 Okay. So we will move on to the next part of our open session. I'm delighted to introduce my good friend and colleague and good friend and colleague of many of you and the genomics community, Hunt Willard. Hunt is extremely well-known to the genomics and genomics community. He has had a long and distinguished career as a geneticist, has earned lots of honors, member of the National Academy of Sciences, member of the National Academy of Medicine. He's a member of AAAS, he's also a designated Howard Hughes Medical Institute professor. For those who aren't familiar with his journey, I had a review, I pretty much knew it by heart. Faculty positions first started at University of Toronto and then moving to faculty at Stanford University. He then became chair of genetics at Case Western University before being recruited to Duke University where he was the, created a new institute in genomics and a whole federated set of things going on at Duke, the major impact of, of activities in genetics and genomics. And then following his stint at Duke, he for a short period of time was the president director of the Marine Biological Laboratory associated with the University of Chicago. But now he's serving a position as director of the Geisinger National Precision Health. And we're familiar with Geisinger at NHGRI and certainly a council because they have some, they have grants from NHGRI and, and, but I, I really thought it would be interesting to have council and people listening into the open session hear about the, what I think is an important part of the genomic medicine ecosystem as one example, and there certainly are others, but Geisinger for a number of years has been building up an interest in implementing genomic medicine within their health system and, and they're building things around it. And it's one of the things that, that brought David Ledbetter, another good friend and colleague to Geisinger and now most recently Hunt, to also, to, to Geisinger to sort of build up around it. And so it's great that we have him here today to give us a broad perspective of what's going on in genomics, population health and precision health at Geisinger. So Hunt, we'll turn it over to you. Thank you, Eric, for the invitation and side benefit to hear your update this morning on, on everything that's going on so impressively. So what I'd like to do, this is this morning, is give you an overview of a variety of different programs all under this umbrella of genomics and population health and precision health at Geisinger, both at what we affectionately call the mother ship up in Danville, Pennsylvania. And then more recently at the unit that I started a year ago here in the Washington, D.C. area just down the road in North Bethesda. And I'll touch on that towards, towards the end. So I thought, I thought I would start with that's still going or did I? OK. All right. Years are gone. Start with what several of us are now using as a vision statement to give you a sense of what we're doing and, and what drives us to do it. And it is not by accident that the, you know, the first words on the title for this talk are clinical imperative in part because, and the main part, because that's really what drives all the decision making and what we do not only at Geisinger itself as a health system, but certainly the unit here in, in the Washington area as well. So it's our belief that universal genomic sequencing will become a routine part of public health in medicine. I think that's probably shared by many of you in this room and those watching online. And, but to do that, we're going to have to demonstrate increasing clinical utility and personal value of genomic information, both for individuals and the populations and communities in which they live. And it's our sense that Geisinger is and has been an ideal health care laboratory, if you will, for implementation of genomic precision health. And I think what has separated Geisinger apart from many other places and certainly what drew me to it, to them, is that it's our conviction that this is not just going to happen someday. It is not an aspirational goal for the future, but it can happen today. It will no doubt change over time and get deeper and richer and more valuable over time. But there is information that is ready to be shared today with our patients, with our families and with our communities. So I was frequently, I start with this slide, which I shamelessly stole from David Ledbetter. All the programs at Geisinger were started, at least in the recent past, by Glenn Steele, who was CEO for 14 or 15 years, until a few years ago. And when Glenn left his academic career at that time at the University of Chicago, but Harvard before that and moved to Danville, he called up David Ledbetter and said, you won't believe this place. This is as close to Iceland as you're going to find in the United States, referencing, of course, the efforts to decode and commenting on the population assets that reside and still reside in the central part of Pennsylvania. A stable population, three plus generation families are the norm. If you want to do a family study, you usually just go out somebody's front door and you look at the house on the left and you look at the house on the right and there's the family. And Geisinger was one of the first to adopt to become an integrated health system with both clinical and claims data connected to it. And an EHR adopted over 20 years ago, we're told, we're Epic's second customer. And most remarkably, remarkable to me, who's been at a number of different academic health systems around the country, and actually around two countries, as Erica described, this incredible close trusting relationship with the community that one finds there that is both in the community and is certainly among the provider force in the hospital itself. The hospital in Danville, for those of you who have not been there, is really has the feel of a community center. It is the happy place in town where people go. It is not where people go quivering because they don't want to see their doctor. They go there because that's where they see other members of the community. People are happy. They they they took me when I was looking for a doctor's office when I had only been there about a month. And one of them said, can I help you, sir? You look you look lost. And I said, well, I'm looking for Dr. So-and-so's office. And they said, no, no problem. I know just where that is. Be happy to take you up there. And I thought it was just a pleasant employee. It wasn't a pleasant employee at all. It was a pleasant member of the community who was there to visit some relatives. And of course, they had been there before and knew exactly what it was. And she chatted perfectly the whole way through about what a wonderful place it was. So it really is a fundamentally very different experience in health care and what drives much of what we all do there. I've got a couple of slides here, not to give you information that you don't already know because you all do, but because it gives you a sense of where we come from and a sense of what is driving us in these genomics and precision health programs. We all know there's this broad impact of genetic variants and mutations on essentially every aspect of medicine. And we are increasingly learning that Mendelian disorders and polygenic common