 I have to tell you, for a couple of weeks now, I've really been quite proud of myself, because when we got together to talk about this workshop, Francis said, well, Alan, why don't you take the last talk? And I'll say that's fantastic. What better than to have your boss say he wants you to bat cleanup? I thought, you know, I've got a lot of pride. I just looked at the agenda, and counting the two times that Francis had himself bat, which is a different issue, it turns out I'm not the cleanest bat. I'm the ninth position in the batting order, so that's probably more correctly. And I hope by the end of the talk, maybe you won't realize that. So what I'm really talking about is how wonderful it is that we had these GWAS studies, but in fact, how do we translate those into something to improve diagnostics, therapeutics, and particularly in some ways, prevention? So there are sort of two major points here. The first is the use of genetic information regarding common disease to individualize providers' approach to patients, and to also change patients' behaviors in ways that lead to improved health, so-called personalized medicine in many ways. The second is the use of genetic information regarding common disease to understand the biology of human disease, to lead to improved diagnostic therapeutic and preventive approaches. I'm going to spend most of my time talking about that second one, because the whole personalized, for several reasons, including the personalized medicine is probably a three-day seminar rather than a 20-minute talk, but I will, at times, bring in a little bit of this. Now, of course, we spent the whole day talking about GWAS, and most of us who spent time in genetics, either practicing medical genetics or trying to write about it, have spent time thinking about single gene disorders, and now what is this about genetics and common disease? And it's really been the theme for the day. We're moving from thinking about the large effects of single genes in the rare or single genes, so-called single gene diseases, and I put those in parentheses because there's probably no disease that only one gene really has an effect on, to the smaller effects of multiple genes in common complex diseases. Now, one way to sort of just sort of make a quick distinction in your mind between these two kinds of situations I thought was to talk about a typical single gene disorder, and several have already been mentioned today, but since I come from the NIH, I thought I should be erudite and quote the literature, reference the literature for you, so I've referenced my favorite, I hate to pick favorites here, but I have referenced my favorite journal here. And those of you who buy your own groceries undeadly, at least read this journal. I'd like to, if any of you write for this journal, sometimes I'd love to meet you. This is from the Weekly World News. I take particular pride in this because I was the only medical geneticist in Vermont at the time that disappeared, creature captured live in Vermont, bat with a human face, he's smart as a whip, says stunned scientist. Even though I wasn't only a medical geneticist, and though I'm often stunned, I'm not the stunned scientist who was quoted here, though it would be great to have this on my CV, if it had been me. But this was the kind of the old-term model of a single gene disorder, some strange conglomeration of physical findings, etc. that led to a diagnosis, usually carrying some triple epitomic name and with three people in the world who've had it. Now, obviously the single gene disorders that are much more common than three in the world and some of them are quite important for health. But in general, single gene disorders are rare enough that they rarely approach a kind of public health concern. And that's why when we start thinking about the impact of GWAS studies on health, there really is a somewhat different impact than even the total impact of single gene disorders. Because when we start talking about GWAS, we're really talking about all these disorders. You will notice, I think, the first page of the handout for my talk starts with a variant of this slide. I tried to put my time to good use during the break this morning and actually updated the slide that you have from 2002 to 2004. You'll notice sort of interest, the only thing that changes between those two years is that diabetes and Alzheimer's have flipped places in terms of, excuse me, Alzheimer's and pneumonia influenza have flipped places in terms of the order of things, both as Alzheimer's becomes a more common cause of death and pneumonia influenza becomes slightly less common. But essentially, if you do it any year after the last number of years, you'd have the same list of 10 disorders. What they all have in common, of course, is that by the very definition, of course, they're common disorders. And that in terms of what we've known about the genetics, all we've really known until quite recently is, gee, if you have a family history of one of these, you should be concerned you have an increased risk of developing this perhaps dying from it, et cetera. But we have not been able, prior to the GWAS kind of era, to identify for most of these, cancer being the one exception where we really have been able to identify a number of specific genes involved because of the very nature of all cancers being genetic, not all hereditary, of course. It's made it easier to find genes involved in cancers. The one list that gets a question mark is injury. Many people would argue, gee, injury, that is by its nature an accident, as it's often called incorrectly. And so genes must not play a role there. Of course, there is a genetic variant that we've known for some time. You don't need a GWAS study to find this genetic variant that makes one much more likely to die of injury than other individuals. As an experienced clinician, I can tell you just looking around the room that I can spot a number of people that have this genetic variant. So without appropriate informed consent, I'm about to tell you a number of you that you're more likely to die of injury than others in this room. And that genetic variant, of course, is the Y chromosome. If you happen to have copies of Y chromosome, you're much more likely to die of injury than if you lack it. But that may not be truly biologic, which is why that gets a question mark. But it's an important