's health act ofInHealth act the language is hereIt authorized the nichd to conductStudy of environmentalInfluences including physical, chemical, biologicalAnd psycho social influences on children's health andThis slide outlines the studyConcepts thatLargely derived from the children'sHealth act that it be a study beginning prior to birth and continuing through age 21 years.This study be national in scope.Again that it it be a study of environmentalInfluences on children's health and development with environmentDefined and the study be adesigned to allow measurement of chronic and intermittent exposuresA number of additionalStudy concepts have been defined from both the children's health act and consequent --Workshop and work of theFederalAdvisory committee.And these are outlined on this study that thisStudy be hypothesis driven with , that there be sufficient power to study the common range ofEnvironmentalExposures but less common outcome, that we look at both the effects of environment and gene environmentIntder actions on child health outcomes and that the study involveA sore psion of multipleAgencies and that the data collectedServe asNational resource forFutureFocusing on the rationale for theChildren'sWhy the focus on children?First children have increased vulnerability to a number of environmentalExposuresThere's alsoWindows of vulnerability particularly early in developmentInute arow when many of the organ systems are forming.Children haveImmature mechanisms forDetox phi cation and protection andDifferences in metabolism and behavior that may yield higher effectiveExposures when children and adults are exposed to theEnvironment.This is a slide taken fromSullivan and environmentalHealth perspectives that looks at some of the factors.I won't go through all of them but if you just look at the top you can see looking at surface area of the body massRatioThat ratio is higher in infants thanAnd higher children than adultsAnd there are a number of other domains you could look at and see how children have highly exposures to environments when placed in the same environmentSo why now?Why do this study now?First there'sIncreasing concernNumerous exposures with suggestions that the exposures lead to adverseOt yoms.And the types of exposures range from changing social environment to increased exposure toTheTo new exposures to new chemicals that have beenIntroduced in the environment.Additional there's increasing concern about diseases and condition of children.Some of which appear to be increasing such as obesity and pos by autism and attention deficit andDisorder theThere's been growing experience with the effectsOf exposures and how theyChild health outcomes. exposures in pregnancy and early childhood like lead and fetal alcohol.And there have beenAdvances in technologicalCapabilitiesMany of which you have already heardAboutToday.FinallyA wide longitudal study.It allows inference regarding cause alt.It allows a study ofOutcomes.And simultaneous and sometimes sinner gistic effects ofExposures.And particularly important for children it facilitates theStudy of developmentalTrajectories how environmentalInfluences at a particular point and time can affect these tray jekt mi -- trajectories.ThisJust a sce matic of the multipleLevelsMeasurement we anticipate in the children's study. will be communityLevel measureNeighborhoods,Schools and communities. of the social environment, friends, family andA number of individualFactorsAnd how all theseInteract with genetics to affectHealth and development over21-year timeNow turning toResearch -- recent milestones and current status of theAfter a number of meetings includingDeliberations of an expert panel and recommendations from the federalAdvisoryIn2,004, the decision to utilize a nationalProbabilitySample was announced. after that the study plan was developed and this wasPresented in September2,004To the federal consortium and later inNovemberThePlan was made public as part of a request for proposals for the van guard center. time, a request for proposal for the coord --Center was released andPublished the growing upHealthy document which I think was included in the packet.If it wasn't I brought extra coppies with me.Briefly the national probability sample was drawn byFirst stage was drawn by the nationalCenter for health statistics101 study locationsWhichForMost part single counties although some inRural areas it involves multipleCounties.Were drawn from the full list of all counties in the United States.13 of these locations areLocations. are locationsWith higher populations and higher-- we anticipate a large number of birthsPer year.62 metropolitan and 26 were non-metropolitan locations.In second stage of sample we'll beSelecting segments or groups of households from within theStudyWeA highly clusteredSample to facilitate the study of community characteristics well as to increase the logisticalEfficiency of the study.Therefore there will -- we anticipate few numberSegments withinLocationWe will be solicitingInput from the successfulAuthors to help define theSegments.There's advantages and disadvantages to usingTraditionalWays of defining segments which rely onSen -- censusBoundaries.And we will be askingAuthors to help usIn defining the segment and see what's possible in their locations but to maintain the Ib tes -- integ thrift Sam they will notActual of the samples tha. will be by the data center in collaboration with theStat tigses from the nationalCenter forStatistics.This is the studyMap.These are theLocationsThatSelectedAcross theTheStep was the selection of the van guard locationsFrom the initial list of study locations eight locations were selected to potentiallyServe as the van guard locations.The van guardLocationsStart data collection a year before the otherLocations and will serve to pilot our procedures andModify them beforeHave theFull compliment of study locations on boardTwo certainty metropolitan and two non-metropolitan locations were rand am -- randomlySelected.This map shows the eight locations that were chosen toPotentially be van guardLocationsThat's an important distinct.Authors were asked potentially versus actual van guard locations.They were asked to proposeProcedures for data collection and one of thoseAreas. the number awards that are made is dependent on vail -- availability of funds and quality of the proposals that weReceive.We anticipateTotal three to eight awards.Therefore somewhere between three to eight van guardLocations.There will be no more thanAward for collection of data in aLocationSo we won't have two entities collecting data in the same county.The f there are three awards our goal toss make in each of the three categories of certainty, non-certainty and non-metropolitan.If there are four our goal toss have one van guardLocation in each of theFourRegions so we can get as broad scpeerks as possible in the van guardPhase so the experience can be applied to development ofProcedures for the full studY.A few otherAspects of the studyPlan.We'llWomen and when possible their partners.Prior to or early in pregnancy with follow-up of children until 21 years of age.For the main locationsTheEnrollment over a fourPeriod and the vanFaces there's an extra extra year so it's five.Data will be collected in face-to-face visits an remoteData collections and will include questionaires and interviews, environmentalSames observations in the home and community, clinical and behavioral assessments, again both p in the home and clinicalSetting, and a number ofSamplesThis is the proposed schedule visit that appeared in the study plan.There's a of15 face-to-face visits proposedWith additional visits for those who are enrolledPreconceptionYou canThey're spreadHome visits and clinic visitsOneVisit in the hospital the time ofDelivery.In addition to the challenges that were out lined in the previous slide these are some of the that weFace in the data collection aspect.Certainly the combination of a probabilitySample withDataCollection conducted through the centers of excellence is a newDesign and something that we're hopeful will be successfulIt looks I think I mentionedEnd date forlet of -- receipt of proposals was a couple weeks ago and it looks like this has fostered some interesting collaborations and we're hopeful this will be a successfulStrikeWe also proposed toMultipleLevels of data in a variety of settings.I have just given an example of some of the environmentalSpecimens in the home, biologicalSames at the time of deliver cri which are guying toRequire relationships with multipleHospitals since we're using a communityBased approach versus hospital recruitment and a number of measures in the community.We also want to captureBoth intermittent and chronic exposure and hope to capture those exposures during critical periods of development.It's the combination of these twoChallenges that led to the preconception component of theStudy to get those earlyExposures in pregnancy that are sometimes short lived.The projected time lineAgain the closing date for receipt of proposals for theCenters andCenter were lastWe hope to select the initialCenters the van guardCenters in2,005 and to complete andPilotInitialProtocol in 2,006.Enroll firstParticipantsEarlyTwenty07 and selectAdditionalCenters 2,006 and 2,007.Preliminary results should be able in 1,009 to 2,010.We've had gone going and will continue haveOn-going meetings, peer reviews, workshops and consultations and I just wanted to mention one of those of the in September2,004 we had aWorkshop on theCollection and use of genetic information this.Brought together experts in theGovernmentExplore dunts and challenges and provideRecommendations to the nationalChildren's stud yi. the focus was on appropriateCollection and storage of biologicalSamples and there is aReport that will available at our websiteProbably the end this weekAnd this is the website if you want additional information.Again IBring if anybody is interested I brought someCopies the growing up healthy document. Thank you very much, Dr. Brenner.Now let me inviteStephen finn from theDepartment of veterans affairsStephen will be followed by Alan good mocker then by the committee's ownWayne

Hi I'm StevePardon meThe -- imgiing to try to make this very brief because I know you are running behind scheduleSome of the material I have overlaps with what's been presentsAnd I have -- presented and I have to that ourPlanning is in the very early route ameantry stages and really we don't haveAPlan.And it's great honor to be able and privilege to come to you all just to sort of give you an idea what we've been thinking about.This has been an idea that's been evolving within the department of veterans affairs now for aboutTwo three years.Many of you may gnat know -- know this the largest integratedHealthCertainly in United StatesAndElsewhereAnd we do haveA integrated intermural researchProgram.So to many people it's thought to be sort of a naturalThinking or notTheOfBoth research in gee nom -- genomics as asClinicalGenomic medicine could be brought to bear in a systemLike ours.The goals of this program really would be threefold.Much of what has been discussed is research and development related to genetics and this would be particularly in regard toClinicalThat wouldDrug response and prevent adverse reactions.We already know now that there are commercially available tests that relate to genetic susceptibility and there's no doubt that there beManyComing on to the market and in the scientific marketplace in the very near future.One of the questions we have is how do you implement these sorts of things inAn actual clinical health system and weEarlyIn this process develop the research andForThese kindsTests and intervention within a clinical health system?Obviously we'd like to pursue the same kinds ofResearch that have been described -- described here in terms of understanding better roles of genetic factors in both the prevention and causization of disease.Then we need like everyone else to think aboutWhat theSystems look like forCollectingAnd making these dataAvailable.The obvious question is why would the department of veterans affairs be doing this?I think that's a reasonableQuestion.As I saidA large integrated health system which -- with a very relatively stablePatient population.TheWithin our system is far far less now than in commercialCare these days.And it's very large system with somewhere around million active users.We probably have the most advanced electronicHealth record in the world which collectsCopius amounts of dataClinical, administrative, demographic, et cetera.As I mention we have a veryLargeIntramural researchMany investigators already doing genomics at a verySmall scale and of the goals of course would be to coordinate andMuch of what's being doneIntoA more organized and centralizedActivityAnd again as a health care system we can'tIgnore this sort of insip yent issues, the clinical issues that I think are on the horizon.We've actually now had an opportunity to discuss with veteran service organizations with patients and somewhat surprisingly we often hear about patient concerns.ADesireAmong patients in our system that we've heardObviously doneAllNecessaryEthicalAnd add Mort --Controls and governance but that given thatThey think this would be importantPart of the medical care they receive.And actually have given a lot of support and enthusiasm for thinking further about this effort.There are a lot of existing resources as I mentionedWe've alreadySeveralSanctionedDnA repositories. of these have have imNated from on-going clinicalTrials or other research and I suspect like many research organizationsThere are probably otherSmaller biorepositories that aren't registers and we don't know about. one of the issues to try get a handle on all that's already out thereWe'reVery early in the planning. ofIt's been very interesting to read and about what other people are thinking technically and we have a lot to learn and gather I think.Pos -- possibly by being a little bit behind theCurve we can as was mentioned benefit from theWork of others andDo things in a way that beCongruent with other studies on-going.We're a number ofTechniques well as obviously we're not guying to go outAs was suggested in the biobank and immediately enroll5million people into a database. -- we've discussed all sorts of fazed entries andVariableSpecimen collections and probably like the other studies will settle upon a hybrid approach which involves a of those.One of the issues again as in a slightly different position because we're not exclusively a research organization, we're not a privateOrWe are a federal health careWe would obviously insist on absolute control and ownership over all the materialsAndThatWere gathered as part of thisEffort. already have in place because we're researchOrganizationA fairly strigent set of policies for human subjects protections andIntellectual property, conflict of interest, privacy, scientificMerit evaluation, et cetera.And we are also in theProcess of designing additionalFurther protections for thisWhich would again like the other projects involveAn independentOversight board composed of both federal andRepresentativesIssues that we've struggled with are no different than what it sounds like that everyone else has struggled with.Protection of confidentiality.Since one of our -- a particular issue one of our strengths we think would be to link any data that weWith ourHealthOf course this presentsLots of questions farConfidentialityPrivacy. not completely new to us.Our health record obviously already has lot ofSensitive information in itAbout patients HIV status, and alcohol, so we really feel although need toBeCertain thisCompletely new ground for us.We'reSensitive to the notion of scploiation of patients.We've got a very -- exploitation of patients.We've-- enrollment in our studies the agriement is often in the neighborhood of 80-90 percent of patients whoVolunteer and retention rates are often mid to high 90 percent.Because of that weFeel a special reason to make sure because veterans tend to haveA, feel a special bond to the department of veterans affairs we have to be absolutely sure there'sSense of taking advantageOf patients.Either with their participation in the study or the use of informationThat'sWe're a working on hard on collaborations.We're to several otherFederal agencies.Particularly inPeriod of budget os austerity we think it's important toThinkWhat we can do corroboratively as opposed to independently.We're look very carefully at the lo j's -- logistics.Who the patient sample would be.How it would be enrolled.Our thoughts are we wouldActually do this through our clinical programs.I mean essential we've gotLabs eight00 labs already around the country thatAssist in speshmanCollection. course that we have to deal with transport, storage andAll the rest that's beenWe need to think aboutWhatUnique exposure data we would to collect from patients and how thatHappenCost is a big issue.We've not decided -- well not decided but not figured out how this would be funded. currentResearch budget in and of itself is infisht -- inefficient to pond -- fund this effort.My suspicion it would be throughSpecial programs through the department of veterans affairs well as collaborations with otherAgencies.A big ush issue that'sCome up is the intellectualProperty issue.There are strong commercial interests in this kindInformationAnd we really had to grapple early on with that.I'll just stop there since I think the issues are similar to otherFolks.

thank very much for your presentation.LetInvite Alan good Macher fromNationalHuman genome research instituteHave been very activeTrying to get somethingLaunched .