disorders thought by guilty textbook authors always have these in different chapters as if they are fundamentally different and they're not fundamentally different. They are in fact part of a continuum, not a dichotomy. And what distinguishes them is not that they are so fundamentally different, but that the impact of individual genome variants, either one or dozens or hundreds, will differ characteristically between those two classes with a very large impact in the case of what we view as Mendelian disorders and individually, relatively smaller impacts in what we recognize as polygenic disorders. So to us, Mendelian conditions seem like the most straightforward place to start a program of broad clinical implementation. They're predictable for the most part and the increasing number of them are actionable depending on, of course, how you define actionable. And although that's by no means the full story of the genomic and genetic contribution to health and disease, it seems like a foundational place to start. This slide, of course, you also know. So the issue is not any longer to become aware of variation in genomes. I'm not sure we'll ever have the end of that list, but we certainly have that in front of us now. So the real question is simply, how do we find and interpret and use whichever ones of those variants we believe matter clinically for a given individual or a given community or population at large, both today and in the future. Well, if we know all of this, then why aren't we doing it already in a widespread manner? And I'm asked to answer that question all the time, so I preempted the question by putting it here. And I think there are a number of key issues that date back when you've been around as long as I have been, date back to the beginnings of medical genetics as an entity and the thinking of it as an entity. So the main reason, of course, is something very familiar to NHGRI and everyone else at the NIH. There's an average and very well-documented 20-year lag on average from a discovery in basic science to its implementation in the clinic. What has changed now is that we're increasingly impatient waiting for that. And you can count on one hand the exceptions to that 20-year rule. CRISPR-Cas is certainly one of those. PCR was another one of those. But there are not very many of them that are distinctly, dramatically shorter than that two-decade lag. I think the second reason is that we need to change and are changing thinking about the impact of genetics and medicine from what many of us learned in during our education that genetics and medicine was interesting, but it was for rare and very highly specialized cases, which took very rare and highly specialized providers to deal with it. And now we change that thinking to something which is far more essential and ubiquitous throughout medicine and healthcare. But it has taken a significant number of decades to move the needle in that direction. I think there all in some in this room, no doubt, will disagree with me on this one. I think there were historically ownership issues dating back to the late 1970s when I was a graduate school and first became aware of this when the College of Medical Genetics was branching out, splintering off from the American Society of Human Genetics. And the concern at that time in some people is this sense that if you think of the genome as another organ, which was actually something Victor McHugh used to talk about as a useful way for students and who couldn't quite grasp what a genome was to just think of it as if it were not the liver, not the kidney, it's the genome. The difficulty with that, of course, is that it led to in some corners a difficulty in figuring out sort of who does the genome. And in the world of medical specialties there was a concern that you would sort of, all right, you cardiologists can have the heart, new nephrologists can have your organs and we'll just take the genome. And that may have been fine in the late 1970s and early 1980s, but now the genome is everything and so suddenly you end up with a potential for competition among specialists rather than a sense of cooperation. Genetic exceptionalism has been with this field since the very beginning and we still talk about and hear about the unsolvable and no doubt scary ethical, social and public social policy dilemmas that confront us. And my comments, just so I'm not misunderstood are not to say that those are unimportant and that we don't in fact have an ongoing and increasing in need to follow all of those issues. But I don't find that to be terribly exceptional. It is also true in many other aspects of medicine if not all aspects of medicine and the notion of genetic exceptionalism which was very much alive and well when I was on the Secretary's Advisory Committee for Genetics and Society still exists in many corners. So we need to be aware of it but I think we do have to find ways to work with it and get to move past it. And then of course there's always an uncertain finish line especially when you're working in a field that is moving very, very quickly. So the argument always was well we don't know enough yet so just wait and we those of us who work in this field will let you know you being the public or you being patients will let you know when the time is right the time is not right today. We'll come back to that. So at Geisinger we decided we don't need to wait any longer that the time in fact was right today albeit for a relatively small number of conditions and I think the tide is in fact turning on that. So the journey at Geisinger if you will and dates back to the beginning of the MyCode Biobank in 2007, shortly after Glenn Steele decided to make what was the first of Geisinger's big bet in launching the Biobank at that time which then turned into a full bore genome sequencing effort in 2014 with the partnership with the Regeneron Pharmaceuticals to carry out research whole exome sequencing on a number of those, a number of our patients. And never in a number of other steps I'm not gonna take us through all of those I'll hit highlights as we go through. But as we look back now from 2019 and you say okay where has Geisinger been successful and why has Geisinger been successful and this is my personal list of this which I share with other health systems as I talk in various places around the country. The first is the success comes from the institutional commitments that Geisinger made and more importantly the people at Geisinger made. The patients come first, this is a clinical imperative. Commitments of time and effort that the whole system that Glenn Steele put in place was in fact to not worry so much about RVUs and keeping track that way but the patient was first whatever you needed to do to make sure that the patient was taken care of that is your time and effort and if that involves genetics and genomics and he would say and it should then that's where I want your time and effort to go. Financial commitments that necessarily come along with that and this sense of clinical urgency that said even in 2007 we're ready to do this I know other people are not ready to do it but we are and we're gonna do that here and of course Geisinger was is an integrated health system. It is easier to have leadership act that way but it does show the importance of whoever is sitting in the CEO's office and sharing