thing to realize, and one of the real reasons for showing this slide is regardless of whether genes play a role in the likelihood of your developing an injury, though in fact they probably do, they clearly do play a role in what happens once you get the injury. And that's not just peculiar injury. It's also true of all the disorders in the slide. We often think about genes and causing disease, but clearly, particularly when we're talking about, or specifically when we're talking about common diseases, genetic variants have much to do with how the individual host handles the disease as well as the therapies we use for the disease once they get it. So if you look at several different people with the same injury, who ends up developing acute respiratory distress syndrome in the ICU, and who doesn't? Well, lots of factors can contribute to that, but we're beginning to be able to identify genes, in fact, to play a role in those kinds of things. So if we're in the era of genomic medicine using the whole genome to understand health, we just have a good GWAS study today and have a new drug tomorrow. After all, last week, genes involved in diabetes, how come there's not a new drug for you to write about by now? It's been several days after all. Well, the problem is that there are all these steps. And basically what I'd like to do is to walk you through this diagram, go through some of it in a little more detail than others, but basically showing the flow from GWAS down to both prevention diagnostics and therapeutics. All three of them just sort of talk with you a bit about each of the steps involved here and why there are both problems here. But while there are problems, there are reasons to have optimism about these various pathways and that we actually will be able to get through them. So the first one, replicate and validate. Well, people have already talked about that several speakers today, so I really don't need to go into that one anymore. The next step, I'm going to try to keep highlighting these in yellow, identify genes and gene products. Once you've replicated and validated the GWAS study, you clearly need to not just, as we've talked about again, not just have the region in mind, but you've got to identify the genes or gene products that are responsible for the etiology of the disorder to be able to really get anywhere. A good example of that is the story that many of you will know now a couple of years old. They're using a GWAS approach, both originally in this study and then a couple of others afterwards, which among them have been able to identify three different genes, which account for approximately 74% of the attributable risk of age-related macular degeneration, which depend upon how you define things as either the leading or the second cause of significant vision loss in the elderly in the U.S. And that's interesting because before that study, of course, no one would have referred or thought of AMD, particularly as a genetic disorder. It was a disorder that was pretty common. We thought, gee, if you had family members that had you were somewhat increased risk for it, but it wasn't a dramatically increased risk. Now, once you've identified the gene or gene product, we'll go down the center aisle here, talk about developing a diagnostic test. And of course, the test methodology is going to vary incredibly depending upon exactly what the gene or protein product perhaps you're looking at. So you can use your imagination. You can run wild in terms of the various technologies and methodologies that one might do to do that. Now, it's important to realize that however, whatever the technology is, you're going to use to develop the diagnostic test. That's only going to happen if someone financially supports the development of the test. Sometimes that comes from the NIH through research dollars. Sometimes it comes from private industry. Particularly, of course, private sector support tends to depend upon at least the perception that there's a market for the test. But this is a real issue, how you go first developing the test and then moving it from the research to the clinical arena and particularly that move from the research to clinical arena because even if you have a well-developed methodology, etc., etc., there are very few clinical labs that perform tests just because they can. They tend to perform tests because you're going to get payment for doing so. So there are all kinds of issues about health economics and other kinds of things mixed up in here. So there are multiple steps really to developing the diagnostic test and it's not just a question of technology or scientific approach. In terms of once one has the test, you actually need to show that the test, I'll go through all these terms with you, that the test really is valid, first of all, the analytic validity, that the test does what you really expect it to do. But even if you have a test with good analytic validity, that does not necessarily mean it's of any use in healthcare. So you need to show both the clinical validity and in some ways, most difficultly, I suppose, but perhaps most importantly, the clinical utility of the test. That's not to say that there aren't lots of genetic tests out there and more broadly, lots of other medical tests that aren't genetic at all. For which clinical utility has never been demonstrated and which in fact, if you did a rigorous study, you probably would not be able to demonstrate true clinical utility. They are used and sometimes they're useful and sometimes they're not. It's interesting as we get to sort of genetic testing, this is a standard that in general is being utilized to think about new genetic tests, et cetera. We haven't very much retrospectively demanded all three of these for existing medical tests that have nothing to do with genetics itself. But it's a good sort of rubric I think to think about as you think about testing for not just genetic disease but any disease with B gene-based or not. And then of course, even if you go through all those steps, you really have to obtain third-party payer coverage for the test because if you can't cover the lab cost, then not very many healthcare providers are going to order the test and even if a healthcare provider might suggest to a patient, very few patients, though some would, very few patients are going to utilize the test unless their third-party payer