 Great, thanks and thank you all for coming. It's really gratifying to see so many old friends and new friends here And I think we you know have a real opportunity to move this area forward. So this is great What I wanted to do was just give you a little bit of a context for some of the things that NHGRI is doing and kind of you know beat our chest a little bit But but also perhaps let you know as you as you hear topics come up You know during the day people refer to emerge or to other things and so that just to let you kind of know What those what those are You're maybe familiar with the strategic plan that NHGRI put together Eric Green and Mark Geyer About two and a half years ago now that was published in Nature and really taking NHGRI our institute in a direction We hadn't gone before which was was to the patient and to the bedside and particularly Trying to address things that could be done with medicine Sorry with genomics in clinical care in addition to all the other sort of bedrock things that NHGRI does and will continue to do Such as determining the structure of the genome and and it's how it functions and how it how it works So we were asked I was a sort of a subgroup of this to kind of figure out Well, what are the things one could do with with genomic medicine at a time when the term really wasn't even well defined And and we came up with sort of five things and one of them was you know if you could use it to identify risk That would be great We'd like to prevent disease who what physician wouldn't so that would also be very nice Perhaps improve diagnostics improve treatments and increase access So those were sort of the five things that we had focused on and kind of outlining what an agenda might be for for this area And we recognized I think at our third genomic medicine meeting When I sort of threw out a definition and got got queried on it by by several people around the table that we really didn't have a Formal definition and we needed one so we came up with one kind of in consultation with our genomic medicine working group And I'll name them for you in a moment And and then sort of shared it with our council and and this is what we came up with that It was an emerging medical discipline that involves using genomic information about an individual as part of their clinical care for Diagnostic or therapeutic decision-making for example and the other implications of that clinical use in in sort of policy and other other aspects This was a purposely narrow decision Sorry definition and many of the members of our working group said you know I lead a Department of Genomic Medicine and we do a whole lot more than just using the results in clinical care But we wanted to keep it narrow Because we're a small Institute and also we wanted to focus on this new area. We were moving into We also had some some codicils This is when you when you see a short definition and a long list of other things That's kind of gives you an indication of how much controversy there was and putting together the definition But but at any rate there are several other aspects of it that I won't go into here We do have as as Jeff and Rex both mentioned genomic medicine and Eric genomic medicine working group Which plans these meetings as well as provides guidance to NHGRI and other areas They are a subgroup of our advisory council and they help us to to sort of outline all infrastructure needs Identify related efforts and and review progress overall in implementation This is the group here and they are largely Sort of focused in the that corner of the room you might guys might raise your hands there, so okay So there they are if you have any anything about the meeting that you'd like to share with them Especially if it's good, please share it with them if it's if it's if it's if it's not good Rex and I'll be happy to take over that those aspects Yes, and I might also mention Eric and and myself bread was in burger and lower lower Rodriguez are all from NHGRI and working with the with the group I Wanted to list a couple of sort of the early things that that came up that we were a bit surprised to learn Little less than two years ago that were ongoing I think everybody knew that tumor-based genotype driven treatment in cancer was going on but but there were a few groups that were doing risk and susceptibility testing and relatives of Cancer patients who bore mutations and this was going out and actually finding the relatives not just determining that an individual patient had that Those risk variants family history collection was ongoing in several sites a whole exome or genome sequencing for unknown disease diagnosis was just beginning But has taken off Recently and complex disease risk advice was also happening in those sites and Rex Referred to the the summary paper that we published from that meeting really focused on you know What would it take to implement this and maybe teaching other sites who were interested in it what they might need to do In pursuing that so we described some ongoing projects identified some common infrastructure and research needs Which we are now trying to move forward and this meeting is part of that effort And then we outlined an implementation framework for investigating and introducing similar programs elsewhere. So there's a long Framework for engaging institutional leadership choosing the right question choosing an appropriate audience and gating stakeholders, etc. I Wanted to to just sort of show for you that the programs that we've begun and then maybe Kind of draw them together in terms of how this kind of addresses a variety of aspects about implementing Genomic medicine and advancing that strategy Shown here are our major programs the goals of these programs, which I won't read each for you The approximate total amount of money devoted to them in the fiscal years that they are Ongoing so so these are the major programs I wanted to talk a little bit about a merge since there are several emerge PIs in the in the room here And also because it is sort of our flagship effort in this in this area When we started a