 So thank you, Adam. I'm reporting for the genetic architecture of health and disease working group. Can you put the slides up please and The co-chairs for the group where Mike Bamshad and Adam Felsenfeld And if you want to know the membership go into the blue folder the members of the group are Listed there want to thank them for their input so the group the group focused a lot on Goals and less on tactics by design and Here's an outline of what I'll present is is really stepping back the most important thing is what are we doing? What is the overall goal of the effort? Second, why are we doing it? Because this is a strategic planning For NHGRI we looked at some short and medium term steps that we can take to achieve that goal We did evolve a little bit into tactics And I'll make some comments on a few tactics that we thought were important to achieve the goal and then finally as we were reminded And we all know NHGRI has a long tradition of creating community resources And I'll say something about both clinical and basic sciences community resources that will be generated First what is the overarching goal and it's it's a series of steps Really to define the relationship of germline somatic and epigenetic variation to human health and disease related traits as a Means to elucidate pathophysiology. That is what we see as the overarching goal We'll develop and deploy assays that faithfully report disease relevant function of mutations and genes to guide variant interpretation and therapeutic discovery Third, we'll create and make widely available the knowledge base needed to interpret genome sequence variation in the life sciences drug discovery prediction and clinical diagnosis and Finally fourth do so across the range of human diseases and conditions including health by the way health and disease and A range of populations to expand discovery define the genetic architecture and broaden access and we'll do so In a matter of social justice. We want to make this as an access to care We want to make this a diverse have diverse representation oops Why are we doing this? I think it's obvious, but it's important particularly as we often get too far down in the weeds Why are we doing this is really to fundamentally understand the biology of health and disease? To promote drug discovery to improve the diagnosis of disease and enable and improve prediction As for intermediate goals, we would identify variants underlying exemplar conditions that represent the spectrum of health and disease related Phenotypes and HDRI is not going to be able to do all diseases so we thought it was important that we'd form partnerships with other ICs and The private sector and identify exemplar conditions that will serve to expand the effort The the phenotypes would span a spectrum of Mendelian and complex diseases and We assumed from the beginning that Mendelian diseases of course would be one of them Which would form an important except exemplar it would be pediatric and adult diseases also it would span psychiatric metabolic Developmental and infectious disease. We're not excluding infectious disease. We're also not excluding cancer in this initiative We'd look at the molecular and clinical intermediate phenotypes and also importantly modifier genes As we're doing this it's an opportunity Again because we're looking at exemplars and forming a new paradigm really for disease research We can look at differences in study design We can ask ourselves. What's the role of other omics in disease gene discovery? Importantly and we mentioned this I believe yesterday several times the both the scientific aspects and the LC aspects of Recontacting individuals bringing them in and and doing even deeper phenotyping as a way of expanding the research program It's also an opportunity to weigh differences in exomes and genomes It's very popular to today to say that costs are coming down So of course we're going to do genomes We need to remember the costs are coming down for exomes and there's always that ratio that we need to take into account We need to move beyond the rhetoric of bridging Mendelian disease and complex disease and actually design the study from the beginning both in size and in scope So that the Mendelian disease and the complex disease research and form one another and move away from the two The siloed approach and think of the full spectrum of genetic models There was also a lot of enthusiasm in the reality that clinical and personal sequencing is going to increase It was kind of fun in the group To look at people some people we all agreed it was going to increase There were some in the room that thought probably it would double and there were some in the room that we thought it Would go up by thousands of fold literally thousands of fold and so but the bottom line is it's going to increase And so that there's a need for the research that we're all doing to drive discovery First and that will create the tools to increase diagnostic rates and improve translation And then on the flip side There's a need to create an infrastructure so that the clinical data can be used to drive novel discovery So if we do this right as a community both as a research community and a Clinical slash translational community the two can feed off of one another the research will help improve Diagnoses and by creating larger and larger databases of patients that are appropriately consented by the way that will improve the chances for discovery As we slide into tactics there was sort of an elephant a tactical elephant in the room I actually don't know how to spell biggie by the way I don't know if that's how you do it or not. We need to create a database Really that should be maybe a knowledge base Infrastructure that promotes a federated model of data and information sharing including sequencing sequence Existing phenotypic data and ongoing and