 So next up, Aaron Ramos on clinically relevant variants resource. Good afternoon, everyone. I also wanted to extend a welcome to my colleagues from AMP, Association for Molecular Pathologists, for joining us today. And we may also have colleagues from the College of American Pathologists listening via webcast. So if you're there, thank you for joining us. This presentation will have a very similar flow to Anastasia's. In February of 2012, we also brought a concept to Council. The focus was on to develop a resource of potentially actionable genetic variants for use in the clinic. This concept, although I think there was support in general from Council, like Anastasia said, there were significant concerns that were raised that we took back with us and considered to bring back to you here during this Council session. So the original proposal focused on supporting identification and dissemination of consensus information on potentially actionable genetic variants in clinical care. It had three main goals, identifying these genetic variants with implications for clinical care and disseminating the evidence, developing clinical decision support systems for incorporating these variants into clinical care, and then building upon and unifying existing programs with the hopes of reducing duplicative efforts across research and clinical organizations. So to put this into context, we had actually been thinking about such an initiative over the past couple years. Eric has heard from numerous colleagues as he goes to present at various meetings that NHGRI really should take some leadership in integrating all this information on the variants that are being identified. And we've also heard at a variety of population genomics meetings such a need. So based on that, we organized this workshop in December of 2011, titled Characterizing and Displaying Genetic Variants for Clinical Action. And then we took some of those ideas and incorporated them into the concept clearance that we brought to you in February. Again, the concept was deferred. One of the main concerns that we heard from you in February was that this is an important effort and it touches on more than just NHGRI. There's many professional societies that have a stake here that they have relationships and represent important communities that would be using this information in the clinic and that was very important for us to reach out to them to learn what they're doing and see if we could partner in moving such an effort forward. So shortly after council, we did initiate some of these conversations. We've had great interactions with ACMG, AMP, ASHG, and as I said, college American pathologists. Again, we formed a council subgroup to further discuss some of the concerns that were raised in February. Based on that discussion, we revised our concept document and circulated that to our council subgroup. We've had additional conversations with genome staff, with our colleagues and other organizations and around the NIH and slightly revised the concept a bit more and circulated that final concept to the entire council in May. So what we heard from you in February, NHGRI must clearly be viewed as a leader, not just funding another group to produce a gene list. So if we really wanted this initiative to grow legs and be adopted by the community, it had to be seen and understood by the community that we were really the driving force behind this. There was concerns about the number of awards, whether a significant single award or multiple awards would be the appropriate way to go. There was a concern raised for the potential for a single awardee to produce a less optimal product. There was a concern raised that the focus should be on generating that first list of genes and not focusing so much on the variance because we know that that list will continue to grow. The consensus process must include a clear handoff to professional societies for guideline development so that NHGRI can certainly play a role in pulling all this information together, synthesizing what we've learned and then working with the grantee to provide the information in a package that the clinical societies could use to develop guidelines which then could be used by the clinical community. And of course, it'd be best if other ICs collaborate or at least clearly support the program. So we heard the need for this to really be a trans-NIH effort if possible. So again, I wanted to thank the members of our subgroup that participated on our call and subsequent email conversation and also for our colleagues from the professional societies that participated in that call. It was a great discussion. We were able to really expand the discussion around the concerns that were raised and then make revisions to our concept based on these discussions. So to address the first concern raised in February, we did specify involvement of ACMG and AMP as co-leads on this initiative. Actually in the title we included NHGRI along with these organizations and then also specified throughout the document that it was extremely important to collaborate with relevant professional societies and other organizations that are stakeholders in this effort. We emphasize again the need for a collaborative effort. We did discuss the possibility of having multiple awardees, but it was decided that that may not be a workable approach. So although we're sticking with a single awardee, we've emphasized that NHGRI will provide significant leadership through this cooperative agreement. We also clearly articulated that there will be a governance structure that includes NHGRI and then the other professional societies that would be included on the various committees that are formed and of course other stakeholders that we all feel are relevant. We've clarified that the applicant would be expected to describe their rationale for focusing on genes or variants, so whichever approach they choose, we just want a clear description of why they are focusing on that path. We also drew a bright line between synthesizing the evidence and developing consensus findings which we felt is within our purview and then producing those clinical guidelines which would be outside our purviews. We just tried to clarify the language that we use there so everyone understands our role and that we would try to hand off this information in a package that could be used by professional societies to develop these guidelines. And along those lines we eliminated the aim that focused on development of clinical decision support. We heard although the need for clinical decision support tools is certainly an important one, that with this effort we wouldn't want to develop clinical decision support tools on our resource because our resource would have the information on potentially relevant genetic variants that wouldn't have had that sort of stamp