 Yeah. Thank you, Eric. Okay, once a year, and it's usually at the February Council meeting, Terry Minolio gives a report on the activities of the Genomic Medicine Working Group. And take it away, Terry. Great. Actually, we have tended to do these at the September Council meeting, but last September Council was jam-packed, so we thought we would postpone a bit. So just to remind you, there are several working groups of this Council. One of them is on genomic medicine, and we established this one shortly after the strategic plan was released in February of 2011, basically to advise us and assist us in identifying the research needed to evaluate and implement this field, including reviewing current progress, identifying key advances, planning meetings, facilitating collaborations, and then looking at, as we identified needs, how do we then build the long-term infrastructure for those to fill those. This is the current makeup of the working group. You'll notice several past Council members as well as two current ones, Howard Jacob and Dan Rodin, and I'll call on you after I'm finished to correct any of the mistakes that I made in this. So you have to pay attention, Dan. Yeah, sorry. So one of the things that we do, one of our key activities, is to lead a series of genomic medicine meetings. We started this in June of 2011, and I won't go through all of them. Well, I go through all of them, but not in any detail. We subsequently published a paper on this one in genetics and medicine. The second one was on forming collaborations. This is the Duke-Meetree project, which subsequently went into a large-scale collaboration. The third one was on stakeholders. The fourth on physician education. Out of that grew the Inner Society Coordinating Committee that Eric mentioned earlier, and I'll talk about a little bit. We had a fifth one on federal strategies that actually is becoming quite useful now that we're looking at the Precision Medicine Initiative and the impetus from the White House. Our sixth one on sort of global efforts in implementing genomic medicine. I actually reported to you on back last February, so I'll only touch on this one. But that one occurred since our last report to you, as well as the seventh in October on genomic clinical decision support. And we have an eighth coming up in June where the working group said, you know, we've been at this four years now. Let's take a step back and kind of look at the entire portfolio and see, you know, where we are and where we'd like to go. So the sixth meeting, as I mentioned, I described to you about a year ago, looking to engage international agencies, explore activities, identify how we might be able to collaborate. One of the neat things about this was that it included parts of the world that we haven't typically had involved in many of these discussions, and so we were very happy to have them there. And just a couple of kind of nifty projects that we heard about there. One in Singapore, which is doing testing for stromal corneal dystrophies, which are opacities that occur in the cornea that are heavily determined by just a few genes, one of them being TGF-beta-induced protein or TGF-bi. One of the actionable aspects of this is that people who have this condition or who are prone to it should not undergo LASIK therapy, a keratoplasty, because it can recur or actually accelerate in the operated eye. So this is worth knowing, and they are implementing screening of family members because these variants tend to be common in Singapore. There's also an Estonian program that actually was just approved back in December, the next phase of that I had previously reported to you on the plans for developing an Estonian array, but now they have a pilot project for actual implementation using their exceedingly well-connected electronic medical record system. Actually, they have kind of an electronic health system throughout the country, which is fabulous. So that one is moving forward as well. And we also talked a little bit about Stevens-Johnson syndrome and some screening efforts and prevention efforts going on in Thailand. This is a particular problem there because of the high frequency of the risk alleles that have been identified to date in that part of the world, as well as a high frequency of the use of several of the drugs that lead to this. So it's an important topic there. And what they described to us was what they call a pharmacogenomics card, which is really just like a credit card that they give patients who have been screened that includes their name, the outcome of the assay, the date, the interpretation, and the interpretation for this patient is that they have a high risk of developing Stevens-Johnson, which is an exfoliating skin condition. It's an absolutely horrible thing. It's like having a third degree burn across your entire skin surface and actually internally, as well, and a very high mortality rate. And then on the back of this card, as you can see, there are suggestions and contact information and that for practitioners. One of the interesting things about this is while this has been very effective in dealing with an individual patient and clinician, patients go to many different clinicians. And so there actually is a recurrence risk in Thailand and other countries of people who, amazingly enough, have had Stevens-Johnson and still are re-prescribed the causative agents and develop it again. There are also cases where people have been appropriately screened and their doctor is notified, but some other doctor is not notified and that doctor prescribes the drug and there have