covers the cost of the test. Another part of this is actually covering the healthcare provider time involved in the testing which can be significant, particularly with newer genetic tests that haven't been used routinely in medicine. Take a lot of explanation often or discussion between the healthcare provider and the patients and of course we have a healthcare system that tends not to reward providers for time spent simply talking to a patient. So there are a number of financial hurdles here. Sometimes you can get around the need to cover health professional time specifically in terms of a test but you certainly need to be able to pay the lab in some manner if you're going to have the test reach-wide use. So going down the other arm here that has to do with developing therapeutics, you really need to define the function of the gene or the gene product if you're going to get very far with that. So here Nick Wade I don't think is here today but here's his story from last week about the diabetes genes findings and part of the story says, quote, the importance of the new genes is that they point to previously unknown pathways involved in diabetes. Several of the new variant genes make the pancreatic beta cells produce less insulin, Dr. Al Chiller said. That suggests that diabetes may start as a disease of too little insulin production even though patients turn up in the doctor's office making too much insulin to which their tissues have become resistant. Of course speculating upon the fact the function of a gene in the New York Times does not necessarily make it true. The lots of readers probably think so and I'm sure you're aware of the power of your pens when you write these things but clearly that's an important point that already David Alchiller and others involved in this are trying to figure out what is the function of the genes implicated because it's by understanding the function that you're really going to get somewhere. So even if you understand the function what you need to do next will base upon your understanding of the function you need to identify a drug target. And this gets a lot of attention in the biotech press amongst other places. That's an example of it. Of course you can use more or less conventional strategies once you have found a new drug target develop a new drug. Again you need to have the idea there's going to be a market there. Most drug development is done in the private sector and so there needs to be a feeling amongst some part of the private sector in a way that there is a market for it. One thing to talk about which I'm just going to throw this in as a parenthetical interesting I think important fact. We talk about whether it be genome-wide association some other things are happening in genomics. It's important to stress that a lot of the new drugs we're talking about aren't simply as old new drugs tend to be tweaking something so you add a hydroxyl group here you take away a methyl group to get better coverage or better transmission across a blood-brain barrier. We're talking about completely new categories of drugs for a number of these diseases. The interesting thing I think to think about is that if we say that we humans have some place roughly around 20,000 genes well maybe not all of them are going to turn out to be good drug targets. They may not all be drugable quote-unquote. If one guesses and it's still guessed at this point that perhaps half the human genome presents drugable targets the genes of the proteins they produce probably about 10,000 genes. Currently if we look at all the drugs in the pharmacopeia they target about 500 genes in their products. So that would argue that 95% of potential sort of drug space is unoccupied at present. So that by understanding again the way the genes work in disease it may be to understand mechanisms of disease in ways differently than we have before. So the principle we go back to the sort of about adult onset macular degeneration the genes that have been shown to have this large role in attributable risk are involved in inflammation it appears. So that has led to very interesting thoughts about G maybe we should try using drugs that attack the inflammatory pathway. Now they could be old drugs that we've had do with inflammation or one would hope eventually of understanding the precise mechanisms here perhaps some newly designed drugs to be very specific in terms of their effects. But a lot of this again is understanding the basic biology through our knowledge of genetics. So how would you design a candidate drug once you've identified a drug target? Well there are lots of ways to do them. One of the things in terms of the genomics approach to particularly try to occupy this other 95% of the drug space out there is the idea of the use of so-called chemical genomics. The NIH has a chemical genomic center which is shown there. It's part of a larger initiative the Molecular Libraries Network which has been started by the NIH which has multiple components to it including lots of extramural labs ways something called PubCAM where the results are shared, et cetera, et cetera. The idea is to use high throughput screens to understand both the action of genes that are newly discovered but also very importantly to make a huge difference in terms of developing some new candidate drugs. Now of course even if you do that you've got to do clinical trials to show that the drug is safe and it's efficacious and you've got to get an FDA approval. So this is in your handout it's just a diagram courtesy of Chris Austin who runs the NIH chemical genomic center showing basically with some approximate time horizons for you there the stages of drug development with basic biomedical research which has a very indefinite time frame to it and then this Molecular Libraries Initiative that I mentioned goes a little further in that and there are other efforts in the public sector to do that but this is probably the largest one to move a little closer a little farther down the field in terms of achieving the ultimate goal of actually having a new drug but there's still many steps beyond that. So if you're talking about GWAS leading to a completely new drug then you have multiple steps that need to be taken and that will take some years and it's important for both you obviously and your readers to understand that. Now there may be some shortcuts for instance if we go back to