of approval from the professional guidelines. We just wanted to make it clear what this information will be used for and that clinical decision support tools can be developed down the road that this program is one step in that path. So after we circulated that revised draft to our council subgroup, we've had again follow-up conversations and made some relatively minor revisions. We did however remove the organization names from the title. We heard from NIH, also the director, that non-federal groups can't be listed as participating organizations on any funding opportunities. And again the reason that we just included these societies in the title was to indicate to the community that we're serious about working with other societies and making this a collaborative effort. I think in the end by removing the institutions from the title, it probably benefits all of us because it allows us to be more inclusive and make sure that we hear from you and others who the relevant societies are and include them in the process. So again, we've had some great conversations with College of American Pathologists and also follow-up conversations with ASHG. We've been able to incorporate those groups as well in the revision. So we've changed our name again. For those of you, even prior to the workshop, we had been referring to this resource as ClinBase and then we learned that that name was trademarked. So then we thought about ClinAction. That sounds reasonably good because we're thinking about actionable variants. Although we've heard from some of you that action implies actually taking an action and that we didn't want to confuse the community by thinking that all the variants in this resource meant that you needed to take action. So that one's out. For a while we were calling this the resource formerly known as ClinAction. And you could superimpose my face there on Edvard Munch's The Scream, which recently sold for $120 million. So we decided to be boring and just refer to this as a clinically relevant variance resource and hopefully if this moves forward work with the awardee and the steering committee to come up with a more appropriate name. And we're just going to leave it at that. So I've summarized some of the changes that we made and just to articulate what this looks like in our revised Purpose and Goals. So this was our original Purpose and Goals statement. We've modified the Purpose to read to support a process for identification and dissemination of consensus information on genetic variants relevant to clinical care. So we removed that emphasis on potentially actionable. The first goal, identify genetic variants with implications for clinical care and disseminate the evidence. This was a little bit broad and the disseminating the evidence part needed to be described a bit more. So identify genetic variants with likely implications for clinical care. And incorporate these variants and evidence into a resource that can serve as a substrate for development and practice guidelines. I mentioned we eliminated that second aim of focusing on development of clinical decision support tools and that was changed to focus on establishing this process for transferring the information to appropriate organizations for development of these guidelines. So again, hopefully the grantee and the steering committee can work with the societies to make sure we collect the right information, we package it in a way that can be useful for the societies to review and make further decisions on which variants they'd like to recommend us moving forward for clinical use. And the third aim hasn't changed. This is an important one. Build upon existing programs, unify these efforts, reduce duplicative efforts across research and clinical organizations. And just to drill this home, the text has changed. We emphasize that this needs to be a multi-institutional approach, again to bring in similar efforts and diverse perspectives. We've highlighted again the close involvement with other professional societies and a jointly appointed steering committee. We will work with our professional society colleagues to facilitate consultation with other important stakeholders, including regulatory agencies, payers, clinicians, et cetera. The applicants are expected to survey the landscape of ethical, legal, social, and policy issues regarding results reporting and try to integrate these and build these into this proposed effort. Applicants are expected to describe their plans, and the text highlighted in orange is new, for engagement and integration with ongoing efforts, data synthesis, curation, development of consensus findings, handoff to clinical organizations, again, as I've mentioned, for development of these practice guidelines and dissemination. Approaches for grouping or binning genes or variants into categories of clinical relevance and plans for dealing with perfusion of variants of unknown significance or for focusing on particular variants or genes, at least as an initial manageable approach. There hasn't been any change to the anticipated funding, so this is what you saw presented in February. The only other comment that I would make is that we have reached out to numerous other IC colleagues to find out if they're doing similar efforts, because we heard from you we didn't want to be duplicating any other efforts across the NIH. And besides the work we are already aware of at NIDMS with the farm GKB, there hasn't been anything else presented to us. In fact, a couple of our colleagues at other institutes said that they really support NHGRI taking a leadership position in such an initiative. So I'll just end there and thank our council subgroup and other colleagues for helping move this forward. And I guess actually, Eric, if we could ask any of our colleagues from the professional societies that have been working with us, if you wanted to add any comments before we open it up to council? Mary? Switch on that microphone. If you turn on, we'll make it live. Thanks. It's Mary Williams from the Association for Molecular Pathology. Thanks so much for the proposal. I can tell you that our members are mostly in translational research and clinical practice. Genomics is moving so fast into clinical practice that it's now being described as the Wild West out there. And that doesn't make our members feel very good because that gives sort of the picture that decisions, clinical decisions are being made around a poker table in a saloon or that surgery is happening on the bar. And so there's guidelines that need to be written to help guide our colleagues in clinical practice. And these guidelines are very expensive to produce and they're for evidence-based guidelines, not just consensus guidelines. And they need to be coming out not just once every three years. They need to be coming out with multiple guidelines per