those commitments with the people who work for him or her or with him or her. The sponsorship of the overall effort certainly the leadership as I just said but it goes throughout the entire system of 13 hospitals in the case of Geisinger and it's driven by clinical leaders. This was not of course CEO that always run the risk that they get too far ahead of the troops and then they don't last as CEO very long. He lasted a good long time 15 years and that's because the clinical leadership adopted his sense of commitment to the patients and in bringing genetics and genomics to that. The key lessons then and I'll touch more on these as we go forward. Engaging the community and consumers there was a good long effort the first year to engage the community. They were very trusting communities to are a trusting community. So perhaps that engagement was more straightforward than it might be in other places but nonetheless that was a critical first step and we continually go back to continue to keep engaging those individuals. We engaged the providers especially the primary care physicians because they were gonna be frontline providers for us. We aligned the clinical and this is David Ledbetter aligned the research and the clinical missions so that they were completely hand in glove. Essentially all of the research at Geisinger is directly if not pointing towards and engaging the ultimate clinical mission of the institution. Geisinger despite its size is remarkably nimble and evolves quickly when it's necessary to evolve rather than being sort of caught in a we've always done it this way mentality. And one of the other key lessons was to make it easy and not a burden. The minute we were introducing things and we were told this was going to be a burden we simply backed up reevaluated it remodeled this until it would be easy. And we have primary care physicians who are now our strongest champions who go around saying they made it easy and that made all the difference. Well it wasn't necessarily our first impulse but it became the first impulse because of the individuals we were working with. So the MyCode Projector it's official name the MyCode Community Health Initiative has had a very high consent rate throughout research consent rate throughout the different clinics maybe 65 to 85% consent rate depending on the clinic the clinics that are being tested and this is again through all 13 hospitals. Consenting done either in person with concentrators sitting in the clinic the clinic waiting room or it can now be done online through the MyGeisinger portal. The in person problems the in person consenting is actually running into some difficulties for a reason that a CEO would love but in this our case we have to deal with it. The waiting times in the waiting rooms are dropping so much at Geisinger that there isn't long enough time to sit them down and do the proper consenting and get them to sign on. And so we now reduce that to giving them materials including how they can log on to their MyGeisinger portal and complete their consenting there. Little over 225,000 patients consented so far 250,000 samples have been obtained blood samples from those individuals. 92,000 research whole exomes have been done to date with another 40 or 50,000 that are in the Regeneron sequencing queue and we are promised those in the next month or so and the overall goal is to have about 250,000 exomes which would be about 10% of little over 10% of the active patient population at Geisinger. Well, then I come back to this again, numbers that are very familiar to all of you in terms of how many genes cause Mendelian disease. This is population based screening for Mendelian disorders. What's the size of that universe that we're dealing with? Protein coding genes in this case. The OMIM tells us that there's at least 3,600 genes with phenotype causing mutations called the clinical genome. We prefer, at least I do, to use it the Mendelome as the term there. And the resource of ClinGen that Eric mentioned previously always increasing the number of genes that are clinically annotated and the number of variants that are thought of and determined to be with high value and high evidence, pathogenic or likely pathogenic. So this all distills then down to simply asking the question which if any of those 7,000 plus variants are found in any of our patients. So we have to date the MyCo team and the genomic screening and counseling programs specifically within that have reported clinically actionable results to almost 1,100 patients at this point out of the 6,500 who are actually eligible for clinical reporting of results. We had to change our consent process partway through when it became very clear that we wanted to be reporting clinical results. So about one and a half to 2% of the patient population for a set of 60 or 70 genes that we are currently reporting results from. And of course that number is as you all know and other places have talked about around the world that number will increase over time as either new genes and or new variants are added to that list. And as we better define medical action ability in art, right now it's a very conservative and strict set of metrics on what is the clinical action ability as defined. But there are measures of personal action ability and we have discussions with our patients all the time about why can't I have results on this or that or that. And I think that's an area that we probably all have to follow very carefully to see whether in fact that can even be menu driven that a patient him or herself will decide what is actionable in their world and whether they want to follow it or not. These are for those who are taking notes at home and want the exact numbers these exact numbers as of the first of this month. I think on the right of the slide are the points I want to make here. So we're reporting results on probably 25 to 30 different clinical conditions but three of those conditions breast and ovarian cancer, familial hypercholesterolemia and Lynch syndrome account for about 50% of the cases that we have clinically returned results to. That number can be looked at two ways. I've had people hear that number and say, well, great, we'll just do the tier one. Those are all the tier. That's why they're called tier one. We'll just report those. I look at this the other way around and say, no, that means there's 50% of patients who are getting results returned to them which would be missed if you only are testing tier one genes. And so in our case, that's 500 to 600 patients, the equivalent number as the tier one conditions. And thus far at Geisinger, again in multiple hospitals, these results have been and have engaged more than 300 different primary care physicians and specialists from at least 14 medical specialties, one of which of course is medical genetics but these are not all going to medical genetics. They're going to the appropriate medical specialties of which there are many and different ones for different patients. So why does this work at Geisinger? Well, as I said before, we were determined to make it easy, not burdensome. Geisinger committed to genomics early and engaged the community in the primary care physicians from the very beginning dating back to now 12 years ago. Geisinger committed to helping the doctors and being viewed as enabling partners for them, not competitors. So