It's real pleasure to be here and talk with the committee about something I thinkThat many of you haveExpressed interest about.The committee's heard something over the lastOh six to nine months about Group that was meeting at nih to look into the scientificQuestions behind a possibleLarge U.S. base gene environment.I'm actually guying to quibble with our own title slide even though we callStudy it's really more of a resource than a study.I think for study the word study many people implies a controlled thing that is really hypothesis driven.You are guying to do a study to answer that hypothesis.We think of this mores a hypothesis informed rather than driven. is it should be a large resourceAvailable to as you will see in a moment basically theResearch community to be able to answer a series of interesting hypothesize and questions.And you have to have someSort of exemplar hypothesize as you design something like that because you might want to seeGee if it couldn't handle the following kind of question why bother having this resource.On other hand if we're thinking about large studies one of the things we kept in our mind as we thought about wasThey obviously will beProviding data for years to comeAnd that for instanceUsing the model as many do when they think about these sort of studies of framingham.If you had gone back to the original days of the framingham study and asked them toDefine the hypothesize they would be using to answerThe 2,005 we would have done aPoor job of that.Wie think theSame kind of thing for the large studiesThe one needs to be thinking very far forward and thinking beyond our ability to think and to be aware of that as we go into itSo obviously there are various kinds approaches to discovering and quantity tating the geneticEnvironmentalContributions toRisk.Case control studies, perspective populationBaseSturdy.Case control studies are great ands that perhaps the importantPart of this slideThat even those of us thinking about this are clearly cog ny distant of the idea caseControlStudies are wonderful and we need continue to have those for buy low medical -- biomedical research but there are some things they can't do.Terry and others talked about some of the thanks they could and could not doamongst theAspects are the bias towards more severe end of the diseaseSpectrum.This recall bias which Terry spoke in about terms of enviromentalExposure and family history.ForFor instance there are several here who have done territory toling research over years we certainly have all learned the lesson that cases tend have different memories from controls.Very importantly the inability usingCaseControlStudies toPredictive biomarkers that sfal the future onset of disease.To good information about those cases before they become cases.Because of course we want to have those early biomarkersNow as you well know we've heard about many of the other countries are planning large population baseStudies of genes environments andHealth.WhyDoesn't that suffice?Those are going to be wonderfulStudies but there are some problems for those in terms of utilizing these.These include and there are others besides theseThree but perhaps the three major ones that other countries do not reflect the populationGroup.But the population Groups in the U.S. particularlyThose very Groups that seem to bePresent most involve with tabbing health desparities.Other countries do notReflect the environmentalFactors found in the U.S.This will vary fromCountry to country how well that reflection is found but it's not a full reflection of some of the environmentalFactors in the U.S.And also this question aboutAccess of particularly U.S. researchers but researchers in general to data from other countries studies.Well as you -- will as you heard been limited.For all of those reasons we thought there was reason to think about a U.S. basedStudy. of you will know about.ThisIn the materials I think it's in everyone's binder that francesWrote anLast summer the case perspective cohort study of genes and environment which I would prefer you to that outlines many of the reasons for thinking about thisWorking Group was con seenedThese areMembers of the core working Group.I should also add that Terry's name did not appear in this and bass thaws -- that's because she along with frances and I wereHelping to sort of pull this together and organize it.Terry was an activeParticipate.SheBeing honest about her relationship with the icelandGroup I am not sure why she refused to mention herRelationship with our Group.Perhaps she was worried about what I mightSay.Shows how well sheKnows our Group.Besides theseFolks there were a number of sub Groups which included anotherFifty people.So there are aboutA total of 60 folks from the United States and from outside theUnited States involved in helping us think this out over the lastSix to nine months.So we're the major recommendations I would emphasize major theDetailedKind of information I'll tell you at end of the talk how to find that.At the end of the day the feeling was cohort should be chose ton match the most recent U.S. census onSix different characteristics in terms of, in terms of sex, in terms of race, ethnicity, geographic region, in terms of education, in terms of urban versusRural residents.It wasFelt the household should be the primarySamplingUnit.That roughly 30 percent of cases should consist ofBiologicalRelated individuals.That is a targetThat there is an advantage to holding it not much above that as well as an advantage to getting it somewhere towards that.And also felt the core should be significant size to achieveAdequatePower for most quantititive diseases.If does not seem obvious by now you haven't paid muchAttention this morning.Of courseDoes significant mean?We did a number of various models to look at this.This is that looks at the minimalDefect --Odds ratioConducted by a genetic variant after five years of follow-up.Looking at various diseases in terms of their incidents per one00 thousandThe populationYear with the assumptions up there 80 percentPower, et cetera, and looked at various cohortSizes, 200,500,000 a million.We also looked at of course because we weren'tJust interested in this alone but looking atDe -- detectiveEnvironmentalIssues for the five years of follow-up for the sameSpectrum of disorders.And finally looked at it in terms of geneEnvironmentalAction which is of course is what we'd be interested in after a five yearFollow-up.There are a number of assumptions et cetera.Part of what this really presents is there's no sudden sweetSpot. no number where you suddenly say gee this is a number you should get.Obviously the smaller the study the easierTo do.So if there's some magic numberBeyond which you don't get larger information.Any kind of design this is guying to weigh the scientificPossibilities versus some the budgetaryConstraints.What else did the Group think about?Well clinicalExample -- exam obviously would be important and thought a baseline assessment should be done which would be limited to four hours. core Group of variables should be collected on all participants and otherVariables that would beAge specific to the participants.Since remember the age of this resource wouldAffect the ages that we see in thePopulation.That biologicalSpecimens shudz be collectedCore laboratory measurements done upon them.The specimens should be stored.The genotype and dnASequencey would be done in terms of follow up there be telephone or e-mail contact every six months and reexamination should be carried out every year four yearPeriod.Public consultation shouldWe shouldAdhere not just scebsive but early and extensive.There was aFeeling for something like this to work for lots ofReasons there has to be feeling as manyAlluded to before that participants are truly participants.And they deserve to feel a senseOwnership of this.That this would include various kind ofTown meetings and focus Groups before one even gotStarted.This should be an open ended informed consent with encrypted database to protect privacy and confidentiality but obviously being completely honest with participants about the limits of protection.That a central R. I. B. would be highlyVacuous -- advantageousWe would not be unchallenging to pull O.Data should be immediately accessible to all investigators who haveR. I. B. approval.I would like to underline that thisPerhaps a distinctive future of -- feature of this design.It's not unique but certainlyVery important part of this to us that this would not be something where a closed Group of investigators haveAccess to the informationThat much of what we were thinking about sort of came from a human genome project type model and part of the power with having data immediately accessible to as many investigators as possible.Here one needs to weigh that against variousKinds of concerns for privacy and confidentiality with participants who we think we using R. I. B. for approval that one could pull that off.So why do this now?Well the urgency of discover Iing and validating these kind of things the same thicks thatGunned others have spokenBeforeAlso we think this will be a powerful stimulus for technology development many of thesePopulationStudies could be we would like to use thisDo some of the work that gilMentions before about driving innovation in terms ofMeasurementBoth environmentalFactors as asBetter describing phene o type with new technologiesAlso thePotential to reduce skyrocketingHealth careCost by understanding the eyedology of disease and people's response toTreatment for disease.By theClose of business today there will ab full report of that working Group.We've been work hard to pull it together. by the end of work day today and since we are federal folks the close of business means midnight, sometime today, if you go to gm. -- genome.gov slash 130-1443SixYou will see aFull report of the work Group.Thank you.

What we can probably do is maybe with the support of ourStaff weJust get a littleHandout of that so people will have that available.Thank veryAnd maureen, Corey, if you give us this perspective from the centers for diseaseControl and prevention then we'll move scpe delicious -- expeditiously to the panelDiscussion that will be led by hunt.Disbl good morning.I guess I am speaker number ten. this time you are all hungry and tired and heard it all so I will try to be very quick so we can have someI will try to offer youA bit of a global perspective on how we canGo aboutCollaboratingWhether it's case control, cohort studies or what have you. of I have to say in this letter of correspondence to natureGenetics last year but because of the format had to condense it to about six00 words.But a full report of thisIs available on ourNow I have three messages to you this morning. they will reflectPartly my own philosophy and what cdc is doing with globalCollaboration with many of theYou have heard from beforeAnd I mentionSpecificallyA couple of thingsThree messages this morning is that globalCollaboration in biobank and populationCohort studies is neededAnd we are beginning to see the elements of that with pcg and U.K. biobank and others because I firmly believe one cohortStudy in country is not enough.No matter how big that study is.Whether has a million people or 2 people you have seen some power calculations from Alan earlier and they were based on measuring one gene andExposure or gene environmentInteraction and you could see thoseMinimalDetectable ratios creeping as you begin look at interactions. you are beginning to look at five or ten genes interacting with five or ten exposures it's going to be quite challenging.TheThing I want to say is that we need process that integrates all of the human genome ep adeem logic information.Whether it comes from cohortStudies or other forms of study.Because for the mostPartMostSuch data still come fromCase control studies.So we need to integrate that data as well.Then the third which IWon't talk about today isNeed to link epidimiology with theEvidence baseProphecies thatIewdz ep deem logicInformation for the policy and practiceSoThat it is a matter -- there is a method to this madness.There is an approach that many of us have learned that allies -- applies not only to expose us but genes and becauseA huge problem literally I to call it human genome ep dealing -- epidemiology.Because the problem is huge on practicalScale. weDeal with primarily these days is the processes ofGeneDiscovery.Like first speaker morning who warned us that we need to put on a different hat when we're talking aboutMulti-phak torl diseases.We're not reallyDiscovering genesDiseases x, y and z but look how howVariation whether it's 10 million zips or three of courseDisease.Why do we need epidemiology?To characterize what we havePopulation.Previous Lance of the gene various, how they affect the burden of disease in terms ofRelative risk, absolute risk, and also the burden of diseaseThen alsoGene, gene and gene environmentalInteraction. have heard of all of these by now you are sick and tired of the study designs.They have their advantages and limitations but there are alsoHybrid study designs.You can conduct a cohort study for which you can measure exposures retrospectively.For example, if you hadCollected information from a newborn blood spot and have sewed it for many years youGo back to that blood spot and measure genes and environment.So can still do a case control study and having theAndi seed ents measured before the case and controls wereCollected.There are couple of myths and stigma aboutAssociationStudiesThatThat we arePresenting in the literaturement the term association study isAlmost like a dirty word this genetics.I think it's function of thePoor quality of the studies not because the field or the ep deem logicApproach to association studies is bad.It's because the studies that have been done are really bad studies where the cases and controls come from differentPop lakes -- populations and are not even comparableAnd incidentallyBoth cohort studies and case control studies are associationStudies.So there is that stigma that associates with that.One thing I wanted to say here thatBecause of the lack of randomizationPeopleTalk about *6 observationStudy as a secondClass science but we don'tDetermine who gets whatWe are essentially randomized.There is a movement in Europe and the U.K.WhereIt really takes the term associationStudy and puts an undermine control clinical trial out.So basicallyYou are randomizing people intoA and b then look at the outcomes later.YouChoose which you get.Just like you don't chooses which drug you get from a controlled clinical trial.So we are taking theAssociation and making it closer to experimentalDesign.We don't have time to talk about this.There also the belief thatCohort studies are inherentlySuperior to case control studies.Or case controlStudies are inherently inferior toThem.I am here to tell you that a wellDesigned populationCase controlStudy is far more superior than aDesigned cohortStudy and effectively there are many things that can only be done in caseControlStudies.Now what we've done at cdc with a lotGlobalPartners is beginPut our finger on the pulse of the so-called world of human genome epidemiology.We have a dataBase of all the literature.This is onlyPublished literature that we've been gathering since October 2,001.Essential there are more thanAssociation studies being published only over the last threeYears.And those numbers are ins -- increasing.Most of the data fromPure associationStudies.Most them areCase control studies.There is an increasing number of studies that focus on gene, gene and geneInteraction and there are a few studies that are justPure prevalence of differentGenetic various in population.We areAffecting a 5 percentRandom sample of this data base to look at the quality of these association studiesment but other people have looked at it and found that many associationsStudies havePoorQuality in terms of ep deem logic parameters.NowThis is a study to look at thePrevalence of the top 50 genes of public health significance that we are collaborating with nih on to measure in the enhance three which is about 8,000Representative sample in the U.S.ThoseSort of 87 snips and 57Genes then trying to correlate those2,000 phene o tipic variables thatAlreadyExist inIn haynes Tree bank.This is anotherExample of aPopulationBase case control study that essentialUsesSurveillanceSystems which arePopulationBase.These are surveillance systems for birth that are doing caseStudies for looking at geneEnvironmentIn relation to birth defects.There is about 10,000 cases in control.And those numbers are going up.If you have a population under surveillance like you have equivalent to a cohortStudy of more than 1 million person or 1Births at leastAnd there are otherSituations where youDoAt leastMassive case studies or cohortStudies like in managedCare organizations.So why do we need to integrate data?We have unmanageableAmounts much data.Two genes, three genes, four genes for most chronic diseases commonDiseasesWe're at least dealing with ten-15Genes.We haveSmall sample size.Whether we look at cohort orCase control studies I hope you -- show you a slide on that.We have smallExpectedEffect size of gene disease associations becauseWhy?Because most genes do not -- are not expected toBy themselves to theDisis of most of these diseases.The rule rather than the exception is to expectRelative risks or observations that are close to 1.3 or 1.4.SoLarge sample prizesTo discover them.You need replication across studies.There is a lot we've beenDealing with with publicationBias that has originated we have acrossPopulations and within populations and you have to need to generateHypothesize.This is fromFrom Greece who is part of the huge movement and has been keeping hisFinger on thePulse of the studies.Most of these are small sample size.Probably two00 or less:Most of theHundreds of gene disease associations haveObservation between 1.0 and 1.4.This is sort of the peak at 1.2So how do we build the knowledge base on genes in population heal ?th the answer is here all of the above.But let me go through this thing with ule.A large population cohort study.A systematicOf all data fromCohort studies, case control or all of them and the approach we're doing is number four which is an acceleratedCensus of both Group and information data usingCorroborative networks and con sorption of all types of study.Of course the right answers number five.What do I mean by that?In 1,998Cdc and many partnersDeveloped a human gee neem epidemiology network which is an openEnded collaboration of both individuals and organizations that are interested in assessing the population impact of genomics on health and how can we use genetic information toImprove health and prevent disease.The has about seven00 people right now from 40 different countries.And it's wide open to anyone who wants to join it.It is a website withInformation exchange.A lot of training and technical assistanceThrough the form of workshops that we've been doing roughly on average one a yearWe're delving -- developing the knowledgeBase.Putting stuff together in terms of synthesis.See the huge studiesData base that I alluded to earlier.In addition we haveSponsoring inSis te mtic review of gene disease association that many authors have described to.We have aData base of two00Meta analyses of different gene disease associations thatIs published elsewhereMention the myth dogWorkshop.I mention theBiobank cohort study meeting we just had.We under the process of forming aNetwork of 14Different networks that exist in the world and many areCancer, some are in disease, et cetera.TheseNetworks ofInvestigator that's haveToPool their data and share information.I'm almost done thank you.And we are developingTheSort ofThe sharing ofBetween networks.Just by the way ofGoing through this wholeCycle fromFunding to publication.Very quickly goingWhere things are right now. are talking about different study design whether it's biobanks in one study or case control studies or con sore shay.People do the studies then report them.Then something else will thatLiterature andThen the funding cycle continuesWe are collaborating with the variousBio banks and we haveFocus primarily on thisRegion hereBut this will influence the study designs as wellI don't have time to go through this.This is courtesy of marta from our office that has super imposeses this on an elephant because defending -- depending on where you are in the and what kind of studies do you only see part of the elephant and what huge net is trying to do is look at the whole elephant together. is briefly the meeting we just had in AtlantaIn collaboration withPg-three.And with nih courtesy of telemiewn.And weBrought together with a smallGroup that talks about theData.This is the outcome of this meeting.One of the outcomes was and we are working on a statement that would beEssentialLy important for publishingStudies that are derived fromBio banks.You might say the data won't be coming until 50 years from now but if you have a statement(Indiscernible].This is a worldWideMovement.U.K., Canada and the U.S. that have been settingStandards forStudies outside genetics.What we're trying to do is influence the contact of biobank projects and studies through the developmentingSimilar criteria.The biobanks themselves are going to put togetherSort ofBest practices for the design and conduct of bio bank then update their online knowledge base with register of studies and tools then having further meetings.So in conclusion this is my three messages for todayOne cohort study in one country is not enoughThere is more than one way to get thereAnd I think all the ways are will get us there.AndWhat we need to do is work all togetherTo really look at this challenging area ahead of us which is how do weSense of the human genome project.Thank you.