been deaths from that. And so one of the things that we're discussing is, is there a way to implement some kind of an electronic system where, if you were to be prescribed one of these drugs anywhere in the country, there would be a quick lookup in a database that says, no, no, no, this person should never get this. And obviously, there are a lot of policy issues that have to be addressed in that, but wouldn't that be a nice thing to have? Recognizing that this idea of a pharmacogenetics card in particular sort of resonated with a lot of the attendees at our meeting, we kind of asked, well, gee, is there some way that we could make this sort of a signature project and get a number of countries, particularly those in Southeast Asia, but not only there, to try to implement this. And so we kind of came back, looked around at NIH and there are very, very few grants funded in this area. There are like two that we are aware of. And so in talking with various sister institutes, about 10 of them, we agreed that it would be worthwhile to have a workshop that basically looked at the state of research in this area and what NIH might or could do. So we have a meeting coming up early next month to review the current state of knowledge, examine the role of genomics and pharmacogenetics in etiology treatment and potentially eradication of the preventable causes of this, with most of which are genetic, and then identify gaps and unmet needs. This is the planning committee and you'll note there are several from our sister agency, the FDA, who also are obviously very interested in this area. And the group that came together for the global leaders meeting wanted to continue to develop other areas of collaboration. And so we kind of spun off from this something we've called the Global Genomic Medicine Collaborative, G2MC, Global Genomic Medicine Collaborative, yes, that is in partnership with the Institute of Medicine. And that group is continuing on. You'll note some well-known faces here as well. And one of the things we recognize is that there are other global groups in genomics, particularly the Global Alliance for Genomics and Health, GA4GH. And they have several similar working groups and areas of emphasis, although they have been primarily focused on research and database generation where the Genomic Medicine Collaboration is focusing much more on implementation in clinical care. And so it made sense to us to really try to get these two groups working together. And we have shared people on working groups, so I'm on some of theirs. We have other NHGRI staff on the GA4GH. And similarly, Peter Goodhans is on one or two of ours as well. So we are working to make that happen. It never happens as easily as you'd like it to, but we're hoping that we can have that occur. And as I mentioned, the goals of this collaborative are really to serve as sort of a nexus or clearinghouse for genomic medicine implementation activities globally, develop opportunities for some demonstration projects like the PGX card that I mentioned, maybe capture and disseminate some best practices and develop a financial model for sustaining these efforts. There is a lot of interest among various governments that actually pursuing this kind of work. Eric mentioned earlier the Inter-Society Coordinating Committee that Wilden has now taken on. That grew out of our fourth Genomic Medicine meeting. Something that is, that we'll be continuing to shepherd kind of through the Genomic Medicine Working Group and through me. Sorry, this is just a screenshot of the Genomics and Genetics Competency Center, the G2C2 resource where we put a lot of the educational products developed. And our colleague, Gene Jenkins, has been leading this admirably for the past about two years. Eric mentioned the training residents in genomics or TRIG model that we learned about from a pathology colleague, Rich Haspel, at Beth Israel Deaconess. And they use what they call a structured approach to learning based on sound curriculum development ideas such as in this sort of landmark resource. They have done needs assessments for this. They're looking at strategies and objectives for teaching based on sort of knowledge-based, performance-based and effective, and I'll describe what those are, and then an evaluation and some dissemination research as well. So the needs assessment was actually done a little bit earlier before they got started in this project, and this is funded by NCI through a grant through NCI. And recognize that really the millennial learner is quite different from the way that I and many others learn in medical school. People in this generation don't go to class, we didn't go to class much, but apparently they don't go at all. And they really, they prefer to sit and listen to lectures at home on their iPads or whatever, and then come in essentially to have discussions. And so this has been referred to as a flip classroom where you send out the lectures, have people watch them, and then they come in for a discussion section that's more performance-based. So one of the things that's really neat about this curriculum is that there are a series of exercises where basically they're given genetic information on, in this example, breast cancer, BRCA1 variants in a given patient. And okay, here's, you know, here are the variants that this person has, how do you interpret these? And then they're asked to link to various databases to learn how to do that, how to interpret them. That's kind of the first lesson. The second lesson is a gene panel, something like MammaPrint or Oncotype DX. The third is a whole