year. So we want to thank the NHGRI for proposing this. Thanks, Mary. Job Hoffman from ASHG. I would just like to thank and congratulate the staff of NHGRI for engaging the community in different ways, I think, than at least I've not seen this in the last decade in the process of a concept clearance. ASHG is pleased to be named in this. I think that we have members who can contribute a great deal to this. And our leadership did react pretty strongly to the original concept clearance, and that's for two reasons. First, because this is so important to all of us. And secondly, because we think it is so broad in this process of development and engagement and then eventually dissemination that we wanted to make sure it's done right. Devil's in the detail, of course. But I think that doing this together, we can get it right. Thank you. Thanks, Joe. College of Medical Genetics. This has been the rate-limiting step in getting genetics and genomics into clinical practice. It has been the existence of guidelines that get it out of the hands of the rare disease experts. And I think Mary hit on one of the clear problems, and I think it's one you're going to have to think about. Guidelines themselves are very expensive, and a lot of the expenses in building the evidence base. But the evidence base can be built in a way that makes it a much shorter trip to the guideline. And I think there's a lot of steps along the way. If you look at Blue Cross Blue Shield, one gene test assessment is $100,000 to do the evidence base and then the guideline that comes off of that. But depending on where you draw your line between informing the guideline and allowing the professional groups, it can be much less expensive. And I think I'd give a fair bit of attention to that. We're extremely interested in this moving forward. But it's not just a laboratory thing, and this is going to be a very strong clinical and multispecialty multidisciplinary, because genetics is multidisciplinary and multi-organ, and many of our conditions spread across multiple systems. So I think it's going to be a very interesting involvement of the medical specialty world in a way that's been very different for the NIH. Thanks, Mike. And I think that's a great point that we want to try to bring those professional societies together at an early stage so we can hear from them what information we need to work with the grantee to collect, how we can package it, present it, and make it the most efficient pipeline as possible to get the information from the beginning packaged in a way that can be used to develop these guidelines. Any other questions or comments? Okay, open it up for council discussion now. Tony. I'd just like to reiterate that final point that although NHGRI wants to take the leadership on providing the database and the evidence behind those variants being clinically relevant, we need to have a plan for how the professional societies are going to develop the guidelines because it can't be done by volunteers. It's going to require funding, and I think that point about it's where you draw the line about what you're funding to gather evidence on what's clinically relevant will lessen the burden to the professional groups to actually develop the guidelines. So I think in a way you'll be taking part of the lead on that side of it as well. It depends on where you draw that line. Mike? I guess I'd characterize the leadership just slightly differently. To me the issue was not so much that NHGRI be the leader although that's fine, but that it be clear that this is the place, that this isn't again just one of many gene lists. I did wonder as we were going through this whether this is a place where other institutes could be engaged in terms of helping to support this because again just like the last one we talked about this is one that multiple institutes surely are interested in. I don't know if that's possible or not. We've actually in my conversations with other institutes trying to get a sense of if there are duplicative efforts I've circulated our plans and have heard back from, of course preliminarily at least one or two institutes that are interested in co-funding. So that's something certainly we're interested in. We recognize this could be a shared effort. I think that'd be really helpful. I infer that the aim is to make this a comprehensive list, a complete list, but the path to how you get there is it going to be prioritized in any way? Yes, so I think in the language of the concept we would ask the grantee to prioritize how they would sort of bin the variants that are compiled into those that are more ready for clinical action. There might be an intermediate bin where there's more information that we need and what is that information and then other bin of clearly these variants aren't ready for incorporation into the clinic and there's other ways to benefit but certainly that's something that we want the grantee to come up with a proposal for prioritization and they would work with the steering committee to figure out the best way to prioritize the variants that we have. What Mike just mentioned I think is really important and it might be that something along these lines could be included in the RFA and what I'm getting at is in addition to it being highly desirable for other institutes to help sponsor an effort like this, I think that the right applicants will also perhaps bring in non-geneticists and I'm thinking for example of a specific situation when we were recently going through lists of things many of us had assumed that long QT associated genes known deleterious mutations in these would be would be in what we call bin one. These are highly actionable. It looks like as you learn more about these things that there are certain long QT associated genes where we know enough to say that's true but others where we don't and it took a cardiologist to tell us that. So that's a long winded way of saying that it might be useful in the RFA to encourage the participation of having expertise in the conditions and not completely just the genetics of those things. I agree with you completely. In fact we thought one and this of course would be up to the grantee but one way to organize sort of sifting through these piles of variants is to organize into sort of domain specialties of disease expertise. So we could bring in experts from cardiology or cancer related expertise, diabetes and then that would not only have the genetics expertise but those very familiar with the conditions to be able to make real decisions. One other question Jim I think I asked you this question four months ago and that is how many genes and variants are there in bin one? Depends on what day you catch me at and if you haven't talked to me yet let's just say that I think most of us feel very comfortable that it would be fewer than a hundred and