you very muchI appreciate it.Well what we're guying to do.We've got such a Rich panel and we have so much to do we're guying to push-- we're going to go ten minutes into lunch section thoughWe still have otherWork we've got to do.But I don't want to short change this panelment we can't do that.We're guying to go tenMinutesOver 1:00.To 1:10 so we're guying to give this a very good listen. that let me turn it over to you to moderate.AgainOn behalf the entire committee thank you all of you who have presented today..

Pleat me add my thanks to the speakers especially for keeping to the time which willKeep us on task.I want toThank theMembers of the task force that put session together.Although if you just walked out theDoor I want to specifically thank Amanda for her diligence and hard work.We do have about half an hour and I want to divide that first into a sort of questions and answer session because imsure members the committee have questions we've been storing up as we've gone along thenTouch on a few general issues.I'd also like to remind especially the committee that although all of this is fascinating we haveDozens of questionsThat we would just like to ourBrains with answers onThe goal, the reason for having thisSession today was for us to decide whether we had at hand all the information we needed or whether there are inGaps and knowledge and bases to make recommendation to the secretary regarding large populationStudies.So let's keep that in the back of the mind.Cause when we're all done ain addition to take a lot of information home we need to assess thatQuestion of whether in fact we're going toContinue any furtherWith this study.So that let me open it up to questions.Ed, I have you first. I think I see one ofMajorBarriers beingR. I. B.s.Having gone through theCalifornia pilot project where every hospital had to get approval through its R. B.It shut down that projectAs a globalProject for the stateSo I have it forDr. BrennerAnd also Dr. Goat Macher.Both of you have dealt with this in your presentation but I see as this aHuge barrier to multi-from studies.So I was interested especially you are dealing withHospitals.How can youDeal with the R. I. B. there?Then Allen you hadA veryPie in the sky approach that many of us have talked about of getting rid of the I. of R. I. B. so we can do multi-institutionalCollaborativeStudies.But I would like to ask the two of you how you plan to actually turn this age round?.

We're luckily at the much earlierStage so I don't have to claim we have a plan.But we can see a way we might get there.Before I even answer your as long as I got the microphone let me take exception to my own presentation by pointing out that since I gaveSome many minutes ago have learned due to technicalProblems the report I promise to be up by close of business todayWill still be up to close of business today but close of business today may be until the nextEnd of this week.So it may take a couple days.In terms of central R. I. B.This was not completely pie in the sky butSome of that.That to really thinkWe thought a study thisScope in lots of ways to work we thought it would require a more centralizedR. I. B. mechanism than is common today.That might not mean one that is completely centralized.In other words, it might well be something where the localInstitution still had somePlan because clearly the localCommunities and populations need to have a role in this.How one does that but still has a centralizedProcess to stream lineWhat would happen for the local ints tygses et cetera there's some -- in this report there will be more detail but it's not that we have a concretePlan exactly how it's guying to happenment on the other handThis is sort of a movement that is afoot inBiomedical research in general.Largely borne out that frustration not just researchers have felt but also institutions have felt as research has gotten both more multi-center and more complex deal with the issues.Those of the genomic and genetic committee have seen it where we went before R. I. B.Ten years ago the universalResponse was of course jee net eeks we don't know big about it so go ahead.Then the universalResponse was genetic we know nothing about it so you can't do anything.So there's been a realization of that.But a lot ofOther non-genetic communities have looked at the question of centralizing this.So we're optimistic it can be done. do realize it would be a challenge and it's not to thatLocal institutions would haveNoReviewYou know oversight at all.

Dr. Brenner, anything to add?.

I would just echo the comments that were just made.We alsoAre hoping that we'll be able to get a more centralizedProcess but we have a van guard phase in place to look at that with a first set of small scale where there are a few number centers then expanding.We do have somethingIn our office looking specifically at theseIssues andChallenges .

I would just like to register this as somethingThat we highlightAsA barrierFor these sorts of studies if we proceed with the report .

We will afterLunch we'll come back a committee discussion of this and we can pursue it then.Kevin I have you then emily.

I haveSomewhat moreGlobal question so I throw it out globally to the entirePanel.A lot of different presentations -- let me first preface that by saying following up on what the doctor brought up about the complex itGroups and how we try toGroup people and how sometimeses that not an accurate way of truly understanding the situation.Many times in the presentationS people mention things like the public responds well to this.Or we're look for public transparency.We have ule truistic participants for the projects of the if you take thatThen put that together with theIdea that I also heard I think several times of Harmonizing these differentDatabases or these differentProjects what I am wondering is do we know or will there be Harmonization of the understandingThat nrtions that these participants will have as to the real risks and benefitsThey see to theseProjects?Lest we assume that we as experts reptsWhat theyProceed to be or understand to be theRisks andBenefits of this type of pursuit of these types of projects and databases and that sort of thing.Because I mean I would imagine even within any nationEven within the U.K. there's incredibleComplexity and you have all kinds of sub populations and sub Groups break out and seeing theseIdenticalProjects and identical processes in very, very different ways with different expectations, motivations, different reasons.Perhaps initially coming to the same conclusionSo in this process of HarmonizationWhat input do they have?Certainly about risk and benefits but also as things go along can they affect change?Are they guying to have input into how the Harmonization is done.I know it's big question but one that is com com I know more and more in theSocial science literature.I think we need toHelp inform us ofBest way to go forward.So I kind of throw that open to anybody who might have a response..

all at once please..

Obviously it's complex issue and gets at the heart ofCommunity basedParticipatory research.I think that you know all we can do isThe best we can co and try our very best to haveOn-going and activeCommunity consultation andInvolvement from the get go. thinkMany of themAnd John and others will talk aboutHow they have done that in theirExisting studies.All you can do isList and try to adapt and modify as you go along.I think perhaps one thing to say there are different levels at which you can consider the public.You got the public as represented in the studiesAnd so you have to make absolutely sure that the risks to themAre minimizedAndThat they understand their relationship with the study but there's also the broader public.It be right forThe public in the study to necessarilySpeak on behalf ofThe broader public, the target public.I mean I was picked up by a member ofWho said to me I saidSlightly glibly we'll maintain a dialogue with the participantsment he said how are you guying to maintain a dialogue with five00 thousandPeople.Of course the answer is youAnd to someExtent of course his point was we are the elected representatives ofThe public.And thereforePerhapsWe should have a role.So I think you have toThink of the public as the public themselves.You can have direct access to them. can have the institutions that onBehalf of thePublic of which there are a number.We the human genetics commission.We have parley men tearians, we house of Lords.So have do theBest you canAnd listenTwo ears one mouthOne would say.

I think have age dialogue with the community I think is making sureThat if people have committee interest present during the design phase I think one thing that happens it's veryDifficult to do is that we design studies and take them into the community and say we are engaging community.That isVery, very difficult thing to do because in a sense when the communityReally challenges us with difficult issues we don't change our strike thatWe justFind ways around it.So we really engaging communities or just doing these things to make sure that we get the necessary approvalOr that we do what we want to do anyway?I think those are issues that we haveReally confrontIn all of this.And I have to say they are very difficultSometimes we don't want to hear what a community has to say.

If I may add.I talked a lot organization of legislation and of ethics.I think the same is -- aim is certainly not have to one legislation that fits all.That's certainly not what's going toRespectful of what participants in communities want but need to beDiscussAnd to have a dialogue where people will understand each other and for we need to talk to our communityBeforeFirst thenGo and try to exchange withBiobanks and biobankers.

Thank you.Emily, I have you next.

So my question is directed to Dr. Brenner.But it may be to the whole U.S. team as wellIn your presentationYou were the only one who mentioned that there actually was an act of congress required toFund your study.And I am curious whether you think thatWill be requiredFor otherLarge studies in the U.S. orIf this is sort of an anomaly that has to do with because it was kids or whatGenesis of that being funded by that mechanism wasAnd whether it's guying to apply more broadly to other population studies theU.S.

Well I guess I canMost specifically about the national children study andI was referring to is the children's health act which authorized the study but I didn't appropriate the funds.So there's a difference between authorizing it and appropriating the funds.In terms of whether future other studies are going to require specificAuthorization probably Dr. Giewten mocker could .

YesI won't make you responsible for funding our study.I think the kind of thing that we're talking about is clear we're talk about the science of it.Not the funding which would be a hugeThe only way toSomethingLike we're describing going forward I think is toOf not just innovative techniques for doing theScience brut innovativeTechniques for doing the funding.Those would includeFor instance thinking about this as a public/private partnership.That's not the first time that's been done and not even the first time it's been done in genetics but the kind of funding something like this would need I think one would need to look at bringing in non-governmentalPayers.The kind of data we think wouldProvideAnd would again be freely accessible to anyone with irb approval whichWould include commercial enties -- entities with approval.We think would be sale yant enough and one could make enoughCase to interestPrivate payers.And we've hadConversations with folks who said gee this is something that we-- you know nobody's signsChecks because there's nothing to sign a check for but this is the kind of thing in fact which it was -- if it was done well we could get getting involved in.AlsoThat's not an unabatedPleasure.If that happens it raisesObviousConcernsOn the parts ofVarious participants.One could projectAboutGee if this is being funded by industryPartlyWhat does that say about how it's being.So one would need to be very thoughtful and have lots of people involved in that conversation.But this kind of thing if it were ever to see the light of dayWould require some innovativeLooks at funding.

Did you say that yours is not-- your study the children's study is notActuallyFunded .

It's authorized but after authorization comes proaption.It's not appropriated.

So you don't have the upon.

We have currently an existingAgency budgetThere is funding for initiation of the study.But to say on the current timeline we would need additional fundingIn 06.

Barbara, I had you next.

Can I just ask a follow-up.So it's not clearWas this the outliear.Is there any otherStudy that we know of in the U.S. that went through thatProcess of congressional act even for authorization or was this an exception?