the AMD story if it turns out the drugs are already out there widely prescribed perhaps as anti-inflammatories if someone does a study to show that they are helpful in AMD then you skip all these other steps of drug development you can use an old drug that's already been clinically approved by the FDA etc etc you just need to expand the indications and the labeling from the FDA which is a lot easier to do than to go through all these steps and much more likely to both shorter time frame and much more likely to lead to success but if you're talking about starting DeNovo really completely new drug then you can shortcut some of these steps but it's still a matter of some years until you're going to see a completely new drug. So looking at our other pathway the prevention pathway you can see here you might well come from diagnostic tests once you have a diagnostic test you could offer that to lots of people and think about prevention strategies so that for instance adult onset macular degeneration you could think about developing a diagnostic test based upon these genes that we've shown are implicated in the disease etiology and you could diagnose people in the population as being a significantly increased risk for this and then for instance you could simply work counseling with those folks about smoking behavior for instance it turns out that the trivial risk if you add smoking and much increases your risk if you have one of these at risk alleles so those kinds of prevention strategies based upon the diagnostic test are one way to go but in fact for some of these you don't even have to develop the diagnostic test you can simply if you can replicate and validate the GWAS study et cetera et cetera you can occasionally go without the test but simply be able to devise prevention and non-drug strategies that would be of use even without a diagnostic test leading into it. Now this is an interesting article from JAMA not very long ago which again talks about AMD considering the part in yellow but I think the part in white is actually interesting just in terms of well done science in terms of the folks right in the article saying wait a minute here we believe it is premature at this time to consider genotyping individuals with various stages of AMD. Screenings should consider one the genotyping of about 30 individuals with drusen pigment changes that's sort of a sign of AMD would be required to identify one individual who is homozygous for the risk allele for both genes and two the observation that many but not all individuals with those genotypes will develop the disease so they're saying wait a minute before you develop some kind of test and try to market it broadly here let's look a little bit basically even though they're not using the terms they're talking about let's look at the clinical validity and clinical utility before we just start doing this test because we can. However in the future a risk profile that includes genetic and environmental factors such as the one calculated here in may ultimately target a screening closer monitoring of individuals who are at higher risk of visual loss due to AMD progression and that's clearly something that many people in the public health community are beginning to think about that once we show genes that are implicated in disease causation to think about finding individuals who have variants to make them more likely develop disease and develop targeted preventive strategies to try to help those individuals which of course are all of us for one disease or another for many of us for multiple diseases but even if you've done that you have to validate these things via outcome studies and the idea there is that you know you might have a test that looks good etc etc but unless we really do rigorous outcome studies to show that making the behavior change etc have a positive impact on eventual health status sort of so what now again lots of things in medicine we've done over the years without showing that they really have a positive impact on health status but the idea is we shouldn't just do this blindly it's going to take some time if you think about all the steps here even if we were had this prevention strategy in place today it would take some time to do a good study that shows by counseling you about your individual risk let's say for AMD and then counseling you about their particularly injurious effects of smoking for you does that really change I mean there are lots of people today who smoke who already know the smoke is not such a great idea for them by adding in their personal risk for AMD is that really going to change their behavior or not we don't know and we don't know how you might do the counseling in order to be able to achieve that so those are the kinds of things that still clearly need to be figured out but even if we do all that will we really make an impact on health so I think to do to make this work it's going to require both informed interested providers and informed interested public that is us and we thank you for your help in accomplishing both of those things actually so there are many ways to talk about this one particular sort of resource I guess and tool to mention to you if you're not already aware of it in terms of reaching healthcare providers or something which has now been around for over a decade called the National Coalition for Health Professional Education in genetics the name may be the only thing that's more unwieldy than the acronym of NICHPAG but NICHPAG is an organization an umbrella organization that includes literally dozens scores actually of health professional organizations everything from hospital chaplains to physician assistants to lots of nursing organizations a lot of medical specialty groups et cetera that's in many ways sort of serving the clearinghouse and a catalyst for health professional education in genetics and particularly some of these newer things and then of course informed and interested public there are multiple ways to try to achieve that we tend to look at you as perhaps the major way to do that we know that you often do not feel that your job is to do our job for us to educate the public but we like to make on good days I guess it is a partnership that we can do that together and even if it's not the prime objective of any of us somehow we'll still get about doing it a specific other tool for this that many of you will