that there's a very fluid set of conversations between especially primary care physicians and the genetic team. And they have what I always describe as a metaphorical hotline on their desk which is calling a genetic counselor. And we actually have a genetic counselor who's on call all the time. It's actually rarely used but the primary care physicians, the fact that they know they can reach a genetic counselor if they're in mid question or answer with a patient and they just simply can't don't know it. They just literally pick up the phone and can get someone who can help them with that. And that has been a strong part of being seen as an enabling partner and not as a competitor. We're not trying to take anyone's patients away from them. And we committed as I said before to fitting into their existing care paths and workflows and we changed those, our workflow repeatedly in order to make sure that that metric is met. Well, however, everything I've just described to you is for the MyCode project which is fundamentally a research project. It started as a research project and it lacks the clinical urgency. And so last year it was our then CEO, David Feinberg who had an epiphany and simply said, well, if everything you tell us about MyCode is as good as you tell us it is then why the heck aren't we just doing this for all of our patients as part of clinical care? Why does it have to be a research project? And so he announced, with very little notice to us, he announced nationally that Geisinger was going to be offering clinical exome sequencing to all of our patients and his genetics and genomics team would take care of that. Well, easy for him to say, he then left Geisinger six months later to take the job as head of Google Health and where I'm sure he will have an equally dramatic impact as he has had at Geisinger. But that allows us, allowed us to launch in the middle of 2018, the clinical exome sequencing project or screening and fundamental routine care. So here we've been looking at the ACMG list of about 60 genes, verbal consent during the clinic visit and this is part of this theme, this was if it's routine care, then we all signed up for all kinds of things for routine tests that our primary care physician says, well, it's time for your colonoscopy. At least if you're old enough, they tell you it's time for your colonoscopy or it's time for your mammogram or maybe we need to get your cholesterol levels checked this time. At that time, we don't sign, at least I never have an informed consent for that particular step. That's an assent or verbal consent that is notified in the electronic health record during that clinic visit. We have come into this from the perspective of it being the perfect learning laboratory for process improvements. Nobody knew how to do this. We didn't know how to do it, we had ideas and so we're doing it slowly with an incremental introduction in different clinics with a freedom periodically to change certain processes and we think, you know, it might go better this way, it might go better that way with an engaged group of primary care physicians and patients who are helping us along the way and informing the way we're doing this. So the goal here is all interested patients. The good thing about David Feinberg and that's him on the left there, the good thing about what he, when he announced it, he didn't say when it would be offered to all patients. He simply said it would be and it is. So we've done about 150 who've had their clinical whole exome sequences done to date with the standard clinical two to three week turnaround time, six positives thus far in the genes that are listed there. Two of them happen to be in BRCA2 and so that's a hit rate if you will of about 3%, not too far off from what we were seeing in the much larger my code data. And all of these have now, those six, this information is feeding directly into their primary care and in many cases into family cascade testing where of course the risk is now 50% for first degree relatives rather than the relatively rare population average. The, I believe four of those six positives were for conditions or risks for conditions where both the risk was unknown to the patient and the doctor and so that is now new information that is available to them. So in setting this up, one of the keys for us has been a minimal time required by the provider to try to keep it the same as any other screening test that's being offered. The primary care physicians are informed of all the positive results with an automatic referral, which we had negotiated with the clinical team, an automatic referral to genetic counseling. So a counselor is also informed at the very same time. The patient is given the opportunity to speak with a genetic counselor even before they speak with their primary care physician. All of this with the overall goal and the reason we call it population health and the reason we call it precision health is because Geisinger wants to keep our patients healthy rather than treating them only when they get sick. There are workflows that I will not take you through in detail both for primary care clinical models where that's the point of entry and how this is offered and carried out. But there's also ones in specialty care clinical models where we have not done this yet but we'll be introducing this in some of our specialty clinics as well. Overlaying if you will, the population health screening against the care that they're already receiving in a specialty sense. Now a key step for us has been what we call, although it just occurred to me that maybe this has been copy written by the NIH just in time physician education. The argument being that not every doctor needs to be an expert in genetic disease and they don't need a textbook to sort of go through a whole catalog of it. They only need to become knowledgeable about the one genetic disease that Mrs. Jones might be at risk of and she's going to be coming in for her office visit tomorrow. So we provide this just in time physician education telling our primary care physicians what they need to know, when they need to know it, all in one page that gives them the cheat sheet if you will of the essential bits of information that they need to know and be willing to discuss with their patients. And we have a series of these and we keep rolling these out so they don't get a book of these, they only get the one that they need for the particular patient that they're going to be encountering that time. And this has been very successfully and enthusiastically received by our primary care physicians. We also have a significant effort in co-developing with clear genetics with introducing chatbots for scaling the consenting and genomic counseling parts of the enterprise. We're often asked, there's an old guys in there, you've got like boatloads of genetic counselors up there and we actually do have, we have something like 25 or 26 genetic counselors but the vast majority of them are not needed for this particular project. We only have about two or three full-time equivalents of genetic counselors to do not only all of them I code but also now the clinical exome project clinical reporting. So it doesn't take a huge number but it will over time take a huge number and scaling of genetic counseling is a critical issue. And we've been testing chatbots from clear