merge actually in 2007 the question there was could we use? Biorepositories which would generally were a hospital Saving its stored samples basically for that had been used for for pathology tests in various laboratories To store away as genomic Resources and get consent for using them in research and so the question was can you do that in an effective way? Is there are there some common methodologies that one can use and particularly could you use electronic medical records to do the phenotyping? And that the answer to that question which was really quite an unknown at the time was a resounding yes And that was really quite quite gratifying and and relief inducing for many of us But then in the in the second phase which began in 2011 we really wanted to begin to do some implementation So so each of the sites was asked to to identify a pilot and those programs are shown here This one at Cincinnati Children's Hospital I will describe a pharmacogenomic project that we're doing across the sites But this one is using a special array for the cytochrome P for 450 2d6 Gene which is a very very difficult gene to genotype and to interpret And they have a different platform that they're using for it And they're using it in interpreting post-operative or the use of post-operative opioids in children Children's Hospital of Pennsylvania is looking at beta adrenergic at agonists and beta adrenergic receptor variants in asthma in particular And how one can choose the best drugs for that at geisinger. There's an IL-28B Project looking at chronic hepatitis C treatment. They're also doing genome sequencing for undiagnosed diseases Marshfield is looking at complement factor H and the risk of age-related macular degeneration because they're heavily focused on eye diseases Mayo has a randomized trial of a genomic risk score for coronary disease versus a Framingham score alone Mount Sinai is is doing a randomized trial of Apo L1 genotype a major risk factor for renal disease in African-American hypertensives as clinical risk factors for hypertensive and phropathy and whether that information Affects then the effectiveness of prevention and management of hypertension in those patients Sorry prevention of nephropathy and management of hypertension in those patients in Northwestern is looking at return of the HFE mutations in Hemochromatosis and factor 5 lighting risk variance on physician and patient attitudes and Vanderbilt is expanding the pharmacogenomics Testing that we are doing overall and that they have been in the lead in prior to our efforts We also have an enhanced partnership with the pharmacogenomics research network that is a multi institutional multi institute effort of NIH But it's led by the National Institute of General Medical Sciences And and this in particular had developed a let's see So that's sort of the Heart Institute and NHGRI And they have developed what a clinical pharmacology implementation consortium Which is primarily focused on developing guidelines for pairing up genes and drugs or gene variants and drugs that may affect prescribing or drug selection and these are published in clinical pharmacology and therapeutics There have been a whole host of them and they're really very very effective in a huge amount of work on on these Investigators part very poorly reimbursed. They would tell us and and I would agree with them But really I think a labor of love in trying to get these guidelines out and they have at least as many more in Development as far as I know so this was a collaborative project or is a collaborative project Using PGRN's very important pharmacogenomics VIP gene sequencing array, which they developed to identify rare sequence variants in 84 pharmacogenomic genes that they as a group identified as being of a high priority 2d6 is on this list, but it has continued to allude totally effective Assessment although that assessment is improving with experience and our plan then was basically to take this array and implemented in about 9,000 patients in the various Emerge centers and Use it for their their basically their clinical care We sorry we liked this model because it could be a court Exported to other CLIA certified labs Obviously this this testing has to be done in a CLIA environment in order to be used in clinical care It permits genotyping of common and rare variants and discovery of new ones and it uses the CPIC guidelines and institutional approvals for Influencing clinical care so that program as it's being implemented is shown here for the various drugs that are being used You'll notice that that there are a number of drugs across the top But it's certainly not 84 of them and the reason for that was that many of those It's not quite clear how to implement them Whereas some of these others particularly those that are used very commonly or an in common across the Emerge sites Clopidogrel, Simvastatin and Warfarin do have Guidelines as well as I think some experience in their use So those are being used at the majority of the the adult sites The pediatric sites of course don't use a lot of these particular drugs And so the chop group is using a variety of others and CCHMC is is focusing on codeine One thing that we would like to see because this is a consortium is that actually with experience and with time They might all come to use all of these drugs. That's kind of a pipe dream on our part But but it doesn't seem totally impossible and in fact a lot of that kind of transference is occurring now As they gain experience with these I did also want to mention that the clinically relevant variants resource or CR VR Program which was to develop and disseminate consensus information on variants that are appropriate for use in in clinical care That is just beginning it builds off of a number of calls for such a database and consensus process One that that I'm familiar with in 2006 was from the National Heart Long and Blood Institute Which basically concluded that when genetic results are under consideration there should be standard criteria or guidelines Developed and followed and they proposed several And