know about but some of you probably won't it is something called the U.S. Surgeon General's Family History Initiative which was started several years ago by then Surgeon General Carmona continues even after his leaving that job and it's a multiple agency in the federal government effort and lots of private non-federal partners at this point to try to encourage use of family history in healthcare with the idea that way before we get to sophisticated genetic tests et cetera family history in some ways is the cheapest the most accessible genetic tests that we've got precise not very but cheap and easy to access yes so this is an attempt to try to make family history more useful in healthcare in various kinds of ways that I'd be happy to talk about so again just to make the point that while many of us of today's state of medical practice have never been proven to improve health or to make sense economically we should use rigorous outcome and cause benefits studies to decide which genomic medicine practices to utilize I'm sure we'll be using some as we as we study them obviously but that's what we seek to do to do this in a kind of rational effective way so I realized I need to come up with an executive summary one of the things I've learned in my eight years within the capital beltway is that nothing is worth knowing unless you can produce it to one page or less something that I know you think you get few column inches we do too sometimes and so the question is how can you reduce this to one page or less so I figured the questions easy I just look at the title of my talk well G was actually deprivation diagnosing and therapeutics for common disease wonderful thing about at the NIH lots of very bright collegial folks so I went around can anybody give me a short answer to this I don't know whether it's a short part to through them but for some reason couldn't could answer that so that you know I thought some more G there must be some people around here and I realized this is an executive summary I am a member of the federal government so I have an executive I have a chief executive so I thought well how executives must know about executive summers perhaps the chief executive would have a nice short answer to this I see some of you look skeptical I can't believe that well sure enough President Bush on April the 10th 2002 on a Saturday morning address actually when he was saying something about the need for genetic non-discrimination legislation he mentioned our age may be known to history as the age of genetic medicine a time when many of the most feared illnesses were overcome well I thought that's of interest that's short it's an executive summary I have unpublished data to suggest that the reason why executive summaries are so important within the capitol boat where because of variants in genes have to do with attention deficit disorder being much more common around here but anyway that were made unpublished I thought that's wonderful and then I realized well you know this is a crowd who may not necessarily believe that everything George Bush says is true I know that you have no just I'm a federal bureaucrat you remember the press so you have no more personal political beliefs than I do clearly so I thought that might not work but still balance I know that you love balance in your stories right you like to have both sides ideally you like to have at least two sides but you like to have balance coverage so I thought aha when I first came to DC there was another chief executive he came from the other party what could be more balanced than that but what's the chance of two chief executives in a row talking about this kind of stuff and I remembered that in fact there was a ceremony at the White House in which Francis was a lead participant at which then President Clinton announced that the draft human genome had been achieved human genome sequence and at that ceremony sure enough here's what Clinton said he said because of the draft sequence now being available it is now conceivable that our children's children will know the term cancer only as a constellation of stars now that shows a couple of things one shows he had a heck of a good speech writer now the exactly now it also some people would say well boy that's gene hype and there's clearly been a lot of gene hype out there and if truth be known of course where our children's children cancer still exists in a couple of generations of course it will still exist however I think there's actually some gene hope there more than gene hype and that is if we look at the family of disorders that we call cancer we compare those to say infectious disease because many people I think more or less correctly say that our knowledge of genetics and genomics in this century will have the kind of impact on health their knowledge of infectious disease in the last century so we compare the family of disorders we call cancer would say tuberculosis I think we'll see a similar kind of evolution in this century for cancers as we did for TB in the last century that is cancer will become as TB has become no longer something that if you did a rigorous three generation family history you would find multiple individuals in the family who in fact had had it several whom have probably have died from it like TB cancer would become something that people no longer have a legitimate personal fear that gee I've got a good chance of developing that during my lifetime like tuberculosis for those relatively rarer individuals who do develop cancer it will become something which in many instances is curable and in others becomes treatable so it becomes a chronic disease rather than a cause of death now like tuberculosis there will still be huge issues about health care access socioeconomic status and other kinds of things that even the age of genomic medicine will still have a huge impact on health care even the age of genomic medicine the bad news is we were all so maybe it's the good news actually we will all still die but presumably we will live longer and healthier but I do want to you know I want to both say that there's is a real if not part of the goal at the end of this rainbow there are some real positive impacts that we can discern GWAS studies and similar work will lead to but also at the same time say it will take some time to get there there are multiple steps we're at the beginning of you know it is