genetics in both for, at both the front end and the back end if you will of the screening programs. So far with quite a bit of success. So four key lessons learned I think which I frame here in the broader context of being part of a learning healthcare system through the lens of Geisinger. We certainly learned that we didn't have to wait until we understand everything. To us that's an unachievable and unthinkable goal and it doesn't serve our patients well. The patients can be served with what we can offer them now. Knowing fully that we'll be offering them more over time if they want it and if their physicians think they should have it. At Geisinger research and clinical care shouldn't be separate. That's an endless and virtuous cycle in a learning healthcare system environment. Works very, very well at Geisinger but in part because that is a highly focused medical center where the research, the rationale for having research is precisely because it informs our clinical care. We have focused in part, this is David Ledbetter's major contribution since he arrived at Geisinger, was focusing that research enterprise and how it can best impact healthcare. What we have found through the process both with my code and with the clinical exome screening program. The first time a patient, the first time a doctor sees a patient who has received something and said directly has a benefit from the research. They suddenly go, ah, now I know why we do research at Geisinger. Prior to that, there's always a little level of skepticism among some providers on why money is going to support the research engine. But in programs like this that now have taken it directly into clinical care, that aha moment is very real for physicians and it's not unusual for other physicians to then approach David or someone else in the research team and sort of say, well, when am I going to get my patient? As if somehow that was up to us as opposed to in fact being up to them. But it shows the level of buy-in if you will from the provider network in part, I think because of that very close adjacency of the research enterprise and the clinical enterprise. And Geisinger was an early adopter as I said before and committed early to having an advanced electronic health record and clinical data warehouses that are available for research and inspection by providers and researchers at Geisinger. And from our perspective, the key lesson learned is to the extent possible make that data as open as possible to others so that they can both learn from that data and then eventually contribute to that dataset. So, 11 now 12 years, Geisinger's major points. We should focus on the endpoint where we can have impact. Our patients count on us and tell us that they are counting on us to do that. For us, we've decided that clinical sequencing should lead and this despite the fact that the vast majority of sequencing that we've done has in fact been research sequencing, not CLIA sequencing. We do CLIA confirmation as part of all of the my code results that are being reported back to our patients, but it started his research sequencing. So, but patients are waiting, which is a point that David Feinberg recognized to his credit. And so from our perspective, as we talk to other health systems around the country, we view it most successfully as let clinical sequencing lead and have research connect to that rather than having research sequencing lead and have to figure out how to then bootstrap that to do clinical. We are strong believers in doing the whole exome and some day the whole genome, not just panels. To be sure, panels are less expensive in the short run, but we think that that short run will, that expediency will be tomorrow's mistake. You end up paying as we learn more genes about more genes and more variants we're gonna end up resequencing and resequencing and resequencing different parts of the exome or the genome. So, Geisinger decided to bite the bullet, if you will, and do the whole exome to start. And we wanted to serve our patients today, while at the same time the research enterprising is preparing for tomorrow, something that we believe in firmly. Other more practical lessons, from our perspective, many of the current clinical guidelines are inadequate and it's now been well demonstrated in the literature that many of those guidelines will miss up to 50% of at risk individuals in a population. So the guidelines are fine for identifying some people who are at risk, but they're missing up to half of them. Whereas, a self-serve and comment that population health screening for disorders that where there are high enough incidents in the population, by definition, miss none of them. Well, it'll always miss some, at least until we do the full genome and fully understand the impact of each and every variant, but population health screening will find the 50% that are currently being missed. Overall population incidence of pathogenic variants, I think all of us, certainly me putting on my textbook author hat, the population incidence of pathogenic variants is much higher than predicted clinically and sometimes much, much higher. So there's a number of ways one can think about that. There are a number of obvious possible explanations and they're probably different explanations for different disorders and different genes and we're just gonna have to, as a group, collectively figure out what those causes are and how we can use that to better inform the risk predictions that we're now doing. Could be incomplete penetrance, could be variable expressivity, could be other polygenic influences, almost certainly that is true, that are modifying that risk either up or down and we can incorporate that over time. And the point that I'm constantly reminded of, even though we all should have known that population screening immediately informs cascade testing and that relatively rare finding then leads to all kinds of first degree and second degree relatives who themselves will be at a far increased risk relative to the general population. So for us, starting with the Mendelon, if you will, is a logical place to start. It is the low hanging fruit. There will be more genes and there'll certainly be variant reclassification over time and so we think of this as a living lab report, if you will. So that we don't have to go back and re-sequence later on, we only have to go back and re-query the data as we either have more genes we need to look at or more variants about which we know something. So it becomes a laboratory report that we can imagine no less than annually updating that laboratory report and so we're now trying to get our patients and our providers used to that concept that this is a not a static lab report, it's simply today's version of your exome report and at Geisinger we will come back and re-issue that report over time. I freely acknowledge what is probably already in many of your heads, which is that, well that'll work at Geisinger because no one ever leaves Danville, Pennsylvania and that to a certain extent is true. That was Glenn Steele's observation. It'll be far more challenging to do that. Not impossible, I think, but far more challenging to do that with the usual churn of patients who leave one area and move to another area and move to different doctors, to different health systems. On the research front, the big opportunity that