exome. The fourth is a whole genome. And each time they're asked to query appropriate databases and interpret them and give advice to a patient, these are done in teams. They've actually done this as a curriculum for residents as well as at meetings. They'll do like an eight-hour session with, you know, two hours on each of those. Very effective and very well received by those who've been involved. One of the neat things about this is that the entire curriculum, all the teaching materials and everything really is available on the American Society for Clinical Pathology website. And if one goes to their website, you can download their materials and use them, sort of customize them as it were. And Rich has published a nice paper on this in the American Journal of Clinical Pathology. When we heard about this, there were several other societies. Remember, the ISCC is actually a group of professional organizations. And the neurologists and the cardiologists and others sort of said, we could do that for our area. And we're putting together a group now to do just that and try to develop modules that could be used by larger numbers of people. The seventh meeting that I mentioned to you was held in October. It was on genomic clinical decision support. Clinical decision support being those little annoying reminders that pop up for clinicians that say, has your patient had their pneumovax or it seems as though they haven't had their colonoscopy. Is there a reason why or whatever. And clinical decision support is a challenge because you have to be careful not to do too much of it or people get tired and they start clicking through the alerts and ignoring them. It's called alert fatigue. You also have to balance off the desires of various institutional councils and others who basically want everything alerted so that they've told the doctors what it is that they need to do and if the doctors don't do it, that's kind of their problem. Obviously, you need to balance those off so that you're not overwhelming people with this kind of information. But for genomics, the clinical decision support probably is, A, essential because the genomic information is so vast. And B, really can be tailored in a way that this really is personalized medicine. And so there are very few people who carry variants that put them at risk for Stevenson syndrome. But boy, when you have one, you want to know it. And so you want to be sure that the CDS only fires when you need it. So it's not only that that person has the variant, but they're about to be prescribed one of these drugs. At any rate, we had a meeting to discuss this. What would be the ideal state? What are the gaps? How can we engage ongoing health IT initiatives such as the Office of the National Coordinator and then to define a prioritized research agenda, recognizing that there's a group at the Institute of Medicine that is also working very actively on genomic clinical decision support as well as in the Office of the National Coordinator. And these were some potential collaborative projects that were identified, developing some use cases, sort of putting together a sandbox where people can kind of go and play with these use cases and various tools and see how they can make them better. A knowledge library, hopefully some kind of an end-to-end project that begins with the evidence and then moves forward to implementation. And a considerable emphasis on the role of the patient as well as the caregiver, somewhat as was described for the ClinGen project and that Genome Connect website that involves patients. The eighth program, as I mentioned, is going to be in June and this is to review our portfolio, again, look at gaps and opportunities for collaboration. Obviously the Precision Medicine Initiative will be probably a little bit better formulated by June and certainly will be the topic of several of those discussions as well. We'd like to engage other NIHICs and other funders in areas that they might be working that we could leverage some of their efforts and look at research needs for NHGRI and other agencies to pursue and maybe also look at ways to capture and disseminate best practices. And then to address questions that have come up in this council, how do we measure really or sets the impact of these programs? So what are good metrics? What are things that are convincing? And what are things that are measurable? Because they can be quite difficult to measure. We're anticipating probably doing a ninth meeting. We do these about once every six to nine months or so. And Howard, Jacob and I have spoken briefly about the potential for some kind of a meeting focusing on how one, how clinical laboratories decide what variants should be reported as kind of secondary findings. It's not kind of the ethics of doing that, but just what criteria do you have and what kind of quality criteria do you need as well as evidence and other things? So stay tuned. We'll be working on developing that. So with that, I'd like to thank everyone who's involved in putting together these programs, particularly our GMWG. And with that, I'll turn to, let's see, Dr. Rodin, would you like to start? You wouldn't like to start? I think the programs that you've put in place are the kinds of things that the Precision Medicine Initiative is gonna require. And so one of the questions that I have when I think about what the Genomic Medicine Working Group has done is sort of how are those efforts gonna be leveraged to sort of expand the scope by an order of magnitude or two? We're all running unlimited bandwidth, but it looks like we're gonna actually