then a list of genetic tests that meet these criteria should be reviewed to identify the tests that are appropriate to consider this was revisited and reconfirmed in 2010 where the one of the prime recommendations was an independent national central advisory committee to review evidence for genetic risk factors and provide that to Institutions and IRBs considering reporting this so this is what the clinically relevant variants resource is designed to do This was an RFA that was issued last year and is about to be awarded So I can't say much more about it, but hopefully at our next meeting you'll hear from them directly But the purpose is to identify and disseminate consensus information on genetic variants relevant to clinical care identify the variants with likely implications for care and incorporate them and and their evidence into a resource for practice guidelines We recognize we're not in the position to to set practice guidelines, but we are in a position to generate the Information and some consensus recommendations that others can use to to generate those Establish a process for transferring this information to the appropriate clinical organizations and build upon existing programs to reduce duplicative efforts one of the things that really surprised me I think and others as well that our June 2011 meeting was that just about every Institution that was trying to do genomic medicine was doing this and they were all reviewing the same evidence You know having basically the same processes and often coming up with the same answers and we thought well That's silly why you know we could cover so many more if we sort of you know shared efforts and split up the work a bit And so that's what CRV is designed to do And this is just a comment on what we mean by actionable, but I won't go into that in detail I think at this point I'll kind of skip over the details of some of our other programs in the interests of time And just sort of ask are we ready? I'm a big Gary Larson fan and this is a mammoth here And these are mammoth pointed pointers look easy Zack it looks like your dog is on to something And I think there really is on mammoth in the in the grass here waiting for us And as as we've heard there are certainly commercial providers that are encouraging this the public is asking for it And and certainly the science is now pushing us in this direction. So so what will it take? We've heard of I think a number of topics that could be included in a strategy Either if we come up with one or those that have been developed by the cap in the UK and other groups And we're trying to address those including, you know, obviously discovering the associations Being done in a merge in our Caesar program and also a program I didn't have time to talk about in newborn sequencing Transportable phenotypes very very important and electronic health record integration also quite important Generations of evidence clinical implications of the variants what evidence is there related to that? Addressing consent and community concerns disseminating methods Reporting variants and using them in clinical care Educating clinicians and patients as was was raised, you know that you do want them to order one of these tests You don't want them to order the wrong one That would be the last thing that that you'd like to see happen appropriate decision support and policy development So I think I'll stop there and be happy to answer any questions Thanks, Terry So one of the things that's not on the list there turn the microphone on I'm sorry. Oh, yeah, it is. I'm sorry. Yeah I have a natural microphone, but yes, I am using this one as well One of the things that's not on the list there relates to economic Activities and I know that there was a an RFA issued from the Common Fund related to the economics of personalized medicine And I was wondering if NHGRI had been involved at all in terms of the project conception and and review Yeah, unfortunately, no that we're involved in many Common Fund programs. So those that are not familiar with the NIH Common Fund It's it's an effort from the office of the director to basically Do things across institutes that no single Institute could do by itself and that would benefit multiple multiple institutes So we we have a variety of those programs were not involved in this one And and it's one that we were kind of keeping an eye on but we're happy that others are taking the fore in that You sure it related to personalized medicine medicine or just health care in general. No, it was definitely for personalized medicine Okay, I'm just looking at it just talks about health economics more broadly I guess I'm not familiar with it having a crisp focus on Personalized medicine and I don't know the personalized medicine would was necessarily implied as being genomic But it but it was the the term personalized medicine was used in the RFA Terry is it's clear from some snippets of conversation. We've had today As well as what we're going to hear this afternoon that the military has a strong appetite and expertise and a lot of resources related to a Number of the genomic medicine activities that you're highlighting and I'm just wondering How how to engage? That important group in a number of things which I assume they cannot be active grantees on and So how does that work? Well, there are a variety of ways I I think I could say we probably haven't been as effective as we could be in doing that and and I'm really thrilled to see as many members of the military here as we have couple of years ago, we we had a delegation that came over from the Air Force that included Dr. Sessions and the the Surgeon General at the time of The Air Force and a number of their colleagues who were approaching us basically to ask, you know We'd like to get into genomics and in our medical care We think it's a way that we can really improve the health care approach and we were delighted to hear that And so we gave them the you know resources and information that were available to us But we also told them about the emerge project And we tell a lot of people about the