everyone's talking about now is for polygenic complex disease and the polygenic scores and how those can be brought into the equation, move to the top of the slide over time and inform our ability to provide reliable and useful risk information. So I come back to this, phrased a little bit differently than I started with. To us at Geisinger, this is not just a matter of technology and science and nor is it of economic models even though we're obviously gonna have to have lots of economic models. I haven't said anything about how this is being paid for yet but I'm sure I'll get asked that question. This reflects our commitment at Geisinger to community partnerships and investing in the health of our community. And for that, we are their trusted healthcare partner throughout the Geisinger catchment area and I think increasingly beyond. So one last slide or two just on what we're doing here in the Washington DC area. When I agreed to come on board to Geisinger it was to develop a unit, a business unit that would be outward facing where we would learn from what's happening at Danville itself and the rest of the Geisinger health system but we would try to decide which of those lessons learned can be translated and transferred to other health systems and hospitals and provider groups around the country. Recognizing that if you've seen one health system you've seen one health system so we're never gonna be able to take everything and expect it to be transferable but no doubt at least for me there are some of those lessons that can be transferred. And so we're now working with like-minded health systems who share that kind of a vision and want to have it for their patients not just for our patients offering clinical genomic sequencing as part of routine clinical care and then combining and sharing data as part of that value proposition so that the more health systems that we're doing this generates a larger data set of both clinical and genomic data that can become used to accelerate research and improve healthcare beyond that. And ultimately in the broader sense going back to another of David Feinberg's statements that he would make repeatedly which is that it's not just about no matter what my people tell me it's not all about just genomics it's the genetic code and the zip code and what he used to call anticipatory medicine with earlier detection of disease but based on variability not just in the genes but in the environment and the lifestyle for each and every individual something which he took and Geisinger takes very seriously for patients throughout central Pennsylvania and in New Jersey at this point. So I will stop at that point and I'm happy to take any questions that the boss says I can entertain. I'm sure there'll be a question. Start here, try it. How are you gonna pay for all of this? So I teed that up by saying Glenn Steele made a place to big bed in 2007 and so David Feinberg was prepared to place the second big bed to get this started. Fully confident that over time we would, we and others would develop the value proposition to convince the payer community that it is worth investing in whole exomes but if we all wait for the evidence to accrue very, very slowly that was incompatible with the clinical imperative that we feel. So he simply said we know what's gonna happen. Geisinger has his own health plan that covers maybe 40% of our patients that we see at Geisinger. The head of the health plan would say I know how this is gonna end up. He said I know the data that this will in fact not only improve health but allow us to spend our dollars meaning the health plans dollars more efficiently and fairly. So yes, go ahead and do it now and in fact it's process improvement dollars that are from the health plan that are paying for some of the early stages of this. But we know we will have to transition and that is a race to the finish line. What's gonna come first, the evidence base which will convince them or more dollars from Geisinger or other health systems to do that. So you talked about how this new approach more unbiased approach is going to reduce the false negatives. But you didn't say anything about the false positives. If you're testing, if you're administrating say a hundred thousand tests to healthy people with no risk, a test that has 99% accuracy you'll have a thousand false positives every year. So what is, is that a consideration as well? So you're talking about technical false positives. So sequencing, I thought you were gonna head down the path of reduced penetrance which is just to me a part. So let me answer the question. I wish you would ask, no. On the reduced penetrance where to a certain extent this is part of clinical medicine it has been for genetics all along of trying to evaluate what the penetrance actually is. And I think we're just now gonna be much smarter about how we collectively can address that particular point. The technical false positives because it would be disingenuous of me to say there are none and there won't be any. I have two answers to that question. One would say, if in fact it turns out to be a false positive. So we have told someone that they're increased risk and therefore there is going to be increased surveillance or attentiveness in the part of their primary care physician and or in the family themselves. And cascade testing is negative. Let's just say they go that route that'll be an expense but it'll be negative by definition in everyone. The only cost of that if you will for that false positive would be the potential for increased anxiety if there is any in that particular family or case. I think I've been quite impressed by the fact that that's actually less frequent than many people were thought was the case for being told of a genetic risk but I recognize that's not a hundred percent. There's obviously a, there's also a real cost because there are some added costs to healthcare. So I don't have a good answer. We're not going to re-confirm all of these. We have been confirming some initially the very first ones that we're coming through with Sanger sequencing with a hundred percent confirmation. We have failed, we have yet to fail to confirm either the ones that came through our research pipeline and sequencing pipeline where we do confirm those. Those are at a hundred percent. That says a lot about Regeneron's quality. The other ones say a lot about our clinical vendor partners. So I hate to say zero but we're approaching zero. So that's not a great answer to your question but the alternative is that we are confirming everything and you're adding enormous expenses. Okay, so I have Jeff. Yeah, thank you for the presentation. I guess I'm interested in sort of long-term data collection here and I know you and I have seen lots of screening tests come and go over the years, met with lots of enthusiasm at the beginning and then fell by the wayside and oftentimes because, or not because you couldn't identify people or who are at risk. That's sort of the low hanging fruit. It's the question of when do the false positives outweigh the benefits of the true positives? And that's a complicated analysis but relatively few things have emerged over time to be evidence driven to that extent. But the other issue of course is not just identifying people at risk but what's their clinical outcome? Has this information impacted the