TheWomen's health initiative was funded that way.I don't know the exactYou know technicalities of whether it was a law or an act or whatever bit was funded by-- a congressionally mandatedLine in the nih budget and the genome project may have been the same.

I two questions about recruitment into these large population studies andDirecting themThe first one to Dr. As well as to Dr. Giewten mocker.TheFirst question has to do directly withDr. Rue tini's talk. course in the literature there's a lot ofInformation out about how race is not an appropriate approximate itty to use when we're trying to make sure we get diverse samples.So I wanted to hear about your thoughts if we think aboutDoing a large populationStudyIn the United StatesWhat are your feelings about, what could we use?I mean is it stillAppropriate to useRace in the sense that making sure you get sample populations from different parts within the United States?Or is that just something we need to completely throw out the door and bring in something new and so what are your ideas on that?I don't know if that was the topic of conversation at all at this meetingThenAgain I also around this topic of recruitment seems like for many of the large population studies the medicalInstitutionIs the placeWhere people getIntoThese types of studies.And we knowThat there isMany people in the United States that notUse medical institutions for their health careDon't have access to it. have insurance, eats.So againIn the conversation I was just wondering if that was something that came up and was there a way to address that?

I think the issue of whether to use race or not is think is somethingThat we talked about multiple times and is reallyMultiple ways to answer that question.I thinkAt a philosophicalLevel if you say what is race I have to go back to whatMy zoology teacherDefined.We don't have that intense of human beings.But as a concept we have used to describe ourselves.WhenTalk to the average people in theStreet they will tell you what they know what race is.But when you go down to the detail of trying toSay what aboutTiger wood what is his race.And then you start to see the level of confusionBut people sort of say I know what that is I know who you are.SoIn terms of designing studies really just come down to what isTrying to do.What are you trying to answer.For example I give the example of eating beef earlier.It's very good example for me because I like to take things at a very simple level.If you want to study how people eat beef then you need toIncorporate that into your study.You won't be able to -- if you want to see why African-Americans haveTwice theRate of type two diabetes then you need to look at the things that African-Americans do for examples that whites don't do in this country that put them at higher risk.Then you need to look at the type of job they get.So I think it's reallyWhat we do is we use approximate sis to define things we want to get it. we to get at income we look atAfrican-Americans tend to be poorer than whites.So it really doesCome down to what is it we are trying to answer.How do we design our studies in a way to make sure that we haveUnder that umbrella the things that we want to measure.For me I look at ethnicity -- ethnicity as a good way of people identifying themselves becauseWhat ethnicity does it createsFlexibility for people toMove betweenGroupsAnd I'll give you an example.In Nigeria for example where I grew upBecause of the way people married and the customIf a(Indiscernible] married a heeb drew theChild isYou ruba.That person come to the United States and I am you ruba but but they haveEeb u so they really have to come to understanding and appreciation for some of these things and also to acknowledge right awayWe don't have-- it's notThe bestAnd to identify the errors or thicks -- things or limitations associated with their desires.

Let me handle your second question first because that's easy.That's theQuestion about the medicalCenter and the bias that would introduce.S one of the several reasons why we saw the household unit as the recruitmentIewn toit get away from that very bias that would obviously contribute.The issue of race and ethnicity you will see was one of the six descriptors that we thought should be used.Ideally we would think suchStudy should reflect the population.Which means ideally it should be a 290 million person study.That probably would be difficultFind a budget for.So what are the key things one needs to include if you are looking at genes, environment and health what are the other descriptors of individuals that make a difference?Well age does, gender does, and for similar reasons race and ethnicityDoSomething to do with one's health status.Many not much of that has to do with genetics but we thought we needed to includeGroups.The problem has become how does one identifyRacial and ethnic Groups in the U.S. we know we do it poorly.There are social defend in additions that are widely used in otherEt cetera.SoIf there t this was a length conversation I should add but the feeling was with all the limitations of that they are so widely accepted, used, et cetera that those-- it makes sense in terms of inclusion of make sure we includeYou knowUse those to make sure we're reflectingThe spectrum of American society.

add something to that. thinkWe have to expect that the outset there are going to be differences in theEnvironment interactions that occur in different racial and ethnic Groups.SoIf you want your study to inform about all the different racial and ethnic Groups then you have no choice but to consider that in the sampling design I. think that's clear.ButIt goes farther than that because it's insufficient just to say we want to include this number ofEach of the racial and ethnic Groups.For example we knowThat individuals that identify as having EuropeanAncestory in America are more geneticallyHome o genius thanIndividuals that self-identify as being African-American or HispanicSo what that means is if you just say yes we're guying to get a certain number ofIndividuals thatIdentify as EuropeanAmerican you might do a decentJob of representing thatBut you might end up with a verySample of Hispanics because you haven't actually done a good job of finding out what's there and figuring out a way to make sure you represent what is there and go one step further than that.So you have to think about for each Group how to represent it then going a step further you have to think really hard theRepresentation in the study.Because if you just go by the proportionateMakeup of the U.S. then it isTrue it is just a factThat you will have morePower to identifyGene by environmentalInteraction in thoseGroups that make up a larger proportion of the U.S. population you have to decide whether or not that's acceptable.

Thank you for that.Reed, I have you next.

I guess the folks from the U.S. governmentAgencies.Given how extraordinarilyExpensive and howThis stuff isDo we have any-- I didn't get the sense and I'm not sure that there is an interrelationship, a functionalCoordinationOf the three activities that we heard aboutWe've got an nih activity, we've got cdc and we've got nichd.Give than nobody really hasThe moneyIt sounds like yet, I mean we got all kind of prom it iss but nobody's got any real hardMoney.Are we still talking about three differentActivitiesOr are we talkingA secretary of healthWho has sat down with these three agencies and said look folksThis is the way it's going to work.Or is there at least in the absence of that somebody guying to the secretary of health saying we've got three different activities that they're going to be coordinated in the following way to make the maximum use of the resources that may be with a prayerWill actually ever get funded. the answer to that?

We've hadExtensiveConversations, all three Groups together.And they are on-goingConsultations amongst the three of us to look at ways they would interrelate.We've hadNumerous onesWith the national children's study thinking about the ways thatRecruitment might be shared.The other kinds of ways that one might both for logistic reasons and also for scientific ones the ways that one might coord night. there are differences about what they want to achieve but they are really complimentary. three of these.And I don't think think of us haveThoughtful about this would say gee of the three this is the most important.This is the second.These are allThings that we thinkThose of us whoChair about health and genes in environment all three of these approaches we think have notValidity but importance and they help compliment each other.That they'reSome overlap between them but the idea is to minimize theOverlap and use theOpportunity to really make them complimentaryAgainst each other.

I am not saying it will be wrong to have some from above us do this but we believe we're doing it already.

My messages the same as Alan.I guess what we're doing at cdc isNotTo replace theStudy but something to needs to be done anyway.Whether there is airn study or not which is sort of this global clab roition -- collaboration.If there are resources in the federalGovernment we'll all line up and work together.We are working together.I mean nih is part of the huge network.We've been part of theDiscussion of.The ncs is three or four agencies coming together .

Have you all put togetherDocumentFor the secretary's reviewAllows the secretary to see how the pieces come together?.

No.We've had various discussions, documents for other people but not had anything because again we don't have a document for the aboutAges because again it was just scientific vaition which we'll put up on the website and make available to people kind thing .

Yes?

I guess I'd like to ask a sort of follow-up question but sort of practical one.Do all of you get your funding through the same appropriations committee?I mean that may be the answer if you have differentAppropriations committee then it's hard toControl tha. so all of your funding coming through the sameCommittees.

Nchd is part of nih so yes we all of ours from the same committee12K3W4R* vA is separate.

I have Joe then Debra.

My question is to everyone I just want to say thank you for the excellent presentation I did learn a lot from you.Maybe too much but you know a lot.The question I have is for those who presented on a very large studies.It's pretty obvious that there's a huge amount of responsibilityThat you have taken on to conduct the studies.One of e thingsIs important to knowBecause it doesn't always get discussed is at what level are you engaged should I say in some evaluative process about what you are doing.There's the research process but then there is the of looking at evaluating you haveCertain goals and objectives but there's the side I mean you spoke about the big management and logisticIssues.And I guess I am look at that asSince most of you are talking about longitude nalStudies and most talking about thaw are guying to have a lot of interaction withLarge number of people I am justConder -- wondering whether or not there's something a component to the work thaw are doing.And if you have it what are you doing?If not, why not?.

From our of view we have evaluation at everyLevel within our company we have all the committees.We have the ethics and governor's council who evaluateCertain elements.Our .

, the welcome trust, theHas its own review of what weThe medical researchCouncil hasAlsoProud urs, formal ones.We are extensivelyInterrogating probably the wrong word by the Parliamentary committees.We have the pressureGroupsAndWe are committed toOpen publication of all ourSides.We have scientificPeer review and ultimately we wouldInvolve theParticipants.It's difficult to I think one of e things it's difficult to know how successful the projects will have been many yearsSo there's sort of a long term evaluation that is important

I think my question has to do more with the formativeType of evaluation which is long term which is lookingThe process as you go.And you have a number of steps, a numberSort ofTargets along the way.Milestones along the way that are telling you whether you are successful or not.And there was not a lot of discussion about that beyond these regulatoryType of oversights but just for you as involved in the project it's pretty critical when you do this particularly when you are dealing with socialEthicalType of issues and you also inneraction with thePerson you are dealing with.That's my question.

Wie were aware of that partly because we've learned from the discussions with John about what bio has been up to.We're also experienced -- influenced by our experience with the human genomeProject.Where our Hallmark was to have clear benchmarks along the way one wouldn't just sort of wave at and say we met it or we didn't but in fact that there wereAndReal results from whether or not one was meeting one's benchmark so there would be expectations for that in various kinds of ways including for variousKinds ofCommunity participation.Those things would be looked at along the way and one wouldReact to how it's guying in terms of reshaping the process as you go.Important for something of thisMagnitude andLength.

We have one finalQuestion then we're guying the to have to wrap up.Debra?.

I am so excited by thisPossibility of doing this in the StatesI have -- I am more interested with theSpecimen access at the end.And I haven't heard a lot of discussionI saw the pictures from the biobank of thisRetrievalProcess for investigatorsAre you giving outSpecimensAre you-- then I hear sequencing.Are you guying to sequence all the genomes of all the participants?Or fudging them of each of theParticipants?And data will beAvailable but specimens won't then the people would be recontacted if they wanted to participate in certain studies because that was also mentioned as aPossibilityAnd a final questionAre you going to -- is it feasible toCollect specimens over time?BecauseAlan you mentioned thatYou could identifyEarly disease biomarkers.PotentiallyBut you can't nuls are collecting specimens over time.So you have a specimenRather thanJustAt enrollmentBut that may not be feasibleLogistically from a storage perspective, from a financial perspective.But it would be a shame to not even consider that as an option .

Absolutely the idea was there would beSamples gotten at baseline.But in fact one would get, get various kinds of Sames whenOne sees people back.AndIt might not be the same sample for everyone.Of course we'll be interested in cases that happen during the study which might guide you. the idea is in having access to people periodically you have the access to potentially get more samples.AsBoth the science advances depending on what the financialSituation is et cetera, also the idea would be if one is thinking about a long term study thatWith thePrice of sequencingComing down, with use of hapa type and other things to sequence onlyPart of the genome miss David nicely took us through earlier that one could imagine in fact having Geo tipic data onFolks that was availableThat would store it's actually stored so it's no longer a sample it's data set tha. data set would againing stored but then shared with folks who had R. I. B. approval to use it kind of thing.SoVery much likeHat mat data or something like thatThat theData would be made Freely available 6,789 samples are obviously both in terms of finances and in terms of aFixed volume harder to think about how to share but that doesn'tMean there aren'tWays to do it

John?

Yes we will send the samples out to a limited number of accreditedLaboratories then the researchers get theResults.But the results areFed back into the resource.That's an importantPoint that as people use the resource theAmount of data in it grows and makesIt available to everybody.

But can the specimens then be used up. thereProblems with freezeThaws.Are they storedOriginally as Al o qats.

Yes that's why we've got so many Al o qats we're helping to predict the meets -- needs ofProducer.It's important you send theSamples to laboratories that are only guying to use verySmallAmounts which means limiting to a relativelySmall number of .

Wonderful.Well thank you againTo the panel.Both for yourFormal presentations.[ Applause ].

Thank you.Let meTry this.We're guying to take our break.Sara came one a good idea which I think makes sense.We'll get our lunch -- well you know you'll do what you need to do then you with will get your lunch. one . . 20 so if youLike do all this in a hurry and let's try to sit down here at 1:30 which is impossible but we're going to try.If I say 1:30 it will1:33 but we'll do it.Then we'll continue thisDiscussionFor the committee on this topic.So you don't have toSwitch gearsBecause you are right there.You it in your head.So we'll do discussion then we'll theFull time that it was to have for the committee to discuss what we've learned and we think we want to do.Then willTake the sectionThat would have been that and take care of theReimbursementDiscussionAnd you have paper in front of youTo look at which you can do.Then we'll be right back on and everything will be wonderful and we'll end right on time it will be just terrific.You should see it.See you all in ten minutes.