a revolutionary era and all that but there are logical steps that need to be completed before we truly see the health benefits some of for some diseases those steps will happen very quickly for others they will be frustratingly slow but it will be an interesting story for all of us so I'm going to stop there Sharon Bagley from Newsweek a question about the part of your slide where you show in the flow chart how some of this work might lead to a diagnostic would it will it be important for any such diagnostic test I guess including those that already exist to achieve clinical validity and utility for it to determine the the expression status the epigenetic status of whatever gene allele you're looking at it's not going to be important for every test to be able to do that but there will be some for which simply knowing the gene sequence isn't going to be enough there be some for you know knowing that won't won't tell you much of anything there are others that will tell you a lot but not the whole story to know the but of course often in medicine you don't need to know the whole story to have a positive impact ideally you want to know the whole story and be able to take all that into consideration so there'll be some situations we don't think we really know yet but there'll be some situation which epigenetic phenomena like other all kinds of other things are very important there'll be some situations where genetic status alone may not tell you much but it's going to be the interaction of that specific genetic variant with some very specific environmental intermediary that makes a difference in health so that even knowing you know genetic status in some situations may not tell you much but if you can you know connect that to specific as we learn these specific something about the specific genetic that extra piece of information that's going to be important and while Bob Langrath Forbes while people geneticists debate whether like that paper whether it's premature to have macular degeneration other genes available as a test isn't someone in Silicon Valley just going to put this stuff up on the web you'll get your own Illumina 300K HAP app or whatever $500 and you'll be able to find out all the things they want you know all the things you want whether or not it's quote premature or not absolutely I look very much forward to your story illuminating that dynamic and explaining to people how they might be able to discern what's you know sort of I mean it's a wonderful you know if we all want to go into snake oil sales together this would be a wonderful 21st century opportunity to do it there's no question and on the other hand if we want to do something that's really wonderful and real benefit to humanity this is also a wonderful opportunity so there there will be I think there's clearly because this is complicated stuff as you all know the question you know discussion we had during lunch how to explain this to people well that's not just of interest to you all it's very much of interest in a clinical setting for instance how to explain this to people so it's a situation where you know people are kind of right for the picking perhaps for people who either innocently they may think they're doing something really worthwhile by bringing these tests to everybody or perhaps not so innocently just thinking gee there's a way to do this and you can go on the web and find some pretty bizarre kinds of offerings there's lots of claims in terms of nutrigenomics and is nutrigenomics a real thing yes absolutely there's something about genomic makeup that interacts with our nutrition to make a difference in who we are absolutely do you understand that very well yet absolutely not but there are people who are willing to do you know take a swab and then you know based upon that do a genetic profile tell you exactly what kinds of diet you should be on but particularly what kind of minerals vitamins other things you might need to take and nicely enough just to make a one-stop shopping they're willing to sell those to you actually just to make life easier for you I'm sure so there's a there's a whole mixed bag out there interested in asking you all who write about this as we can anticipate I think during the course of this calendar year the discovery and publication of dozens of gene variants that are clearly correct in terms of showing common disease at what point do you get to the threshold where at least some segment of the general population says I want to know I want to see my own report card these if there are certainly people out there who take prevented medicine very seriously and are looking for whatever information they can find to try to individualize their own plans at what point does our cautious approach of well you know we really ought to test this out in a research study and we know exactly what the quantitative risk is and prove that there's clinical utility not just validity in the data at what point do we get run over by an avalanche of demand of people who simply want to know now and if we can't tell them that the information's bogus anymore because it's actually turning out I think that we've got real data here are are we in a good position to say just wait a while what do you think I just think it depends on how much will cost because I mean I'm think about the you know different genetic tests for cancers that are out there and people are getting them and that's an interesting point certainly that cost of for instance the BRCA one and BRCA two test which remains in the thousands of dollars is in part because that's exclusively licensed so there's no competition there's no reason that testing for dozens of snips in a given sample should cost more than pennies I mean we indicated the carton cost of a snips about an eighth of a cent so the actual actual laboratory costs are going to be quite small the problem of course is there's going to be a big markup by those who are wanting to put this out there as for-profit enterprise but if there's some kind of competition in that that could drive it down so I don't think we should count on costs being a huge barrier I think people also want to know I don't I wouldn't have a test unless I knew there would be something I could do about the problem I mean if it's hopeless why know I mean maybe to do your will or something but you know and they're you know their whole social science studies