morbidity and mortality of individuals in the geisinger system? Now I think it's obviously premature to answer that question but are you collecting the appropriate data long-term for somebody in 10 years or so to be able to sit down and look at that and say, yes, this is a cost effective way and we've had X impact on morbidity and mortality in our population. Are those the outcomes, evidence-based outcomes that you are committed to to decide whether this is in fact a good thing to be doing? Well, so it's not too early for us to address that although granted that's an anecdotal sense. So of the 1,100 patients who have received results back through the MyCode clinical reporting program, there are easily a dozen cases where the patient, him or herself, thinks it's life-saving. In some cases, everyone thinks it's life-saving. And either life-saving for themselves or for members of their family when they go in and they find a previously undetected small tumor and they only did that test because of receiving a screening result. So there are some clear cases where it is mattered and mattered hugely. And in a community like geisinger, that word gets out very, very quickly among people's neighbors. So there are some cases like that. The real answer to the question, yes, we are following all of those. We have six month follow up after a result has been reported. My sense is we probably wanna go out as far as five years because if we're not finding positive impact within a five-year period of time, the payer community especially is not gonna, I mean, we love them to be interested in the 10 and the 20-year lifetime impact. But with our current system, that's not gonna be true. Probably five years, it may even be too long a timeline. But I'm looking over your shoulder at Pat Diverka who will be tackling many of these kinds of issues, but that is exactly what we're doing. And in an integrated health system, we have all of those clinical data from claims data and ongoing outcomes data, can access that quickly and then follow these over time as the numbers increase and accrue. Yeah, I just thank you for the great presentation and I'm actually completely agree with much of what you said. I do think you have, there's one other thing where you have to be careful of numbers in your population, which is the six downstream relatives. So that has been looked at pretty heavily in the cancer community. It's actually been a huge disappointment that I think the average for some of the big companies is something like one and a half relatives per pro-band or maybe two at most. So I do think your families are much more connected than families in the United States overall. And that actually plays heavily into the economic argument because a lot of the economic argument is the downstream testing. So I do think it'll be interesting to model in your healthcare system versus the experience where this has been looked at for Lynch syndrome and BRCA one in two mutations pretty extensively in other systems, including now companies that are offering free relative testing to try to increase it. That's a great point and part by no means the only part. But one of the reasons we've launched Geisinger National Precision Health is so that we in fact will be working with other health systems who don't have the population benefits of Geisinger. And so we'll have our own comparison data from that route. It's a very good point. It is, there's no question that the population is different in many, many different respects and that's one of them. And thanks again. My question has to do with again the practical, the generalizability of the Geisinger experiment and also some practical points that I wanna learn from your experience. What are you telling the patients? They're so very willing. They're available. They're compliant. And this is being presented to them in part as, it's part of their routine. They're part of their general testing. What is your level of expectations number one? So on a practical basis, what do they expect? When they have a colonoscopy of a different set of expectations. When you have a cholesterol testing, you have a certain set of expectations. When they're having these genomic testing, what are their expectations, number one? Number two, if in fact there's gonna be generalizability, then insurance pairs need to become attuned to what is being done and what is expected. Are you beginning to have conversations with various pairs that if you have, what are some of their thoughts? Are they skeptical? Are they interested? Or is they're buying? Where do we stand right now? So in terms of patient expectations, they expect to get a report, just as you would for a colonoscopy. Most people have to get a negative result, thankfully. And they get that, it's either an entry in their personal portal into their EHR, or they get a note from their doctor. In this case, we actually, they get a copy of the report itself if they want. And failing that, they're getting at least a letter from our genomics group, which outlines exactly what genes were tested, so they have something to have and hold and put in their own file at home and share with others. Their expectation is they would find nothing, because that's how it's explained to them. It's a screening test, and so, and we only anticipate two or 3% of the population will find, with today's version of the test, will find a positive result. So they're anticipating a negative result and many of them get it. Only a few crazy people like me get disappointed when they get a negative result. The rest of them will be happy presumably and go about their business. In terms of the payers, so we've talked to some at two levels. One, what happens when someone comes in with one of these? Okay? So this is what has not gone well, for example, with direct-to-consumer, where they come in and the providers go, I have no idea what this is, and the payers go, we're not gonna pay for this, it was a research study, et cetera, et cetera. This is a clinical study, but they're still coming in with something like that. The ones we have talked to, relatively small number, have said, at that point in time, there is a verifiable high likelihood that they in fact are at risk. And so we would then pay for any confirmation testing or other ancillary testing that would be relevant to that because there has been a clinical test. It's no different from their perspective as if someone had moved across the country, they come in and they're bringing all their old health records with them because it is a clinical test. And so the payers have said at that point in time, it's no longer a screening assay. You're coming in saying you carry this in your genome. All right, that's enough to tip the odds for us. And so we would cover it. Yeah, I also wanna thank you for this talk. It's really interesting to hear what's happened at Geisinger. Now I wanna follow up a little more about the return of negative screening results because you're so concerned rightly to have as many true positives as possible that increases the likelihood of having false negatives. And I think that in the world that you've described so eloquently, the impact of having a negative result and the potential for a false negative result is often not well understood by patients. And so I was wondering, I suspect you have a plan to look over time to see what