The question is what do you believe about the ability to make the determination right now that genetic counselors who are in some way certified should be able to counsel independently and bill independently. What is your thought about that? Put it on the table, or take it off the table? The floor is open. And Deborah Leonard is not here. Let me get her point in right away. She has been emphatic to the point of she jabbed me in the chest when she was talking. Make no mistake. She believes that the answer is yes, that they should be able to. I will get to what her strategy for implementing that is. She is one person who says that should be done now. Okay, Barbara?

And I as well, emphatic yes to the -- and under yes I think we should say the first statement wherein states available, skip the second line and go to the third one where the secretary uses or would use his leadership. And also --

Okay. You only get on that one.

Just for clarification.

Okay.

The N in the interim is going to be the regardless?

Yes. That is why it is there. Okay?

I also fully agree that there is sufficient reason to recommend that they be able to do this. I think that the genetic counselors and certified nurses have established a training program and an evaluation process. I think it is very clear. I think we also had adequate demonstration of that before. And I think that if you look at the proof of practice, it is already demonstrated. So I emphatically believe that yes is the answer for this. And I would recommend that the third comment there, "secretary using his leadership and influence to establish a body of segregation." I think that would move towards assisting this group in obtaining license you're and when they had that, it would be a no-brainer and would be established.

Yes, sir.

I think that license you're and certification is not sufficient to make a recommendation that non-physicians be able to bill directly for services. From our discussion yesterday, as I said, if we're going to be using evidence-based medicine as a basis for making recommendations, they do not provide evidence that non-physicians were able to effectively make those types of determinations compared to other groups. There were not enough studies from a evidence-based perspective which would justify that opinion, is my opinion.

So we've got three saying yes, one so far saying no.

I would say yes with the caveat that when we are talking about Medicare, and I defer to James and others, we can't -- and the secretary can't just declare we are going to now allow these folks to directly bill Medicare. I believe that it would require some sort of change in the statute. Correct me if I'm wrong. But if that's the case, then our recommendation should be more towards urging the secretary to work with Congress on legislation that would do that. And in doing so, it would be incumbent upon the different groups to convince the sponsors in Congress, to convince the secretary to provide the evidence that James is talking about.

To James you have to take away your philosophical hat and we're now at a technical question purely in terms of if we were to make such a recommendation, it is now -- now we're talking about the language. So can the secretary cause this to occur, or does it have to be a congressional change?

I think it would require a congressional change. But also I would say that if there were some type of demonstration through the use of some types of studies which showed that they were as effective.

Yes, different issue.

Okay.

Okay. So the answer is that if the -- for those who are saying yes, that this should happen, the technical way in which a yes gets transmitted to the secretary is that the secretary, we recognize that he or she might not have the power to, by the stroke of a pen, cause it to occur. But has to work through the Congress. And that would be the language. It is a technical issue.

Just for Medicare. The private sector, that is a different thing.

Right, got it.

We can make all sorts of recommendations.

We're at four to one.

I would also like to say yes. And maybe take into consideration the fact that, when we talk about evidence-based medicine, we always have to look at who the people who set the standards for what counts as evidence? How do we go about getting that evidence? And what sorts of motivations have there been in the past to get that evidence? If this profession is seen in its, I think, proper role as a profession to be reimbursed, then of course that will always help, I think, instigate more research into how it can be done better, which of course would be based on studies looking at the evidence. And I'm sure that the evidence will confirm what we're saying. But it would lead to the sorts of improvements and the gathering of data that we're talking about, would also be a good thing. So in one sense, there is a bit of a catch-22 here in the sense that there has not been the motivation. There has not been the emphasis in the past to gather the evidence in such a way as to answer those specific questions. But I think people's experience can also be seen as evidence, and that's strongly in support of saying that.

We're at five. I did a disservice to the conversation by not making one statement up front, let me rush to make it, and it is this: We've had a lot of discussion yesterday about this issue that got to the nature of respect for these professionals. I have talked with almost everyone on this committee at some length over -- about these issues. The one thing that I want to take off this table for this discussion is that if -- that there is not a single person around this table who has anything but respect for the professionals who are working so hard to do this kind of counselling. And that those who may feel differently about this issue do not come at it because they do not care, or respect their colleagues in this field. And I want to just make sure that that is -- for the record, I think is an important point. Because otherwise it could have the effect of chilling the discourse, if you are viewed as to whether you are up or down on genetic counselors and then you are beaten up as you walk towards the McDonald's. I do not want that to be on the table T is not appropriate to do to anyone on this committee. Moving around, yes.

Thank you, REED. You saved me from having to say that. That would be my comment. Because I'm -- I'm voting the no on this. And I'm voting no because I do think that it is -- it will be a stronger case. If you take the effort of building the evidence. Clearly what's in place right now is, from my understanding from yesterday, and if I heard it wrong, I apologize, it is still in the early stages. Everything is in the early stages. Even the -- those who have been -- who have received this level of verification are only two, three years out. And so really there hasn't been enough time to build that evidence. It seems to me that we need to really push towards doing that a little bit more. That is where I'm coming from. And I would choose the -- and I'm one of the ones who really pushes for expeditiously to get it done, and I think it can be.

Agnes and harve and we'll go around.

I would say, yes, that she should go for the first proposal. The one thing that I think that committee presented yesterday, I do not think that they were asked to actually present all of the evidence-based about, you know, what we're discussing now, that the genetic counselors or people providing these kinds of services actually do provide efficient, cost-effective or whatever-it-was. I think if maybe in fact we wanted that, that we could ask that specifically for this committee. I do not think that that would be necessary. I think that maybe if it had to go to Congress, that that information could be presented from the group itself to go along with that recommendation to Congress. The -- I would, though, say that I would rather have the "or" here that without reference to license your because I think it is affected mostly by states and for the secretaries perspective -- perspective, whether he has jurisdiction over state in fact, and that is simply using certification by ABGC, GNC and other certifying organizations since there are other certifying organizations.

So right now you are on the yes side? Okay. Yes?

Just a point of clarification and correction for Joe. I mean the profession of genetic counselling has been around for 20 years. Yes. But it was interpreted that way by some. So I wanted to --

That was not my point. That was not what I was saying.

Good.

I'm -- I'm still where I was yesterday. I am -- I'm persuaded by the statement, particularly by -- from James that there is just not a base of evidence sitting in the literature that tells us yet what we all, those of us who have done this on the front lines, that this is in fact a critically important field that is making a valuable contribution, and a contribution that is absolutely in the middle of the road in terms of how to bring genetic information to the public at large. I do not see in the medical literature the data at that would be necessary to make the case to the secretary that, in fact, the drastic changes that I think are needed will be needed soon. So I'd have to vote no but would then urge that we change some of the language to be much more forceful about the expected role that we see for the profession of genetic counselling going forward.

Okay. We'll come back to that then. All right. I missed a happened here.

Yes. I just wanted to point out that while evidence-based medicine is a wonderful tool for all of us to evaluate our practices by, unfortunately evidence-based medicine does not apply to every medical practice that we do. And that we reimburse for. For example, there is not a lot of large, randomized, blinded, controlled trials about just about anything in genetics. And so if we use that to drive our old policies, I think we are -- are being premature in this. Much of medicine does not have that basis. And that doesn't mean that it is not justy finally reimbursed.

Good.

Okay. Here is what I do. Sorry, a comment and then I'm going to move.

I was just going to respond to that T is true that a lot of the activities that we do in medicine, there have never been randomized clinical trials to show that they work but it does not mean that other observeal studies were not performed. You might even have to resort to such things as a cross-sectional study to use as a evidence-based. But it is sort of like what David eddy has said. 70 percent of the things that we do in medicine have never been tested to see whether or not they work. We just do them because we think they work. Because of that, we tend to justify what we continue to do.

All right. This is -- has been a very good discourse. Very rarely do we actually take votes on stuff. But right now I need to now just sort of take a vote of the committee. I wanted to have the ex officios weighing in, I -- I counted your votes, because first of all you are valuable, it is important to have you here and you have a lot to say on this. I want to see now for the committee members who are here -- wait a minute. Kevin? Can you -- there are seven? Now we had Deborah. She clearly left a proxy. She counts in the seven? I think she was pretty clear. I mean, this was no question about it.

She makes eight.

She makes eight? All right. Of the eight committee members that are here, those members who are here who are voting yes, would you raise your hands. So we've got one, two, three, four. Okay. And those that are voting no, what do we have? One, two. So four to two. I'm trying hard to be diplomatic. And you do not need me.

I'm not a voting member yet. I have not passed through the hoop of fire.

Now you actually would have tipped it more towards the 5 to 2 than the 4 to 2 if I understand you correctly. Which is an important sense of the committee. So I think that the committee has got a sense of it. And so that is where we are on this issue. Now the question becomes how do write, how do we phrase the recommendation about how this would go forward? So now let's specifically focus in on, and I'd like to put as the first way of focusing in on this, would be as the -- where I'm looking for the -- you know, the greatest agreement possible. And I'm wondering whether that is around the language of the secretary using leadership to expeditiously cause something to happen. I'm just trying that first to see where that takes me. But -- so how do you see -- now everyone -- everyone has to get onboard. We've decided that we will make a recommendation. Now the question is how do you make that recommendation work? And who has got a thought there now about which of these options is the best way to make this recommendation happen? What is the most responsible way of getting this done?

We -- just a point of clarification before we get started.

Please.

Does the vote for yes negate the need to gather information, independent of how it is done? Because there are varying ways. I agree with James, that there is more than one way to gather information. And I'm just wondering whether those who voted yes.

Right.

Did that -- because that is -- that is not on the list.

The answer is that -- what I was trying to do by making that -- that sort of point of departure now, by saying that the secretary gets involved, and then all of those sort of gathering the information things are the things that we urge the secretary to cause to happen, is a way of trying to close the gap between the yeses and the nos. Now you can decide, of course, to do it a different way. But I was being fairly transparent or trying to get everyone at least on a common next step. But that may not work. So, please, who has a suggestion about how now, based on the things that are on the page. And/or something new about how do you achieve this? It has to be a specific recommendation. It has to take us from point A to point B. We cannot talk about the theory of it anymore.

I was going to ask Barbara, as a genetic counselor herself, what area does she feel would specifically benefit the field the most?

I think a general recognition of genetic counselling as a legitimate field, legitimate service, is really what would be posted helpful. I think everything after that would fall into place.

So you've got that. That is already done by the vote. Now what do do you? How do you implement it? Let's be specific? Do you say that everyone who is right now a certified ABCG or GNCC would be someone that we would urge the secretary to go back to the language that Cindy said again, the secretary has got to -- for the government has got to say urge Congress to say that if you have those degrees, those certifications, you should be able to go and do it now? Or do you say that you want the secretary to cause the right people to be pulled together to give the best advice as quickly as possible to answer these questions about how to do it, and then take that to the Congress? Do you take it as one step

Maybe I'm misunderstanding. The CPC codes and the billings on the back, all of that are very important. All of the things on the front, to me I'm not really sure that they affect licenseure which I think that we would have any role over or certification which, again, I do not know that it is that important that we have some kind of a national certification. Maybe I did not get the point of yesterday. But I think that -- do we need to even go here? I mean, I agree with all of the recommendations on the back. But are any of these recommendations under yes something that we really want to do?

Okay.

I think the issue of licenseure and certification, I agree it might not be an issue that we specifically have purview however. However, the main impetus of us even getting into this, it is an access and a quality of care issue. And I think -- and that is where I think that the licenseure and the certification comes under. So we're trying to make sure that the people who bill for genetics counselling services are qualified to do so. And I think that we agree as a commit that genetics counselors are qualified to do that. That is where the licenseure comes in. Mentioning licenseure here is no more saying that the secretary has purview over that no more than me mentioning certification here.

No. No. The issue really became one of -- and you are raising an important option, is just to stay moot about it. The question is how do you make sense out of who is in fact a legitimately qualified person? And right now there does not seem to be any real organization that allows you to figure that out.

I'm not convinced that 95 percent of the physicians who give advice on genetics are qualified, and I do to the really see this as an access issue. I think that it is important that you get information from qualified professionals. But I think that the -- that issue is a totally different issue. And I think it deals with the broader medical profession in general. I do not think that we should limit it to say that we've got to get qualified genetic counselors. I think we've got to get medical professionals who have a basic knowledge of genetics.

Well, okay. Good point. Next?

As far as the certification, I mean, one way since you're talking about it, could there be multiple steps to this? We have two certification processes and the training and everything like that. Could you start by saying here is the starting point. Genetic counselors and nurses who have gone through the certification program are going to be accepted as -- and certified and now you need some group to look, come and see, as Joe was mentioning yesterday, are there others that would be included under that umbrella? I mean, I think you've got a starting point with the ABGC and the ghrx CC, and then you can see from there -- and the GNCC, and then you can see from there where you want to go.

That is a specific recommendation and step. So if we understand you, it is the idea, Kimberley, I'm trying to figure out what to do. But at the end of the day, there is a sense by many people, there is a need to try to understand if -- someone is going to say I am a qualified person. And I, therefore, should be able to, you know, bill for this service, and it -- I should be able to do this service and get reimbursed, any reasonable paying organization is going to say, well, who are you? And under what criteria are you saying that you are in fact legitimate and able to do it? Kimberley, you are right. Your point is that you've got doctors and others who may not -- but we're looking at this issue here. And so the notion is that what we have as a specific suggestion is you take the certifying bodies that exist today and you say, okay, this is a good starting point and then urge the secretary, if I understand you, to create or to try to use his influence to create or stimulate the formation of a body that would then deal with all of the one-offs that are going to come up, the single Gene people, someone without a master's degree, who knows who decides that I'm in the club, put me in the club. Someone has to figure that out. And you're asking for two things at once. Start one place and then create a environment, a form that figures out how to deal with all of the people not in this group right now that. Is a suggestion. You've got something to shoot at. Let's decide: Is that the way to do it or not?