emerge project and we figured well, you know That's we're not going to hear anymore, but to our delight Dr. Sessions and her colleagues have have come to emerge meetings have participated very actively and and actually stimulated us to develop a Policy for affiliate membership in emerge and they became our first affiliate member about a month ago We're thrilled to have them and they need to be up on the the list of emerge sites And I'll revise my slides to include them So so that's certainly one way to get involved, you know directly in some of our research programs I think including you in some of our advisory groups and and workshops and things is another way to be very actively involved and we would would welcome suggestions from you as to Ways that we can further your efforts and and we can we can work together We This is an amazing array of NHGRI initiatives and the question I have for you is and looking over some of these initiatives and Trying to partner on some of them. I'm wondering to what extent is NHGRI Interested in evaluating clinical utility not just clinical validity because the clinical validity and the associations and the emerge and the actionable variants are all driven by genotype phenotype sort of analysis, but the Some of the stumbling blocks and implementation By the payers and the health system has has been showing the added value of Using the genome versus not using it So I'm wondering which one of these initiatives delves into the utility of the genome Yeah, no, that's it. That's an important question and you know unfortunately for us a very big question So we're a teeny tiny Institute I think we're the fourth smallest of all of NIH but we like to think that think of ourselves as the mouse that roars So we when we develop technologies and approaches We try to disseminate them and bring them into into other institutes that have far bigger budgets and far bigger Constituencies to be able to test them and much of what they do is disease specific where what we do is not disease specific So so part of what we do is to try to leverage and and you know kind of bring those groups on on board where a lot of the Evidence generation frankly will be done a good example of this is the warfront study so there's a clinical trial the coag trial that was something that we brought to NHLBI and took several years to Kind of get off the ground, but it's off the ground now. Thank goodness We also are recognizing the need for evidence generation and are beginning this really in sort of pilot programs because that's about all that we can afford So the emerge program the the clinical demonstration projects that I showed you are small Some of them are a hundred patients 200 patients They're gonna teach us how to do this kind of research and also what sorts of outcomes a lot of them are process outcomes Rather than patient outcomes, but at least to learn about the process So that's a lot of what emerge is doing in addition the genomic medicine demonstration projects are pilots and they are focused You know primarily on showing evidence that this actually improves care So those are starts their little starts the newborn sequencing program I think we'll be doing some of that as well but we really need that the help and the participation of the larger institutes as well as some of the organized medical systems around the table and I would look at the at the VA and the Military medical systems that that might want to work with us and on perhaps developing some of these in their systems so Mouine has put his finger on the I think what is the the biggest challenge and Terry's answer is is there so we are intimately involved in emerge and and we're doing a big implementation project At Vanderbilt and have been doing it for several years and one of the key pieces is is outcomes the Tension is between process outcomes and health care outcomes and there is a community within the pharmacogenetics space That that feels that there's this I'll use the word and I'm probably using it the wrong The sense of genetic exceptionalism wise genetic information so different from anything else So if I prescribe to joxen In a patient and I don't check their serum creatinine I may give them toxicity because they may have renal dysfunction and if I Adjust the dose based on the serum creatinine I'm doing that because I understand something about the joxen kinetics and I understand something about the joxen pharmacology And I don't do it because there's a randomized clinical trial that says anything about how to adjust the dose and There is this sense that genetics are being held to some different standard than that. I mean we understand That there's lots of things that go into variability in response to clopidogrel, but one of them is a genetic Is it is genetic? variants The CPIC guidelines it's important to say what they are the CPIC guidelines Operate under the premise that you have the genetic information now. What do you do with it the? Premise that many health care systems operate under is do I want that genetic information at all? So once you've decided to get it and I think we're in an environment where some places have it and some places don't Then the question is how will you act on it and there are? individuals who are real Who who who say well, you know There is a little bit of data that you could use see to to sip 2d6 Genotype to select among antidepressants and there's never going to be a clinical trial Because there's because there are many reasons why there's never going to be a clinical trial But given what we know about the pharmacology and the disposition of these drugs This one is a better drug to choose than that one in this particular individual with this particular Genotype based on what we know so there's there's this sense of that you could do Implementation Even in the absence of of any hard data at all and then there's other people who say well the list of gene drug pairs that we've implemented in CPIC is Is pretty comprehensive right now pretty complete and anything beyond that would go beyond data So there's a tension within the