many of us would say far fewer than a hundred again depending on how you set the evidence point. As a follow-up to that then is this a five-year project? I would think it is for two reasons. One is that those lists are going to change as we find out more. The other thing that I think clinicians need really that bin one is what do I need to tell people and what is life threatening in the short term that I can do something about. That is the although difficult easiest question. There are many other questions about how to characterize these results that vary on all kinds of parameters including the impact on people learning this kind of information. I think that there is plenty to be done here. I would say the first year particularly we need to work with the steering committee to get the framework in place to test it out on these first sets of variants and then we want to take that framework and apply it to other variants along the way so it could take a couple years to work through that and then we could also towards the end come back and revisit some of the variants that now may have more information and decisions on. We'll do Mike and then Carlos. I would only encourage you to... Wait. I'm not sure it's on. Maybe it was on. All right. Only to encourage you to sort of recognize how important informatics is going to be in this. Positions don't follow practice guidelines. You know it's rarely over 50% in reality when you really go out and survey them. Clinical decision support tools integrated into electronic medical records is where this is going to get disseminated so that it's well vetted and it gives people guidance in the clinical scenario they're sitting in and so the EMR efforts that are ongoing through NCBI and other... or NLM to develop those standards and things are going to get attached to this pretty closely I think to be successful. That's a good point. So first I want to say I think this is a really important thing to do and I really support the idea that NHGRI's going to take this on as a kind of flagship thing to put their imprimatur on or our imprimatur on is... The thing that concerns me a little bit is distinguishing it from other existing efforts from OMEM to HMGD to all the other databases that folks have tried to put together on what are important variants that you need to flag and know about and secondly how it will overlap with and I think it should go hand in hand in dealing in centers and the work that they're doing and so I imagine we're talking about both having a really great database of known and really critically important and bona fide highly penetrant alleles is one thing and another is things that you need to screen and know about because it would be really hazard is not to return that information to participants once you know and so figuring that fine line is really the whole challenge that this faces and in some sense it's not an informatics problem I mean the informaticians can build you the databases and they can curate them and they can do it really carefully so that it's not polluted and so on but where you draw that line is a totally different issue and so I think you really want to think hard about what it is you're going to ask of this resource particularly if you're not going to want to fund this into perpetuity but rather create it in such a way so that it's a really good systematic way of building that resource so that you can continue to build it and make it available that's a great point and part of the reason we're trying to engage the societies and other stakeholders early through the steering committee and other committees is to hear from them exactly what data points are easily synchronizing the information that we have yeah so I think those are great points yeah and I think to your point one of the things that this has over OMIM and several other resources is exactly that process to engage the stakeholders there's a little bit of experience with this in pharmacogenetics research network with the CPIC guidelines and I think that sort of provides a little bit of a model for how to go forward was there any thought given in terms of reach through I appreciate the way you kind of drew the semi-permeable line there between creating the evidence etc and then handing it off for the guidelines what if the guidelines are bad what if there's no takers nobody you know we've already spent our money on creating a guideline for the last eight you gave us can't handle another eight what becomes responsibility of identifying these if there's no receptor node well I think at that point we'd have to revisit our role our best to put the information in a way that can be used again working with the societies we do here it's expensive but if we can take on some of that by curating the information and moving it forward but you know we certainly want to evaluate this resource along the way and make sure that the information that we're presenting is being used hopefully it will be and I expect it will be but I mean it's a fair point and we can come back here and revisit how we want to move forward in helping facilitate getting these guidelines to come out of the resource that we put together but that'll have to be collaborative again with the societies and other folks we must have learned a lot from the copy number variant guidelines and sort of establishment of that David Ledbetter's talk at the at the ARILE meeting since then is this the same kind of problem trying to figure out I mean I know it's different types of data that you're dealing with here but is that what the issue is is that what you're trying to learn by doing this RFA or is it and you know what I'm talking about Eric the ISCA consortium the international standards for cytogenomics arrays actually I'm going to go the ISCA is having their their international meeting today and tomorrow so I'm going to go to that meeting but I mean that is one example of an approach for pulling this information together so they have a database that can be used for the cytogenomics community I'm not exactly clear on the approach they took to coming up with the data that's included in that database but we certainly one we can learn from their approach and two any information that we can integrate from the evidence they already have into our resource I was thinking about the buy-in that Pearl just mentioned that somebody I think at least a lot of people accepted that I don't know what that process was and who was involved and whether it was the groups that are talking about this one as well but yeah I mean we certainly can learn more from David and ISCA along the way that's a good point okay seeing no more discussion I'm looking for a motion on this concept clearance approve a motion second yep okay any other discussion before we vote okay all in favor opposed abstain okay it approves thank you air