Could I just make a friendly amendment to it? I think that it is important to take this conference suggestion, if we're going to take it, and to be very clear about the nature of it. There is -- you are talking about groups -- there is a siloing risk here. You need to eliminate that. If you are going to get groups to work together, you need to find a common ground. And so if we're directing or making a strong suggestion, then we need to make sure that the group, whenever it is formed, is a group working towards a common ground in a collaborative way to make this happen. I just want to add that language.

A very important point. That is a very important point. And by the way, in all of this, I want to make the moderating comment that Cindy's point is, I think, very, very important, in a realistic way, is that this is going to be subject to a sub lick discourse beyond our recommendation -- to a public discourse, beyond our recommendations. So I think that what we are doing is that we are signaling a direction. We are also signaling caveats that need to be carefully considered in the interim period, while this goes through the public policy discourse. Because, again, the secretary cannot just, with a stroke of a pen, make any of this happen. And so we're signaling things that ought to occur, and hopefully stimulating a lot of people in this room, and those on the webcast listening to us carefully, to create the tales that are needed to be able to -- so we're fast-forwarding this whole field simply by the recommendations that we're making. That is actually I think what is ultimately occurring in this room right now. Someone's hand I missed. I believe somebody. Okay. You guys have to deal with specifically does -- is Kevin's point the -- is Kevin the point that we're going to -- is that the one that wins or not? And someone has to knock it down. Because right now it is gaining momentum.

I would just go -- remind everyone of Barbara's comment. I mean, to me the three messages are: The need for genetic counselling services, and when you have been consistent around that language by qualified provider who is are many disciplines, and the point of access; I mean, this bottom line, I think you've -- again, what, for the food of the American public, what are we talking about? Those are -- for the good of the American public, what are we talking about? And you need to discuss reimbursement.

All right. Kevin has got it on a going, going, gone basis. Agnes?

I think if we went with Kevin's recommendation, what would happen is that that would limit the number of healthcare providers that people would have access to. And I think we want to make sure that people do have the access. The main point that I think that we're trying to continually get at is that the public needs access to qualified healthcare professionals and that genetic counselors are qualified and that they should have access to reimbursement.

Now, I'm not sure though -- and I want to respect your point even in rushing this thing through, but I'm not sure that I see the limitation. I think that what Kevin is saying is that you've got a place, you are signaling that we accept that there are some people who have created something, that makes sense. And then he is saying expeditiously let's get to the process of how do you create the requirements, the conditions, the processes that allow others to be designated. I do not think he's -- because they are -- I mean, I just do not see how that is diminutive.

Not diminutive. But in terms of limitations, that we are now going to create another sort of more centralized body for certification.

Right. Now the philosophy here, just to make sure that everyone is clear on this, is that you could then, the alternative, and I do not know whether this is what you have in mind, the alternative would seem to be that every organization with a interest in this could then certify, designate and say, okay, well, me too. And so at some point you are sort of left with, if you were trying to pay for this, you have to administer this, or make use about this, or worried about a malpractice of this, because, you know, you used -- it is like, well, who are you? Someone, somewhere along the line, I think what he is saying is has to make sense out of this. And so you do not have the wild, wild west. And I think that -- and certainly don't want him coming to us.

It -- it appears to me that there is some sort of a parallel about this, and in thinking about it in the capacity of certain physician skills. For example, if I am someone who wants to just simply do spinal surgery, I must first of all qualify as a or the peedist, and then perhaps do a -- as a or the though peedicist and then perhaps do subspecialty work and then only work on the sake rum, having made that my derivative, the same thing for a person who is a disease counselor, that person must qualify in the general capacity before they can then focus. The point that I'm trying to make is there is a extant certification process for someone in general. If someone wants to be in a minor part of the practice, they must first achieve that and that is already in place.

So what I think you are saying for the purposes of this activity is, A, we are not trained, smart enough or have the time to figure all of that out. B, we know that someone needs to figure it out. And we are urging the secretary, therefore to figure it out, or to use his influence to convene those necessary to figure this out?

That is sort of a overview of what I was commenting on. But the point that I'm saying is that there already exists places that -- sufficient certification in place.

I understand.

So those are models that might be used to apply to this activity? Or are you saying push this into those very centers? Are you saying push this into existing form that already created to do this? To do this kind of work?

Certification in some fields, for example to become a OB/GYN doctor.

Right.

I go through a board exam and recertify, that is already set in place, same process for encounselling. Licensing, as we all know, it is -- is a state process. The reason that I raised my question to Barbara was to -- not that I think the secretary has to do this, but whether that would be politically the most advantageous thing to the genetic counselors to -- or whoever is going to do it, to help them move forward.

All right. I saw one other hand, and I want to do that. I missed you. The -- I think it was you, Kimberley.

The only question that I had was whether this is really what the genetic counselors want. I think if they want us to give message to the secretary that we need national certification to make sure people who are qualified are giving genetic counselling services I would be much more supportive of it. But I want to ensure that that is what they are interested in.

Kimberley, I appreciate that. We did hear wonderfully from the genetic counselors yesterday and they gave us good input. At some point, I think that the committee has to decide what it thinks that it wants to do. And we've got a lot of input. We have differences of opinion even around our own table. And so I appreciate the point. The genetic counselors were able to express, if I can try to summarize what we heard, that they have their mechanic civils, their -- there are a couple of organizations speaking eloquently about what they do, even in their own discourse there was some issues that came up as to whether or not you have masters level nurses, and there are their own challenges that they have to work through together. But they did not -- and they were not asked, according to the point of agnes, they did not teach us with what to do about the single Gene people, you know, all of the other perm utations, and so we do not quite know their guidance on that point. To conclude this, I'm trying to do a quantum calculus here to get your point in here. And I cannot figure out a way to do it, other than to simply say that I do not think that we can be more prescriptive than what we have, than what we've gotten to. I do not know when it should be that this all goes and gets pushed into the ABMS, which it can't. Or, I mean, something like that. At the end of the day, we can only do the best that we can in determines -- terms of this recommendation and then let the process unfold, as it needs to. We are making a pretty clear statement. This is a bold statement, I think, to make quite frankly in terms of moving this issue forward, one that is of concern to our members. And so I think we've pushed this pretty far. I think that the next step -- and again by the way the other issue is that the reimbursement committee report is going to go out for public comment, so we're going to get a bunch of stuff back anyway. This is not the last time that we're going to see this, and we'll probably get beaten up on all sides and we'll have done our job wonderfully. Cynthia?

Can I just make a recommendation that sort of builds on what Kevin had articulated? That is following the model of registered dietitians, the way that they got some coverage under Medicare for medical nutrition therapy for certain cases, I cannot remember now whether it was diabetes, cardiovascular disease, something like that, there were a couple of indications, was that Congress put into the statute that the national academy of sciences would conduct a study and look into many of the same issues that we have at the top of the -- back of this paper here, and, you know, what -- dealing with cost-effectiveness and appropriateness and all of that, and then based on that study, and it was done, Congress looked at it and said, oh, for these two indications it does make sense for these individuals to be able to directly bill Medicare for their services and therefore we will allow that to happen in those cases. So what if our recommendation is asking the secretary to direct -- direct the NAS, or to fund some study, using the registered dietitian model. It would on vieat the need really for Congress to step in . [ please stand by ]

I think that your suggestion makes all of the sense in the world. Even those not in favor of the proposal were in the favor of expeditious. I think that none of us would disagree that we would not want to say that you can go to Congress, get permission to do the analysis and come in.

I band to remind the -- those of you on the NIH study on the genetic workforce, looking at specialists, primary care providers. And if we could build off of that.

Okay.

That excellence, and not --

That helps then.

Cindy has that end, and needs to roll that in. Here is what we'll do next. We'll bring it to closure. I need a reality check from Sara and Cindy. The reimbursement policy coverage thing has been kicking around now for a good while. It has gotten better every day with all of the input. What is our time line for when we absolutely expect and must have that report go out for public comment?

That is one thing, we've got -- I do not know how you want to handle it, whether you want to blow them off or what. We have two remaining recommendations, unrelated to genetic counselling, I think. And I do not want to jinx it. But they are probably in the no-brainer category where we might get quick consensus. Do you want to turn to those?

I will suspend it for a second. Thank you. Thank God that you raised it. Just for the moment, what is the time line of when this report has to go out? Right away is the answer? So in other words -- and so I think what that means is -- let me just make sure. Does that mean, therefore, that the one thing that we are not going to do is to put in the things that we've -- that we've done today and yesterday, all of the work that we've done, and then come back and revisit it at the next meeting. We are actually intending that it goes out before the next meeting?

Well, let me just say that it is always up to you, if the committee does not feel that at the end of this meeting they are ready to go out with a report for public comment, we can wait until June. But, I mean, I think that you want to do something. I think that your goal was to have the report finished.

All right. Second question. Would you, Cindy, be willing, and again you tell me about the process, that given how much work we did on that report, this meeting, that the committee, the subcommittee, you know, do a last draft on this. And then it will go out before June, but givinging folks, if they have just any little comment that they want to make, you can decide whether we use it or not. You can make sure that everyone is sort of -- sees what it will be before it goes out for public comment, knowing, again, that going out for public comment means just that, it does not have to be -- it is not absolutely perfect. We will get comments back, and then we'll come back and change it again. I think we're agreeing we are not going to wait until June to send it out. The questions that I'm asking specifically is that would you object to having people at least send in e-mail comments on what would be now the last draft?

That will work.

That will work? Okay. With that, could you pull out the summary? Can anyone find their last two recommendations from yesterday?

There.

Those, by the way, who are public comment people, I hope that none of you have to catch a plane. But -- because we're coming to you. Not too many minutes latement.

The last two, it is on the summary document that was in everyone's folders. They deal with the broader issues. And just to summarize, the first one, dealing with provider education and training, it addresses the fact that there is a lot more work that needs to be done in making sure that the current medical workforce is adequately schooled in genetics and genomics such that they can provide the requisite care to their patient and so this recommendation essentially pulls from something that was recommended to the secretary last year, and you can read it. It basically asks the secretary to develop a plan for HHS agencies to work with the state, federal and private organizations, essentially to help medical professionals so that they have the tools they need. And also urges the secretary to incorporate genetics and genomics into HHS initiatives. That is the first one with regard to education and training.

Anyone with any big issue with that?

I move that we accept.

Going, going, going?

Okay.

Done. Next?

Okay. The last one, public awareness. Recognizes the lack of knowledge or a -- complete information available to the public with regard to genetics or genomics states the fact that we need to get out to the public reliable and truth worthy information about genetic technologies, and it talks about the development of performance and efficiency members -- measures, based upon evidence based clinical guidelines, that would better enable consumers and patients to evaluate health plans and health providers. It is sort of vague and fuzzy. I do not know if we want to be more specific than that. It really does not say who would develop these things. It would be good to get some input from members of the committee, as to what we might suggest here.

This one does not actually read like a recommendation. It is just a statement of motherhood and apple pie, which is fine as a statement. And that is actually in the text. But we're not actually making a recommendation to have the secretary do anything.

Good point.

I'm not sure that we actually need it. The next stands well by itself.

Yes.

The only thing that might apply to HHS is to provide a direct recommendation about initiatives like the surgeon general, which is something that HHS is spearheading anyway. And to encourage or to suggest, or whatever language you want to use. And by the way, if such recommendation needs -- is changed, I would to suggest to add the word family history somewhere.

Well, I think what this is getting at, by the way, I think we're -- everyone understands it. But, again, this is the consumerism movement where now people are having to make more choices that are financially -- and other risks for them about where they go for care, and the nature of the benefit packages that they are offered. And so what this is sort of getting at, is saying that we want to -- I think that what the recommendation would be, hunt, might be more around the secretary of health would make available through government, Internet Web sites, information that helps a person make better and more informed choices in this regard. Such as -- and including family history. But it would be -- when you go, I'm one of the people that are addicted to, see I use it all the time, the national eyewear medicine Web site.

Oh, really?

Any way, gu in, you know, and you --

Club med.

That is it.

Pub med. That's it. Would you have there, the secretary would help to make sure that that type of information was on a pub med kind of sight.

But do we have enough information to -- at least I do not feel that I have enough information to say whether that should be the surgeon general's side or a CDC site or any other site?

It should not matter as far as this committee. Because you ask HHS to do it. And then they figure it out.

Yes.

You are saying that HHS should use its resources to make this information available to the public? Guidance and education to the public? That is what this is getting at? So with that as perhaps a friendly amendment. The HHS -- we would urge the secretary to make HHS resources appropriately available to guide people in making -- making these kinds of more informed choices and decisions. Okay. Done. We'll conclude this and move to the public comment. Let me just ask one favor of you in terms of the -- the report that Cindy sends back out, and it would be this. Normally I'm not a big fand of people who, if you send them an E-mail to a multiple list and they have to tell you yes and send it to everyone, you know, so that you get a thousand e-mails that do not make any sense. In this case, I think that it does make sense that if you make a comment on the report, you might want to click everyone. And so everyone sees the comments that are going back and forth. At the end of the day, Cindy and the committee have the responsibility for taking that stuff and weaving it into a final document. I think in this case it is good that we are sharing and rethinking our thoughts. You do not get to reargue the issue. The question is how do we do it. All of you are terrific. That was -- and you guys are a terrific committee, and even people who do not agree, you work together. You are a model of democracy. Public comment, speaking of democracy? Susan, Susan manly, national society of genetic counselors, I want you to sit right there. Where is the microphone? Head of the table. The table. They will make the microphone work.