have to run on even more limited bandwidth. And that's a good thing. I mean, if the efforts of this institute have been to not only sequence the genomes, the genome and the genomes, but to actually figure out what that means for human health, then these meetings have been an important starting point, and they really are just a starting point. I don't have anything more to add to that. Great. Just before, was it directly to this point? Oh, please, go ahead. To that pertain to the question I was gonna ask is, I sense, and maybe it's in the catbird seat that I rest in, is this field's about to explode and at all fronts. And my question really as a community, are we ready for it? And we've been working on that interface between practice and research, rightly so, and again, complimenting you that you've done a great job in facilitating those discussions. But again, what can we do as a community to get us ready for this explosion that I sense is here? Sure, now it's an excellent question and a huge problem. I think one of the things we need to do is to learn from our programs, what are the big barriers? What are the real stomach blocks? Just to take as a simple example in a merge, I think we recognized when we first started looking at some of the arrhythmia genes. Gee, these genes, if you have variants in these, they're supposed to be really bad things, they can cause certain death and that sort of thing. And then you start to look and see, well, gee, we had 40 people, really none of them, only one had a prolonged QT, none of them really had any evidence of family history of sudden cardiac arrest or whatever. So we started asking the question, well, gee, what really is the penetrance of these things? How often do you see these variants in unselected populations and what do they mean in terms of health? And that's where the sort of phase three of a merge, as Dan said, a merge kind of changes every time, as do many of our programs every time they were new. So the whole purpose of that program is to look at 25,000 people with all these variants and see if they have any phenotypic evidence at all. That's just one example. In the Ignite program, for example, we are recognizing that you can't, the things that you can do at a duker, University of Texas or wherever, you can't necessarily do out in a VA hospital or out in, you know, Podunk U or whatever. And so trying to figure out what works and what doesn't in smaller settings is another area. But I think one of the things we really need to do very actively is figure out, you know, what are the lessons, what are the barriers that we've run up against and then use our programs to address those and then hope that that will be taken up by others. I got my degree at Podunk U. It also seems that the president's national, U.S. national research cohort is an opportunity here. Really we can push that interface between research and practice even further from 25,000 to more than a million. That's a real opportunity for us. Totally agree. Howard, Jacob, do you want to come in? Yeah, so I think, Eric, to your point, one of the issues that we were talking about at the Undiagnosed Disease Steering Committee a couple weeks ago at Stanford, we had a face-to-face meeting is that, well, I think there's more and more consensus towards what information do you put together for calling a variant being causal? If it's in the literature, it becomes quite easy, but what types of functional information do you need to add if you don't have another patient? How do you deal with that? And then the whole secondary issue is becoming a major deal and that the different labs that are doing this are all making these calls and how do we come up with strategies around making it? So I think the technology of sequencing is getting really, really good, obviously, but the interpretation and how do we leverage data across sites I think is really important. So that was the discussion we were having is it sounds really easy, but how do we actually put some firm boundaries around what is a secondary, reportable thing for a clinical purpose versus what are we used to doing in research? I think these lines are, they seem concrete, but as you really get in and start looking at it, they're really quite blurry and so I think these, looking at these areas are incredibly important. Carol. So regarding secondary findings, so the American College of Medical Genetics and Genomics did publish a list? I mean, is that a good starting point for this discussion? Absolutely, and the SCN5A gene that we mentioned, a couple of councils ago, is on that list and it's one of the most devastating because it's associated with some cardiac death. So that's a good place to start, but even there you have penetrance and other issues. Howard, did you wanna? Yeah, and there's not wide agreement on that. There's a tremendous variability around how people are using those guidelines and where to go forward on that. So there's a lot to be done around that. So I think it's a great discussion point, but it's a long way away from how people are gonna practice medicine with it and how we're gonna use it. Carlos, could we let Jim comment on that? Yeah. I was just gonna say that the NHGRI is of course sponsoring the ClinGen program and one of the whole points of it is to figure out actionability, how to aggregate adjudications of variants, et cetera. So there is a large, large effort that's going on with that. I was going to mention like my ClinGen colleague that this is one of the things that ClinGen's taking on. The thing that really worries me is as we move forward and NIH is paying