live clinical data and The NIH broadly an NHGRI in particular should consider convening a meeting to define multiple models of such an alliance or such a commons And so at the moment I think it's dangerous early on to think of one particular model This is a great opportunity to look at Multiple models and think about how this could be best be done The other tactics is of course we need to select our example our phenotypes. I Already mentioned the NHGRI should look for opportunities for partnering with other ICs and the private Community as that loops back at how we'd select we'd selfish we'd be a bit selfish or Eric would be a bit selfish And and maybe select some of the phenotypes depending on the partnerships that could be form The sample sizes need to be large and this is a maybe of putting on changing hats and the sort of geeky statistical hat We often write sentences that the the power is adequate and In this particular case the power needs to be more than adequate of the power needs to be high and And I'll with that comp that sentence I'll jump down to the last bullet that we don't want to compromise at this stage with these exemplar phenotypes That it's best to maybe do fewer phenotypes or do less in a very comprehensive way For NHGRI then it is to do more phenotypes and have more partnerships to make our constituents may be happy But more compromises would need to be made on the way I've already mentioned this, but we'll need to have this as a multi ethnic Initiative not for political correctness reasons, but for sound scientific reasons, but because it's multi ethnic will be able to capture a Fuller spectrum of genetic information and in that way we can drive discoveries in one group That would have been frankly impossible in another group Looping back then to the concept of creating resources Which I think is in a very important as we think about the large-scale programs and developing resources for the scientific community I divided this into two components one the translational slash clinical community If we can if we do the previous job and achieve the previous goal It will define the context in which the genome scale sequencing improve patient outcomes Second it will prove the understanding of the translational utility and validity of genomic variants by multiple approaches It'll also again if we do it right and this is probably I don't know if NHGRI has done a lot of this or not We need to bring cost cost effectiveness and comparative effectiveness research into our realm and look at the comparative Effectiveness of genome sequencing including the indirect costs of downstream outcomes both positive and negative Finally, we'll develop and apply in this in a diverse populations to ensure maximal application and also access to care The group had a particular fondness for creating resources for the basic science community It's important, you know the pendulum is swinging in NHGRI and probably NIH wide to being more translational and it's obvious And I think it's it's the right time to do that But we can't forget that by doing this translational resource research will create resources for the basic sciences And then this particular context will define the molecular cellular and organismal function of genome sequences So as to inform basic biology as the as as to the interpretation of sequence variation And then below that if we accomplish this upper goal in this community resource It will just open many many doors for the basic sciences tools for modulating and measuring sequences at scale Large-scale functional characteristics of variants and development of computational models that accurately predict molecular Consequences of that variation. We can understand better the mechanisms underscore mechanisms of cis and trans gene regulation And also the functions of non-coding genomic sequences, which really is our next frontier So with that I'll thank again the committee and open up for questions and criticisms nice wave Questions So everybody had their coffee. I think it'd be great if you could start piloting some of the other ohms now I think other ohm except up why wait five years. I think we're already seeing the value in many other Situations, I think what will happen is you'll go back and wish you had done it five years earlier if you wait five years from now I don't think we're saying for this plan. We would wait five years until we would initiate the plan This is a five-year plan. So starting pilots now. I would more than agree with you Yeah, Eric Yeah, I wanted to make a couple just make a comment about the discussion about a commons This is this and the need for sort of the shared data resources. This is being discussed a lot I don't think Phil Bourne is here today, but clearly a big emphasis now in his role at NIH more broadly And I think you refer to that more broadly is to there's a creation of these data commons across multiple different disciplines Hearing what you said I think your point was which is probably fair is that an HR I should show a major leadership role in What it needs for the genomics initiatives it wants to pursue and whether that's done on our own or done cooperatively Etc. Etc. That's to be those those are details to be determined but one thing that hasn't been mentioned I want to put David elsewhere on the spot, but I don't actually mind doing that is That some of those sorts of ideas Have come up around this new global alliance which has that discussion about well But hasn't come up at all at least in the plenary part of this And I didn't know if David wanted to I'm sure lots people are very interested in lots of things associated with global lines But since this was the first time that was sort of mentioned at the platform I just wonder if you want to say some things and so it was a big part of our discussion we We purposefully did not put or label it bug