pharmacogenetics community for sure, but I'd be interested in hearing from you from you You know what what what's the right way forward in this given these kinds of? Precedents that we have you know in clinical pharmaco in clinical pharmacology without worrying about clinical pharmacogenetics For a second that we understand what there is around variability in response to certain drugs We understand the factors and we implement them clinically every single day And most of what we do clinically when we practice medicine is not based on randomized clinical trials anyway So so how is it that we're gonna? Are we going to use genetic information or not? It's clear that this is a test that is here whether you want to use it or not So I'd be interested your response that rant I mean this this is I think This is the crux of the issue here and if we can develop the right partnerships around Deploying the genome in a way that's consistent with evidence as well as consistent with personalized medicine I mean we have to have our you know both our cake and eat it too. We can't we can't treat the genome Exceptionally, but we can't even give it a pass. I mean it shouldn't be a genetic exceptionalism or reverse genetic exceptionalism I mean every biomarker or or test we do usually falls under evidentiary Thresholds and you know for coverage and reimbursement and and so on and so forth So I think that the demonstration projects. I mean once you have the genome you can deploy it You know a bit at the time if you take a drug you check out You know whether or not you have a slow metabolizer or a fast metabolizer But the question is why should we have the genome in the first place? I think I'll address this a little bit in the afternoon Jim Evans had has made a bold proposal that we should all have our genome tested not because of the pharmacogenomic But to find the rare generic diseases that are not being captured And then once you have that genome you made a case to have it and everybody's medical record Then you can deploy it a little bit at the time But it's it's a I think a longitudinal discussion that will probably span over multiple years because that's You know, we're not going to have the genome and pay for it no matter how cheap it will become because There are downstream effects and cascading You know once you have the genome you're going to have the interpretation of the genome and then the More more tests and and so on and so forth So we have to confront this in one way or another I will I will say one more thing that is that the one thing we want to make sure of is that along the way We don't make therapeutic decisions based on genomic information that could turn out bad for the patient that would be Bad for the patient bad for us and bad for the field. So I don't think we've gotten there yet So so I can't think of a scenario under which we would use genetic information to guide therapy with with platelet inhibitor drugs for example that would would be harmful for the patient I can make something up But I don't think that's going to happen Don't thinking it doesn't mean make it so but don't think it's going to happen So I think that's an important part of this as well and that relates directly to the issue of you know sequencing your genome and and then finding rare rare diseases most of those rare variants are of uncertain significance anyway So just to build on what has been said first of all, I love the phrase. So thank you for that genetic exceptionalism Well, the reason I think it's important is I think that we are actually on the cusp of a cultural challenge here I mean, I think historically biomedical science has made huge investments with the firm belief conviction commitment that discovery could only be good We haven't shared with you that the occasional cynical health services researcher will occasionally make a little graph that compares the NIH budget Going up up up with the number of uninsured So that's actually the value question here. Well to be fair No, no, no, but the point is that We have never actually held biomedical discoveries to some sort of value question And I think right now with implementation of the ACA with the economic climate, which I know is high pressure stuff at NIH and across the federal government But I think particularly acute for NIH just because of things that have to be stopped or put on hold and so forth So I totally get all that I do think that is going to be a central Strategic question and the cultural issue it seems to me I was thrilled to hear you say that your military colleagues wanted to actually be part of the Working group or steering group. I think that's a good thing. In fact, I'd make a recommendation that a lot of these Similar types of projects you would actually seek out that kind of input because I think the other Approach we've always taken is that what we mean by dissemination and putting stuff into practice is this top-down model So to trickle down and I think we have enough evidence that this just doesn't work And so I think the feedback back from care delivery Projects is also very important. What does this variance mean in real life practice? What happens when people make therapeutic decisions based on genetic information that they think are terrific? And it just doesn't work out so well because if we're not actively putting that in place We're not going to know about it so so I think that's a great series of discussions and issues that Help frame the next series of presentations that we're going to have so I'd encourage everybody to think about this We hope to have a lot more discussion about this going forward because I think it's important It's highly relevant to the question of do we need a coordinated strategy across federal Agencies and so to that end we're going to hear a series of presentations from Federal agencies about their perspectives on this So I think these are themes that we're going to come back to over and over again during the course of this meeting So let's let's move on to the next presentation, which is Larry Myers from the Department of Veterans Affairs