about the people who are information seekers and the people who are not you know we known for now gosh 10 years what the major common risk factor for Alzheimer's disease is whether you have the and yet there's been very little uptake of that information because there's nothing you can do and it's a pretty horrible idea that you'd have this cloud following you around from then on after you've had your genetic test a lot of the kinds of things though that come out in the next a few years or this year won't be quite that dark in their implications but they won't either be connected with a certainty that you can interfere if you're at higher risk for diabetes or for a heart attack watching your diet and exercising would that be useful even if you couldn't prove right now that your particular gene genetic predisposition was going to be helped by those those factors I I do think it could be added incentive I mean as you said at most it may increase your risk 20% but okay as a chronic dieter that I am you know if I knew I had alleles that you know would increase my risk of diabetes um that might you know be a good boost so Larry you should tell them about this multiplex project which is just getting underway which is attempting to assess this in the real world by offering real people the chance to have this information and see what they do with it so Allen essentially outlined almost a decades worth of research bringing these tests to their final stages and in collaboration with a social behavioral branch in our institute Colleen McRide and I decided we should start down this path even though we pick genes last year we're not going to deal with the flood that's coming out this year and we will be offering testing for five different chronic diseases heart disease can't a couple different kinds of cancer osteoporosis diabetes to individuals that are work that are covered by the Henry Ford health system so they're they're in a covered HMO like organization and this is the really early-stage project we'll be offering this multiplex test where they can find out what their risk is for these complex diseases some of which were found by whole genome association studies and our major outcomes and measures are going to be first of all do they do they understand the test because this is hard stuff to package as you guys are struggling how you write about this this will be hard stuff to package for the general public and whether or not they find the test useful what's their attitudes about it most of the early indications will be and my behavioral biology people hit me for talking about this but they seem really is somewhat marketing issues not testing the market but see how people deal with this ultimately we will be able to follow them up long-term all it's a relatively small sample to see whether or not people who have some of the worst combinations of mutations actually lose weight or go on exercise program more immediately will be able to see based on the report card these folks are going to get a genetic report card it's going to come in the mail a little folder that will tell them how they scored we'll be able to follow them and see what they avail themselves of in the programs that are available as part of the health system so there's wellness programs smoking cessation programs so our outcome will be does your genotype make you more likely to go and enroll on one of these programs or at least inquire to one of these programs I just I've always been just this one's available I mean he's been using my all right all right very articulate all right all right all right no no the thing that that I that I still have a little bit of trouble with in all this is what makes genetics so special I mean you can listen to WTOP radio and they'll there's a place up in Rockville that'll test you for every known heart problem there is and some people are running up there to get it and some people aren't I mean is there's there's something special about the kind of information or the increased risk factors that that the genetic studies are going to give or is it just because it's less painful and you can just do it with a needle stick or a vocal swab or something like that that's one thing I I mean I've thought about this all along I mean there are obviously familial implications but you're not talking about that now necessarily you're talking about individuals are going to change their health behavior right I can answer before Francis does because this will be the short answer is that we don't know whether it's going to be special about genetics we think there might be and part of it builds upon this foundation where for better for worse we've convinced the public genetics is very important and deterministic now we have to back off a little bit and say well it's not as deterministic as we were telling you before there are variants that occur that have little sight increases of risk but I think the real answer is not sure we know whether genetics will be different and I'm going to also for Francis and say absolutely we don't know but it's also the breadth of the information there's almost no piece of this that's unique but the breadth of the information as well the the ability once we have enough of this to be able to tell you know in their genetic report card not just talk about one disease in terms of your risk but talk about multiple multiple diseases now you could say that's like a whole body scan or something well but most the whole body scans aren't found any science we would hope that this would be I guess the other thing is that it has the potential at least of making these predictions before there is even the tiniest indication of actual pathology you don't have to have an abnormal body scan outcome before the data may give you some information so because genetic information is a permanent it's there it's there as soon as you want to look at it whereas most of the other things we do to sort of make predictions about future risk you already are having a high blood glucose or high cholesterol you've got degeneration of your spine or you've got a coronary artery that maybe isn't quite doing its thing because you just had a thallium stress test this has the potential of moving the timetable back to an earlier point so that you could begin to practice prevention before you're already sort of half in the grave we used to say that on rounds actually