global lines because we wanted to have multiple models Yesterday in our discussion the global alliance was was mentioned in your breakout group Maybe for everybody else who's here who it wasn't part of that breakout group, and I know we're very interested I don't know David you just want to say a few things a part of what we need guidance from NHGRI needs guidance for is really What's so hard for us is trying to figure out what are what are different groups doing and where do we need to be? Participants and where do we need to be funders and where do we need to be activists and so on so forth Let me make a point and I'll turn it over to David for make a couple comments about global alliance I think what the group is saying though for the at least for these exemplar phenotypes in this particular domain And I don't mean this as a criticism of anyone. We need to move beyond discussions. We need to move beyond you know Basically, you know more and more meetings. We there's for a few of these exemplars I think we need to put models into place and start bringing these data together at least for these exemplar phenotypes And I think this is a place where NHGRI could form a major leadership role David, do you want to say a few words generally and the global alliance? No, well, I think it's not the right time or place to Distract with the global as there's a we can circulate There's a website a lot of people in this room have been at meetings of it and and all that So I don't want to do that The only I'd say is I think that I just highlight the point that that Eric just said which is I do think There's a question of is what we need another meeting and you know to discuss what we might do I agree strongly with the idea We shouldn't pick a winner and that we should try different models But I think there've actually been many many meetings and as you said it's time to get on with it I think the global alliance is and many people in this room are actually getting on with it It's not just the talking There's actually APIs and there's data sharing projects and all these things But I strongly always endorse innovation diversity and friendly competition among different models And I think that the idea that NHGRI shouldn't pick a winner But should encourage that is certainly certainly right But Maynard also made the point which I do agree with which is we've been talking about this for a long time We should not say oh, we're definitely making progress because we may not be making as much as we need and Urgency around that a sense of commitment is very important I think that the only point I'll make is there probably won't be one winner There may be different models that work best under different conditions Debbie Nickerson than Jim then you and then Richard You know there are many different approaches and ways that we can fulfill some of the goals Some of them are much harder to achieve than others from the perspective of the Mendelian project Putting out complete exomes with phenotypes has been extremely difficult on the other hand putting out variant allele frequencies Would be of enormous value to the broad community both for discovery purposes how often has this allele been seen and for clinical purposes when we talk about variants of unknown significance so Knowing what the frequency of an allele is in the general population and whether it's been seen in the homozygous state would be enormously valuable This is not as complicated as many of the other things that we're talking about and in terms of priority This is low-hanging fruit that NHGRI with all of the exomes that have been produced Could really play a leadership role in just getting variant frequencies out in public be an enormous contribution. I Just have to note so Rick that I have to note even though I know I'm jumping in that we've done some of this and and one of the some of the DAX have Disallowed it in the last two weeks so actually before we get to meetings and grand proclamations Just NIH getting its sort of housed together on what's allowed and what's not because literally the work is done And it's been pulled back. I Was going to agree with David's point, but I do think that we've talked about this talked about this talked about this We need to have and try different models and NHGRI should lead the way We continually I could go back. I could redact four years I could go back another four years right to it was always a Message that we needed to learn how to integrate and share in different ways And I think we need to test some of those models. It's more important now than ever And I think say, you know, I Would worry less about other ICs I would worry less about different groups, but I do think there's a there's a big interest and everyone is interested in this and and I agree with David the NIH needs to determine what is valuable and and what is really shareable and I Think sometimes they're cautioned it Too much caution on the parts of the ICs prevent sharing in in novel ways Jim I Think we all agree these ideas are very important But we have to move on and the fact of the matter is with copying them a variation This has been done for 10 years by decipher in 100 countries The legalities have been worked out the consentings have been worked out. Why not see how that model worked Agree Ewing, I think you were next then Richard. Yeah, so this This obviously has quite a lot of history and then one thing I would encourage it Which I said also in the breakout meeting is that I do feel in this science We don't put enough into the implementation teams. We don't put enough I know this is self-serving for me myself, but and for the ebi, but we don't put enough depth into the engineering teams behind this There are a few places that do if you go out to other sciences that do this scale of data high-energy physics astronomy Oceanography they are much