I thought this would be good timing. Good afternoon. I'm Susan manly, chair of the professional issues committee within the national society of genetic counselors. As you know, NSGC represents over 2,000 member genetic counselors practicing in a variety of medical specialties, providing genetic counselling in prenatal, pediatric and adult settings, as well as working in re erch and bioBennettic companies. We would like to thank the committee for taking their testimony into account when developing the draft resolutions and reports and would like to have input where appropriate as we move forward with the important issues discussed in this meeting, primarily billing and reimbursement for genetic services and the development of population based genetic data bases. With regards to reimbursement and coverage issues, as you heard yesterday, counselors are uniquely qualified to provide genetic counselling services. Without reimbursement for these services, the public's access to appropriate genetic services faces a limited future. It is critical to note that masters trained genetickic counselors currently make up over 50 percent of practices genetic specialists, meaning that genetic counselors are providing a majority of genetic counselling services and will likely continue to do so in the future. Although additional studies must be done to clearly define the value and cost-effective of genetic counselling services as conducted by specific providers there are already many examples cited on genetic services through invited testimony yesterday. The issue of reimbursement for genetic counselling services and in particular those provided by Masters level genetic counselors is critical when we consider the impact on the genetics workforce. Specifically if genetic -- if genetic counselling services provided by genetic counselors and other non-physician service providers are not reimbursed, it will continue to impact access to quality services nationally. This committee is in the position to make recommendations regarding the future of genetic services and healthcare. Currently the educational and credentialing structure exists to produce quality, certified genetics provisionals. However without adequate reimbursement, public health could be compromised provision of increasingly available genetic services by uninformed healthcare providers without specialized training. As was proposed yesterday by the working group the NSGC approachates the support of this committee and strongly encourages you to continue to develop recommendations that explicitly support the recognition of non-physician genetic services providers, specifically including Masters trained genetic counselors holding credentials that document knowledge on human genetics and clinical genetics expertise. We also hope that SACGHS will advocate in all manners appropriate for the development of CPT coding which is specific to genetic counselling providers and for third party pairs and CMS to recognize the importance of reimbursement and coverage for genetic coverage services by appropriate providers. Lastly, you can recommend that studies be funded to continue to assess the value and cost-effectiveness of genetic counselling provided by non-physicians. With reimbursement, call fide genetic counselling providers can become even more valuable in the financial realm of US healthcare. And allow more medical facilities to offer quality genetic services to the public. Finally, the national society of genetic counselors applaused SACGHS for considering the logistical and genetic issues required for large population-based genetic studies, many of our members function as research coordinators including the provision of informed consent. NSGC members recognize that the scientific data arising from population-based studies will have a powerful impact on the data available to provide clinical information to patients in the future.

Great. Thank you. Susan, that is terrific. I just would say that -- and that is a very important state. So now though, given where the committee is, I really, really, really hope, at least as the compare of the committee -- as the chair of the committee, that you -- your community now will take the initiative and really move forward and provide very detailed and very -- very explicit suggestions into the public discourse around how you actually now, you know, accomplish this certification. And not just for the -- you know, for the small group that have, you know, added. I mean, you have to really figure out how this is going to work. You heard us 12 times saying, you know there are fundamental questions that need to be dealt with and answered. And you guys have opinions about it. And you probably know others. But I think that the ball is really now back in ya'll's court, in the community to respect the professionalism of what you do to figure this out and make suggestions. I appreciate your comments. I think now you threw it at us and now we ran with it, and now the question is you all will have a lot of work to do. And I know that that is what you wanted.

And we know that already as well.

I figured that. Susan, you have been terrific so much. Thank you.

Thank you.

Greg? Greg? Please, come in. Introduce yourself for the record. Yes?

Okay.

My name is Stephanie mench.

How do you spell that.

The last name is mend E-nend S-h, and I'm a a consultant to the advanced medical technology association. We represent manufacturers of diagnostic tests and genetics test, among other medical devices, which is why we're interested in the activities of this committee. We're -- we'd like to thank you, first for the opportunity to make comments during this session. And we're very pleased for the amount of time that you've spent deliberating on issues that our members consider to be very important relating to the coverage and reimbursement of genetics test because we do believe that for the tests themselves, how Medicare treats them will have an impact on access. And we understand that there are certain limitations in terms of prevention, information and how the agency views these tests, and what they are used for. But we do appreciate the amount of time and effort that this committee has put into understanding the issues, and hopefully your report will have a major -- be a major source of support to move this forward through the agency, through Medicare and other agencies that are related. We did committee specific comment almost line-by-line comments in September and appreciate how much work has been done since then on the draft. And we do look forward to being -- doing a very careful review of the report when it comes out for public comment in the next few months. What I passed around is advamed's policy statement on another section of the Medicare modernization act, which we hope that you'll also address in your report, even if it is just to acknowledge to the -- cms that you are interested in having or implementing this section of the report. And it has to do with how new tests are paid under the fee schedule, the clinical lab fee schedule. You did mention the mma provision having to -- to do with coverage in the report. But this is section 942 also talks about the disposition of new tests. And it puts into place a very thoughtful process, a public, open, transparent process. And we think that this is important because we would like to be sure that the agency and the contractors in the field who may be doing gap filling understand completely what is required of them to develop cost data for new tests, and that this information, the data, is made public. Advamed has summarized what is in the law itself at the beginning of the policy statement. But we've also, because statute is fairly broad as it is written, we've offered our suggestions for additional regulatory provisions that we believe can be implemented on a regulatory level. There is an open meeting, a town hall meeting that CMS held in January to take comments. And we provided our comments to CMS at that time on new tests, on implementing the section. And it is our understanding that regulations, a notice of proposed regulation will come out in late spring or early summer to implement these provisions. And so the timing of your final report will be right on time if you were to just mention that you are interested in how CMS is carrying out this provision of the law. And I think that that is pretty much what we're asking for, is to -- to just have your recognition that these provisions are important, and that some stakeholders like avamed and others in the lab are very interested in being able to have the best that we can get for new tests understanding the limits of the current Medicare fee schedule. And again, thank you for this opportunity to comment and we hope that you will consider making a recommendation in your final report that relates to implementing the new test section as well. Thank you.

Thank you very much. And let me also thank you all for a very, really well-done briefing paper. One page, front and back. Very specific. And absolutely right to the point on every point that you are making, at least we understand -- you know, we understand the point that you are making very clearly, and obviously a lot of work went into this.

Thank you.

I think it stands on its own. We have this. And we will certainly study it. Does anyone have a question? Again, very well done. Thank you very much.

Thank you.

Maureen Smith from new Gene projects, northwestern university.

Good afternoon. Would I like to take us back to the topic from this morning on large population studies. I represent the new Gene product, a genetic banking study. It is a prospect based initiative who wishes to develop a diverse sample and facilitate research on the genetic factors and environmental factors contributing to disease. We comprise a sample collection and storage system with the ability to regularly update participants health status and retrospective and prospective data from electronic medical records. The project received initial seed funding from the northwestern university and its healthcare partners. I will shorten my statements, and this has been fairly extensively discussed this morning. I just wanted to make a few points. One is we -- the new gene study is conducted throughout the northwestern healthcare system, including five hospitals and numerous outpatient clinical sites throughout the Chicagoland area. And we are an approved IRB study through the northwestern university IRB and have a certificate of confidentiality from the NRH. And I want to point out that we have spent time since the inception of the study in early 2002, up till the present time, and continue to work very closely with our IRV. And it has been a very lengthy process of education and work. And so I wanted to point out that I think it does take a huge effort to educate IRB's about this type of research. Our research -- or recruitment started late November 2002. And we had very modest initial accrual goals so that we might better understand how to best educate and work with our physician and participant populations. As well as to evaluate how to improve recruitment in our informed consenting processes. We have found people to be responsive to learning about the study, and agreeing to participate. However that certainly does vary given the situation in which participants are approached. But while the public appears interested, interested in participation and studies of this type, we are aware of the need to continuously examine the ethical, legal and social issues associated with acquiring, maintaining and managing personal health as a large resource. Therefore, we recently served as a site for the department of energy funded LC study of informed consent for population based genetic research. This project assessed the participant knowledge of our study with the goal of improving the informed consent process for large population research. And results of this study have been presented at scientific meetings, and we are in the process of publishing that data. The longitudinal and population-based design of this study, physicians new gene as well as similar studies to be a resource for a breadth of studies, and I will not go into those as they were extensively discussed this morning. We believe that our project has begun to demonstrate the value of such collections for research as over the past six months, even a small population study, we have distributed samples for three different research studies within our university. And these investigations included such varied and common conditions as aneurysms, neural tube defects and head, neck and lung cancel. In conclusion, we believe that large population studies will offer great benefits to society and will enhance our understanding of how environment, lifestyle, genetic and other factors contribute to health and disease. The experiences and expertise of existing population studies in the U.S., particularly in the areas of informed consent, building sophisticated data management and sample storage systems, developing privacy policies, and establishing community trust can be leveraged to provide a framework and guidelines for further studies. As others in the international community work to create country-specific longitudal population cohorts we believe that preexisting US-based population repositories should be fully developed into a national not for property consortium.

Thank you, for that.

Thank you.

And it is also -- thank you for letting us know that the new gene project is available as a resource as we look forward to these issues going forward. I know that several of us will probably try to take advantage of that. And so thank you for taking the time to make sure that we know what it is that you are doing.

Thank you.

Appreciate it.

Finally, marry steal Williams, the association of molecular pathology. Welcome.

Thank you. I'll need to provide a new written document to Sara based on yesterday's discussions, her verbal comments are a little bit different than the document that I provided you with earlier, Dr. Tuckson, members of committee, good afternoon, I am the director of scientific programs for the association for molecular pathology, I speak to you today as a representative of our group. We are an international, not for profit educational society representing over 1200 physicians, doctoral scientists and other professionals who perform genetic testing as well as other tests based on acid technology. The membership is from a wide variety of healthcare settings, both public and private, as well as from the IVD industry. AMP members are involved in every aspect of genetic testing, research and education. My purpose today is to provide comments on several issues currently under consideration by the SACGHS. First, a review of molecular CPT code reimbursement. We strongly support the proposal in the coverage and reimbursement document to request CMS to review and revise reimbursement for molecular CPT codes. As the number of available genetic tests and their use in routine diagnostic grows, laboratories will not be able to continue absorbing the losses associated with genetic testing as they do today. We strongly support the SACGHS recommendation for CMS to review and revise reimbursement for molecular CPT codes. AMP, through its resources and knowledge of this subject, stands ready to assist CMS in carrying out this recommendation. Second, change in the definition of a genetic test. AMP's position remains in strong support of the limitation in the definition of a genetic test to inheritable germ-line variationings and not including somatic variations. If a genetic test is more broadly defined as any molecular biology type test then there need to be a distinction that allows for a discussion of the ethical, social and regulatory issues to inheritable genetic tests separate for testing from some attic mutations. This distinction is not relevant to the coverage report but may be relevant to future reports of the SACGHS. Third, better coverage and reimbursement for genetic counselling services. AMP members performing genetic tests work closely with genetic counselors and medical enettetyists, providing essential services to patients and their families that are tile-intensive and not adequately reimbursed. AMP's strongly supports a recommendation to design genetic counselors as alyid health professionals, allowed to direct bill and to review the billing codes associated with genetic counselling services. Last, gene patent. AMP asks that SACGHS give full consideration to the negative impact of exclusive licensing and enforcement practices for gene patents on the future of genetic testing. We understand that SACGHS has set this as a high priority but has decided to wait for the national academy of sciences study for intellectual study related to genomics. We urge you to promptly set this as a agenda for your committee as soon as the report is available. On behalf of AMP, I thank you for the opportunity to speak with you today. AMP remains available to the SACGHS to assist with or provide information for your thoughtful deliberations and important work.

Mary, thank you very much. And thanks for making sure that we are staying closely connected with the association. That is important, that you are clearly with us. And as we go forward. The patent thing we talked about yesterday and we're right onboard there, waiting for the NAS report as well. We to not have a lot of time. I appreciated the guidance around the laboratory testing thing. I'm not sure what we might do with that comment right now. Then we'll take it as a -- you've made a point and we've got to deal with it at some point. So we'll probably get back to it. Thank you. Good job.

All right. We're going to move forward, and invite Dr. Joseph Boone, assistant director for science, division of laboratory systems centers for disease control and prevention and Stephen Groft helping us to look at the issue of the summary report for providing quality laboratory testing for rare diseases, follow-up and future activities. You will remember that they had this conference in Atlanta in May of '04. They are making plans for a second conference. The executive summary of the proceedings is in tab 5 of the briefing book. While the conference was conceived as a plan to address access and quality of laboratory testing issues for rare genetic diseases or conditions it wound up identifying a number of issues beyond quality assurance. The group soon expanded the conference to include other topic of interests, many of which intersect with the interests of this committee. Therefore, we want to -- we'll be learning about that and seeing how it dovetails with our activity. Thank you, Joe.