kind of screening behaviors or not people engage in. But if you, or to see what the impact of a false, not false, sorry, of a negative report has on, because I think generally speaking, there is a significant risk that people will say, well, I'm clear, no Lynch syndrome, no of the other really, really rare colon cancer related mutations. So maybe I won't go ahead and do that colonoscopy. I'm sure from the moment I asked about this, you already had an answer for me, so I'll stop. But I'm very curious about, you're monitoring what happens with the negative results. No, that's a terrific question. So the information we provide both to the patient and his or her physician, all of that is explained. It doesn't mean it's absorbed, but it's explained. So we're upfront about that, including the fact that we don't know, I mean, these are only exomes, there's other mutations that are out there. This is, it is a screening test, not a definitive diagnostic test. So that part of it is taken care of. But I think over time, we will have to, our physician group, I think understands the point you are making. And it'll have to wait over time in order to go back to them and say, are you detecting in the population of patients who have previously received, quote, a negative, that they are resisting the truly fun medical test like colonoscopies, because they think, come on, my odds have gone way down. What we have been reassuring the providers is, and even to the clinical leadership when we were sort of planning the program, is we could see a day in which, from a triage standpoint, we're increasing surveillance for the people who we now think are at higher risk because of this test. But we're not yet ready to reduce the surveillance of the ones who we declare to be negative for exactly the reason that you said. So we're telling them to keep it level. Someday, so this is where I will say it's not today, but it is someday. Someday maybe we will be able with the combination of polygenic scores and this kind of screening and everything else, you do triage, you take the high risk decile and the lowest risk decile and they in fact get, I used to tell my medical students, I mean, the fact that you're told when you're 50 years old to go get a colonoscopy is not because when you were 49 years old in 11 months, you had zero risk and suddenly you woke up the next day and you were at high risk. That was simply a population average and this is one way to get around the population average or to make good use of the data that we have so we don't have to follow the population average. But it's a terrific point that you raise and we're only gonna know the answer by following the patients over a series of years, especially for tests that they don't necessarily want like a colonoscopy. So aside from the just in time modules you mentioned, if you had to do any other special training for your physicians? For the consenting part, one of the routes we have thought of for consenting and have been exercising for consenting on this is to allow the physicians themselves to consent their patients just as they do and they say, you know, I think it's time for your colonoscopy, that's a informal but verbal consent process that the primary care physician him or herself would carry out. So but that's not really special training. That's just in fact many of the ones we've been talking to say, no, we want, it's my patient, I wanna be the one having this conversation with them. That may change over time as we bring in more primary care physicians and we started with the ones who are the real believers in our program and really like it and even at Geisinger, I'm sure there's some who either are less excited about it or frankly don't think it's a good use of their effort and then we'll have to have additional educational ones but the just in time documents are the one because they didn't want it to mess with their workflow. And so by definition, if we say, well, you're gonna need this whole CME module that you have to take before we will, it would never have worked and people have tried that kind of thing and guess what? It doesn't work, right? Because nobody will go do that. I was, my question was gonna relate to that is are you making any of those just in time documents more widely available? Well, so through our unit in what we talked to other health systems about, I mean, our notion is that we can provide end to end solutions across whatever part of a role out there would wanna do. And I would say that the existence of the just in time documents is the one that they are the most excited about. And so I think the answer will be yes, we will do that. But you will develop the model by which those would be available more broadly. Well, they'd be given to those individuals the part where we would then have to take on the burden, the necessity of updating them periodically which we would do in-house in probably a less formal way but if we're now gonna provide those to the outside world, we would have to do that in a formal way so people know they're looking at the 2019 version and not something that is now three years out of date. Is that what you wanna do long-term? You want that? I'm just trying to think, do you want that responsibility long-term or is there opportunities to have a different model of developing those? Well, I mean, there are business opportunities whether it's our business opportunity or someone else's business opportunity to make it their job to provide those. It runs antithetical to what the world most of us grew up in which is that the more you wanna learn, the more you have to read and it gets thicker and thicker and thicker and thicker here, it's sort of the cheat sheet model. But yeah, I think there are, it could be done by us, it could be done by someone else and it could be done in a for-profit or just downloaded off the web model. How are you handling variant reinterpretation over time? So going back to the exomes and churning them repeatedly, is that something you do the laboratory does, is it automated? How does that work? It's not automated, I think it's certainly on our to-do list for our unit here would be to develop a way so that as much of that could be automated as possible. In a screening modality, it probably wouldn't be quite as labor-intensive a process as in a diagnostic modality as you surely can understand better than I can. So we're committed to do it for ours but the numbers are small at this point. It's, you talk about something that's not scalable and I can't figure out how to get chat bots to do this either so it's going to have to be automated so that we know exactly if you say all right, we're testing these genes and that you automatically update the number of pathogenic or likely pathogenic ones and your something pops up on our screen that says there's significant number of changes now and in X percent of cases. So I think it can be automated. I don't think that's a huge burden. It just has to be done that way and that's certainly something that's on our plan. Okay, thank you so much, that was very informative. Fortunately, we're at the lunch break so those of you that want to continue the discussion with Dr. Rillage, please come forward. Otherwise, let's be back here to start at 1 p.m. Everybody has ordered lunch so we'll bring that in for the council members here. Okay, see you at one.