yeah well it does have these semantic consequences of exactly who's normal anymore especially if we are all recognizing that we have that sort of DNA equivalent of original sin we're all flawed but it's also basically the idea that one could perform interventions to make a difference in terms of outcome not simply saying gee you're not healthy anymore but in fact talk about individualized prevention and other kinds of maybe treatment modalities that would stop you from becoming disease it would be a little discouraged by looking at people who know absolutely for sure positively as you said that smoking is probably not a good thing absolutely a little just dieting and so is eating more vegetables and I mean in a way you keep coming back to all the things that you already know that your mother told you should do anyway and also but we do have to be a little discouraged but not totally discouraged because for one thing we don't know and this is a big huge question if instead of hearing gee smoking in general is dangerous for you kind of thing if you understood something about particular individual susceptibility and also if you understood about something and smoking is probably not going to be a good example in fact but something you could do that would make a difference in terms of outcome then then it might be of more value that you should find the allele that prevents you from getting sick from smoking that might tell you something about the biology but I mean that you should see about R.J. Reynolds as a partner instead of Pfizer or Novartis and then you have to also maybe be a little concerned because if you're talking about you know looking at alleles that increase your risk of heart disease 20% and people who have a family history of heart disease they don't have the allele then they may think they can get away with not living out and part of this again is to I I purposely spent much less time talking about the personalized medicine model than I did about the other stuff and again I would argue that by understanding more genes involved in heart disease we're going to repeat the story that we got from the hypercholesterolemia we'll learn other things about the basic biology that goes to heart attack and obviously be multiple different biological pathways that all end up the common end too often of heart attack but we'll learn much more about the biology disease that will come up with other kinds of things that will make a difference so it's not personalized medicine absolutely important part of this but it's not the whole story personalized medicine and report card thing the thing that I think I would find discouraging and I've talked to some other people is this idea that more and more genes are now being implicated so I mean there could turn out to be a hundred genes or you know genomic regions that are associated with diabetes or obesity in which case we would all have one or several of them but what do you do with it? Sure but it'd be important again not just to know what your total risk is so that may be important but to understand the variants that you have that confer increased risk how do they translate from a variant to disease and maybe they're peculiar things and the steps that lead to diabetes depending upon those risk alleles they require a different kind of thing so maybe you know for one diets we'll make a difference for another one diet has absolutely no difference whatsoever but in fact for instance let's say that you know your increased risk for diabetes some receptor in some place or others over expressed then maybe some new small molecular drug that was specifically designed to sit on that receptor and block it maybe that's what you should be taking instead of worrying so much about exactly how many donuts you're having after lunch zinc zinc that's yeah I I just speaking personally as someone who confronts this as potential news I I think there's sort of an analogous question to what consumers will will make of this and that is what what reporters will make of it I was struck in one of these diabetes papers last week this sentence while the a type 2 diabetes variants discussed in this report each conveys a substantial population attributable risk 5 to 27 percent of each locus each contributes very modestly to overall variants and diabetes risk 0.04 to 0.5 percent total 2.3 combined across all eight snips so you know I think the this this is actually you know was was an issue last week about what what does one say about this you know it's obviously an incredible scientific accomplishment but what does it mean and of course there's always the big push to sort of you know speculate on what the medical kind of very utilitarian outcome will be but I think that both the reporters and the consumers what they're going to make of it really depends on how much magical thinking we're going to invest in you know single digit changes or X expressions of our risk for for diseases and that's why I think this is going to be a hard story to sell even as this tsunami you know breaks over us maybe I could comment on that that a bit we didn't have time really to talk about population attributable risk and what those measures mean and they are you know fairly complicated concepts but they do depend a fair amount on both the size of the risk associated and the prevalence of the variant and so if you have a variant that is not very common you're going to have a low attributable risk familial hypercholesterolemia that variant is very very rare and yet it opened the doorway to lipid lowering and we're hoping to find other genes very much like that so so I think you know we shouldn't sort of you know throw up our hands and say gosh it's only 0.5% of the of the variants of of diabetes in this population and other populations because really what we're looking for is clues to pathophysiology and I think part of the reaction that many of you are having is the idea that when you're writing a story for somebody of course you realize that as we as all of us do that most people are narcissistic and when you write the story they want to know gee I've got diabetes or so it's in my family they've just found these new genes so what does it mean for me? and it's a longer story to talk about it in terms of the public health kind of sense and understanding the biology of disease is different from saying you know this is the particular