Thanks very much. I'm going to -- it is unfortunate that Dr. McCabe is not here, because some of the things that we're going to be presenting are certainly relevant to this -- a precursor to this committee because we are really addressing some of the issues that have been raised before, in particular the issue of translation of research findings in the clinical practice, and the issue of access and quality of laboratory services. The -- as Dr. Tuckson mentioned, we did have a conference in May of 2004. And that conference did address primarily a set of issues that was raised by this committee previously. It had as partners emry university, NIH and CDC, and that's the reason that we're doing this tag team presentation today. [ please stand by ] In terms of U.S. -- 78 percent of the clinical -- some of the -- 78 percent of the tests are being done in the U.S. 22 percent of these tests are being sent outside of the country. And 33 percent of the testing, these gene tests, are for research only, laboratories. That is the tests themselves. If you look at the distribution of laboratories, research only laboratories accounting for 40 percent of the U.S. laboratories in the gene test. None US laboratories account for 30 percent of all of the labs listed. This was in 2004. The data has not changed very much since that time, if you look at the -- another thing that is important to look at, real quickly, is the fact that other things that are tested for, many of those tests are available from only one laboratory, or from a very small number of laboratories, which makes some of the quality assurance practices that we had a's like to have in place difficult to do. There's very few tests that are actually available through the college of American pathology survey program, and similarly in Europe there are very few tests monitored in a quality assurance mode. And so in the -- in the summary slide, I think that the main thing to focus in on here is the fact that we're following further -- falling further and further behind in terms of development of gene tests. Rare disease associations are being found at the rate of about 20 per month. And the new testing that we are able to incorporate is about ten per month. And so we're running 50% behind in terms of developing new tests to address the conditions that are being found in the gene finding, and that gap really does need to be closed. And so the results of our first conference was that we actually formed a -- a North American laboratory network for rare disease genetic testing, and that network is comprised of laboratories that are all certified and we'll -- will report the limitations of the tests in their reports. They are going to work to -- collectively to increase the development of new tests, to foster research and clinical laboratory partnerships and serve as the backup resource for additional tests. There was an organizational meeting in which -- which Steve is going to talk to you about in a moment. There were about six laboratories that -- that formed this original a -- alliance of testing laboratories. In addition, the American Society of the human genetics, and the office of rare disease research from -- protections agreed to provide education to researches and RNRB's, which is something that was really needed. NIH has a pilot program to fund translation of research tests in the clinical tests, and that program is -- we want to see that expanded. Expanded in a -- in a logical manner. And then we are going to have a -- planning to have a meeting later this year, which Steve will tell you a little bit about. And so we're on a pathway. I think that it is -- it is the right pathway. We're not confused. I think we know where we're going. And Steve is going to tell you a little bit about how we might get there.

Thank you very much, Joe. You saw the stop lights, the red lights, green lights, yellow lights and sometimes I think we're working all at one time, and so we're not sure how we're going to get there. As you will see, the last slide in the presentation, that is even more of the confusion that we're adding into the situation. So I'll try to get this moving. Okay. We -- we have a -- we do have a meeting planned on March the 17th, prior to the American college of American genetics to start to crystallize and finalize many of the discussions that have been held previously, both at the meeting last year in May at the Centers for Disease Control and Prevention and at emry university in Atlanta, and a number of discussions that have been held by a lot of participants since then to -- to look at the -- presenting this at the September 2005 conference here in Washington. But we've been working on identifying major issues, and target audiences that need to be at the meeting in September. We'll be looking at the conference agenda, and then assure that there is broad-based participation in the meeting, the roll-out or integration meeting in September. And so we still were in the planning stages, but things are coming together rather nicely. I -- I think -- it seems like for the first time we've within able to get many of the major participants who we had to get together to really effect an effort that would have some outcomes that were -- that could move forward. We are getting together here finally. And so it is good to see. And at the conference, in September, again, it will be in Washington. It will be a two-day session, there will be planery sessions to review them. Again, we're working all of thesish issues up that Joe talked about, as far as the vision and egg the things we need to discuss to give us direction and movement. And the momentum to move forward. Okay. A couple of the issues that we need to work on, are trying to establish the priorities for developing genetic tests for rare diseases with there being so many disorders that we -- we could look at and really start to work on. We really have to try to -- try to identify those priorities and the criteria for selecting them. And so it -- it is just an area that we hope to hear from a lot of people on how we're going to go about this. The -- the conditions for the clinical laboratory participation, we currently at -- at the office of rare ditz eases -- diseases have a small program with the national human genome research institute within the clinical center to develop these genetic tests for rare -- four rare disorders last year which we did under the direction of bill GALL, the clinical director for the human genome re serch institute and this year we hope to expand that to 16, maybe 20 more tests that we will develop, mostly for the use of the intramural research program. And so we wanted to go forth and start in the intramural program, get direction, experiences, and then move possibly into the extramural program. And as we -- as we were moving forward last year in developing these genetic tests, we came to the conclusion that this was something that was -- that is quite capable of doing in the extramural program and now we are looking for partnerships within the NIH system to expand the whole -- the whole program to increase the number of genetic tests that are developed for rare disoffereds. And when you have a total of 6,000 or 7,000 rare diseases, you know it is quite a task. Where do you start? And how do you continue on? How do you gain the interest? There certainly has been a lot of interest in moving this move forward, to have the tests move out of the research stage, and into the -- the stage of clinical accessibility for the public. And the next three slides that you have, and that are available nor anyone who may be looking in, through the -- for anyone who may be looking in through the Web site, we've spoken about the long term vision and the short term vision for what we want to accomplish and where we want to go. I will not spent too much time because I know that the day is drawing to a close and people have to catch their plans, a number of areas that we want to talk about, and we are going to discussion the successes, how will we measure this and identify it for the patient's families, and for the priders, we have to discuss the success of the system and the services that would provide these services to the public. And we hope to evaluate whatever success we're able to achieve through pre and post surveys of the laboratories, the consumers and advocacy groups, the center for Medicare, Medicaid services and then other payers and then to monitor the tests that will become available, and to monitor the quality of the tests as well as any adverse events that might occur that seem to be a major concern these days, as they should be. And then we hope to look to the roadblocks and then remove them creating the models generating the energy to move forwards towards a solution and, again, we know there is a lot of passion involving individual rare diseases. But I think we have to look at this in a sense that we are not -- we are not going to be able to do all of the rare diseases at one time. We will start in a systematic fashion and continue to move through and to complete as many that are possible. At the present time -- and that -- that currently are in the research stage or in the research laboratories, and I guess we've been hearing about the need to do this for many years, from a lot of the patient advocacy groups who, of course, would like to have a genetic test available for their disorder. There is always a concern that, if they are available from a research laboratory, that the research money would dry up and the project would die. It may never be available for use in the clinical services. And so I think those are some of the areas that we're looking at, and some of the need tas we're trying to work with, as we move forward. And this is a slide that we've tried to put together. And we could not put all of those different lights in there too as well. But you see the fume of partners that we have to -- that we're dealing with. And actually it has been very nice progress, I think, as we move forward from the planning last year, from the Atlanta, May meeting in Atlanta, to where we are today and the number of groups involved are numerous. And yet there has been a good sense of a need to move forward quickly. And as expeditiously as possible. And so I think we'll just end it with that one. And we'll try to answer any of your questions that you might have.

Thank you both very, very important work. The floor is open. Any questions?

Just a point of information. Are there press depths or other examples where the -- where HHS steps in to fryer advertise development of tests for -- to pry or I advertise development of tests -- to pry or I advertise a development of tests -- to priorize development of tests?

You know, I do not know of any. Looking back on when we started with the orphan drug act back in 1983, we tried to identify compounds that were available , so on the shelves of companies that were not being developed and we've pride to provide incentives. But we tried to identify compounds that would be useful. And then we went ahead, funding research, trying to support research for those areas. I think that the scientists, the laboratory people will identify those. And as I mentioned, some of the first areas that we would like to work with are those that are already in the research laboratories, maybe could move over to the clinical side.

And we -- we've talked about the federal process, but we also have a private sector process that is engaged in this -- this overall activity with us. There were some 50 people that were our original meeting. And we hoped to have maybe as many as a couple of hundred people at -- at the September meeting that have been -- we get the same message from the people in the private sector, that the rare disease community is coming to them with funds in hand, wanting tests developed. And they simply do not have enough capacity to move these tests through the system.

And for the mess part, we probably will not be establishing -- for the most part, we probably will not be establishing the priorities. I think this is where the community will come forward. We are looking for a cooperative effort among the patient advocacy groups, all of the government agencies that have to work together on this issue. The last slide, I think you can point in there who is going to bring the test, the need for certain tests, and everyone will bring the tests forward to us for consideration. We will not be the sole source of funding. Advocacy groups want to do this, and others.

A quick question, based on what you said then, are primarily then the barriers to getting these tests developed the laboratories just not having the capabilities? Are they more financial? Or both?

It is a little of boat. I mean, I -- the -- doctor ledbetter at em o r y university indicates of course that there is enough capacity to do these tests within the United States but some of the tests are going abroad. And you have to ask the question, well, why is that occurring? I think there are several reasons that that is occurring. I really applaud NIH for taking this initiative to try to put the researcher are the clinical LAN in a -- in a partnership so that those -- that transition period hopefully will take less time and will be able to move tests more rapidly through. And this -- this really is just a network that is starting to build too. Because there are a few labs that are in this. And it is a -- if the pilot really works well, then certainly we can engage, I think, more enjetic testing laboratories in this -- this -- for genetic testing laboratories in this process.

And I think with so many rare disorders, there are so many possible conditions that might exist that can you not say it is this or that. There are many different possibilities here. But we are hoping to have pilot projects involving different laboratories so we gain the experiences of commercial laboratories as well as certified lab raties, some that are ultra-orphan disorders, the small prevalence diseases that we'll look at to see how things are done, and how we might be able to use those experiences to extend out to the entire community.

Thank you both. We very much appreciate it. And look forward to the updates after the meeting. Thank you both. All right. We are just going to have a couple of minutes and then we are going to know that people -- some of you really need to get out of here, and so we're just going to end a little early, I think. Let me summarize a couple of things that I think that we said that we would do. This is not going to come out real well, because I -- I thought we would have a few more minutes to actually organize this, but anyway -- and so the main thing is that, Sara knows what we're supposed to do. On the genetic discrimination discussion, before you go, Maureen, because there is something that says that you are supposed to do something. On the genetic discrimination, we are going to do the DVD. I did the narration this morning. And so that -- I am not the limiting step in this equation. Can you not blame me. And so we've approved the script. That is moving forward. The public comments to the secretary are being collected, and those will go forward to the secretary. The legal analysis, we are not going to wait for the legal analysis to get done. But in the body of the letter to the secretary, we're going to urge the secretary to use all of his influence to expedite the legal analysis from the various departments, and everyone that is involved with that. And then we're requesting that the secretary hold the stakeholder meeting to help broker any differences that may exist in that community, to move that forward. Those are the things that we agreed to on the genetic discrimination. On the health infrastructure, there we are going to -- I think we wanted to send a letter to brailer, urging -- saying thank you and urging again that we want them to remember what we're true trying to do here, and the family history issues are being thwarted as he unveils his plans. And that Maureen is to work with Allen Guttmacher to draft the letter to brailer. You did it?

We spoke with Alan yesterday. And so I think that he is taking the lead on behalf of all of us.

It is the wait for Alan to leave and then give him the assignment. That will teach you -- teach you all to leave.

That's right.

For the -- whatever the -- the howe committee, what is it calld? The disorders committee. Any of you that have comments that you want reflected there, go to Joe. So that Joe can -- Joe tellfair can carry the water for us on that committee. On the reimbursement, I will not summarize that again. If you all did not get that last time, shame on you. And I want to also just --

Large population studies, we're writing a letter to the secretary with the number of points that we're going to make.

All right. So we've got the large pop. We've got that. That is in our notes. I want to welcome to the committee, I thought that Joe tellfair was terrific. And what a terrific addition to the committee. Kevin, we'll just wait for him to leave and then we'll say nice things about him. But Kevin, really, welcome. And I just think that that -- that this is really one. What a -- this is really fun. What a great group. The ex officios, thank you all very much for coming, and you will of the contributions that the ex officios made. Terrific. The webcast people, thank you all for that. Again, there are a lot of people out there that care about this. So thank you for that. Thanks to the sound man, you were terrific, and keeping us on track. And Sara and the team, always, just stellar behind the scenes. Every single person to be commented. [ APPLAUSE ]

Now the people that deserve the biggest applause are the audience. I mean, how they can sit through this stuff and they do not get to talk and they just have to be talked at. We really appreciate the involvement of you all, and your expertise. Any member of the committee, last words?

One last comment, I say this at the end of the meeting, that I still want to at least keep in our minds that we do have a duty to the public to let them know about our proceedings, the things that are going on and the federal register may not be the best place, and so I think we still have a duty.

I will piggyback on also the comment that I made at the start of the meeting, still I want us to somehow -- even though we have a lot on our plans it is how do we get to the education of the American public, important what you are say, standing on its own about what we are doing, about you it is educating the public around these issues. It is important. I'm glad that we got it into the -- into that recommendation at the end, where the secretary on the coverage of reimbursement issue, where we can start to get the secretary using the -- the information distribution mechanisms at his disposal to start to educate people about these things, I think that is important. I piggyback you on that. Anyone else with comments? With that, all of you, a hard two days. Good for all of you. Thank you all. [ conclusion ]