for less and less of genome sequencing, the incentives to share data have to be made really explicit, right? As I say to people, did you read that paper on a million MRIs that was in nature last week? No, you didn't, because they didn't write it because people don't share MRI data. But that's what we risk being the de facto state, right? There's nothing about genomic data that makes it more shareable than other kinds of data except that the NIH has used its carrots and sticks to say, if you wanna get a grant, you gotta share your genetic data and that's why the field has had this sort of culture of sharing. And so when we think about the Global Alliance projects and beacons and all the security concerns, we really need to think very hard about the incentive structure to really allow the data to be shared or else it's gonna be a big problem, right? And I think Bob, last time you mentioned that the ACMG had put in their sort of code of ethics that if you run a lab, sorry, the what? ABMG, okay. That if you run a lab, you're sort of obligated to share data. And I think ClinGen's doing some of that at the variant level. We wanna start doing that at the individual level, but it really is, I think, gonna be one of the biggest bottlenecks to our being able to aggregate this kind of data. Now, that's an excellent point if I could just follow up and then I'll call on Bob and you may remember and Eric slides on the Precision Medicine Initiative, one of the things he said was going to be very different about this is the involvement of participants. And one of the things we're really anticipating is we will have participants who want their data out there and we will have them actively engaged and then we can deal with a lot of the consent issues. So just to this point, Lusso. Yeah, because sometimes it's not only the participants wanting the institutions that hold the rest of the data need to participate in some form. So I think that's important. The other minor thing I just had a protest about clinical decision support and not it's just not the annoying pop-ups that show up. There's more to it, but that's the manifestation of a sometimes bad implemented one. Good point. So Bob and then Artie. So I just wanted to make two comments. One is about the educational issues. So I think there are different levels on which this can happen. I put together something similar to this for our UCSF medical school curriculum that we just had it last week where I had a bunch of students go through variants and go through databases and figure out what's going on and it was a very good flip classroom situation. And a couple of pathologists that I know actually took my stuff and used it for their teaching. And I'm thinking this, what these guys have done is an order of magnitude better than what I did. This ASCP thing. So I'm assuming that AMP as well as the association of professors of medical and human genetics know about this curricula and that we can sort of start getting it infiltrating into both student and resident education. So both AMP and the APHMG and many other CAP and others are members of this inter-society coordinating committee. How the messages get from their representatives to their leadership, but we just try to keep repeating it as much as we can. Well, I'll work on AMP. That would be great. I'm sort of getting involved with them. The other issue about the sharing of data, I think these volunteer efforts and I'm a member of the ClinGen consortium and also the Global Alliance. I think they're all really terrific but fundamentally I think that CMS and the FDA are gonna have to make sharing data a requirement to provide clinical services. Period. I think it's gotta be a regulation. Thanks, and you'll have the opportunity to share some of those thoughts soon. Yes, Artie. So I feel an obligation to plug an Institute of Medicine report that came out a few weeks ago on sharing of clinical trial data. I was on the committee that wrote that report and one funny comment, one serious comment. The funny comment is that everyone else on the committee was a clinical trial list of some sort. And I said, oh, well, the genomicists have been doing this for years now. Why can't you guys just do it? And they were like, oh, the genomicists are very different. You know. And so I thought. And but more seriously, the report does have a range of different policy options that everyone who is interested in the question of sharing, particularly clinical trial data should consider. I will agree with Bob that it's without some sort of regulatory hammer though, such as what EMA is doing in the European Medicines Agency. I suspect it'll be much more of a challenge than we would hope it would to be. Additionally, I do think that the report itself does not call for FDA regulation. I think that it would have to be something that Congress would have to become interested in. But I think that that is something that should be on Congress's agenda at some point. Great points. Okay, I think that'll do it. Let's take it here. Probably not. Okay. Now this came out of Eric's presentation, came out of a request from council to get a report or an update on the Alzheimer's disease sequencing project. And is this our NIA contingent over here? This is Marilyn Miller, is a program director at NIA and has been taking the lead on the Alzheimer's program. And Dr. Schellenberg is from the University of Pennsylvania and Dr. Mayhew. Mayhew, sorry. Oh, so is Dr. Mayhew not with us? Okay. He didn't die. He's still with us. Anyway, they're available for the discussion part of this. So Eric, take us away.