happier about 10 20 men engineering teams that back these implementations than we are in this area I just got it gotta get our we've got to get our head around the right size for these For these sorts of data-sharing aspects into the right place and not try and do it with two or three postdocs I was gonna say I think that comments particularly important when doing it at scale Richard Then over here then so I'm moving to a new point. Is that a place? I think it's probably time. Yes So my question is about whether you discuss the issue of the relationship between a lily discovery and function and Broadly, I know we're going to bring this up later. I want to preempt it Broadly speaking you can find a genetic signal to locate an allele and then go figure out what its function is or else you can measure the function of all possible alleles and Correlate that with all possible genetic signals and I wondered if you discover discuss that point and how much you're going to drive Discovery just by genetic signals given the state of the art so others should correct me No, we didn't discuss that specifically the way this group is structured and modeled we would do Disease discovery first and function second and maybe as a complementary approach I don't know what you're going to talk about later The other group is probably doing function first and discovery second And it's going to be interesting to contrast those two approaches You know it could be for example that it's going to be very difficult to make Disease discovery without having knowledge of function outside of genic regions You know that the signal-to-noise ratio may not be there, so Yes, go ahead So I think it's also time to think about different paradigms to Not only get consent, but perhaps operate on data that you would not necessarily need consent if you leave the data where they are import the computation which we can do and Take advantage of that data without necessarily hoarding it in one place Which is what some patients are very concerned with so we're doing that for VA data even I think with genetic VA data the approach could be similar right and we're not Again, that's why it's important to have other models We're not limiting ourselves to bringing all the data into some centralized database or information base We're going beyond that Sharon than Maynard just quick to follow up on Richard's comment I mean discovery is always going to lead function No one cared about the function of triplet repeats until we discovered that triplet repeat size affected disease No one cared about gene dosage Effects until people showed the duplications cause disease So I think we have to push new ways of discovery So we find new mechanisms of genomic alterations that cause disease and Then we can do comprehensive functional analysis of that type Mm-hmm. I personally agree with that, but my guess is there are others who? Reverse the order Maynard so just on on this issue of Alternate models for handling the data. I think I was the one who kind of push the discussion most strongly in that direction It's a kind of a cause of mine I've been heavily involved in this discussion for longer than I like to recollect and Actually, don't share the view that we're making progress Certainly not making progress relative to the baseline the rapidly shifting baseline about how information is being kind of handled more broadly and in the world But in any event if I were to make one comment about why we actually might need more meetings is that I I think that the Problem with the dynamic of this discussion Has really been a push toward premature consensus One meeting after another Tries to define kind of what what an optimum path forward would be When I think we're clearly headed toward multiple paths and we need to start to think it's not a long list There are only three or four reasonable possibilities, but I believe that there exists no document That defines these tries to flesh them out and look at what their strengths and weaknesses the really predictable strengths and weaknesses will be and That that's what I was kind of pushing for and I think the NHRI has a lot of leverage in this area This is something that cuts across all disease areas, which makes it a good NHGRI project You know for people interested in this I Would recommend a article in the New Yorker Just the last couple of issues on it a diagnostic odyssey case of a fairly typical sort And I would simply argue that that article Shows what failure looks like This there's been institutional failure and I think a kind of community failure We simply didn't meet the entirely predictable needs of the physicians the family and so forth Involved in this case and the case that's described there is just the the leading edge of what's going to be a really a vast amount of activity and I don't see the plan on the table or the set of plans that Are going to assure That we do better going forward. So that's where I was coming from understood, but I think I Still would like to quote David those. I think we need to get on with it I think there there are there are models that are in place in particular domains and some of those are Ready to be launched. Otherwise. I'm afraid we're gonna have this endless cycle of discussion and theoretical debate So just this one quick comment on that is that I I don't actually sure we will get on with things and we must But I don't agree with it as a policy position Because that's one model one model is business as usual projected forward in some chaotic way and I can write a scenario. I think most of us could write a scenario is where that's going to lead us And I don't think that's where we want to go Other comments were probably winding down Adam Mike Things that with the committee talked about that this discussion is missed in terms of emphasis Do you have a comment? No? All right. Thank you