 Take a moment maybe to thank Dr. Ginsberg and Dr. Manolio and the organizing committee for inviting me here to talk about the NHGRI Clinical Sequencing Exploratory Research Program. I am the NHGRI Program Officer for CSER, which means that there are a number of grantees and many many investigators who actually do the hard work and heavy lifting. I'll acknowledge them at the end, but I do want to acknowledge at the outset that this is this is a tremendously collaborative opportunity. So, okay, here's my slides. Let me right-button. I'm clicking. There we go. Okay, so this is a familiar slide to all of you, so I don't need to spend a lot of time on it, but let's take a look at similar data in a different way. So in clinical sequencing, what we're trying to do is to bring the value of clinical sequencing to the treatment of patients. And so if you consider a clinical decision that has to be made at the level of a patient and you look at the increasing amount of information that's going to be gleaned, not just from sequencing and SNPs and so forth, but the future promises to bring in functional genetics and possibly proteomics. We're talking about a huge number of facts per clinical decision, per person. I should mention to you that this is a schematic. It is not database at all, so take these numbers with a grain of salt. They are courtesy of Dan Maisis. And let me also mention that as the amount of information that we collect in the clinical setting increases, the amount that we are going to actually find to be clinically relevant is likely to be relatively constant. So the realm of traditional health care will probably only consider a very small subset of this information. And furthermore, human cognitive capacity, at least as far as we know, is really quite limited. And so I think what we're struggling to deal with in the realm of clinical sequencing is this gap, right? So I think this brings at least a few implications. One that I think is that we have to be convinced that this additional data is necessary to collect. So there has to be some clinical utility to it. A second implication, I believe, is that there needs to be some serious filtering going on here. I think that the ability to filter for patient context, disease context and so forth is going to be critical. And not to mention figuring out, at least at the sequence level, which variants are actually actionable, right? And then a third, I think, implication is that obviously this small set of information that's relevant to the decision at hand will need to be communicated in an intuitive way to the patient and to the physician. Because obviously they will need to be aware that all of this information is going to be assayed, but only some small subset of information is going to be directly relevant to them. Okay, so those were just a few issues, and obviously this is a huge area that a number of us are struggling with. In 2010, and again in 2012, NHGRI issued a request for applications to fund grants studying the challenges inherent to incorporating clinical sequencing into clinical care. I've mentioned to you that I think the challenge really here is to look at clinical sequencing in the clinical workflow. We touched on a number of areas in the RFA, the generation and the interpretation of the genomic sequence data, both kind of the technical challenge as well as the annotation challenge and interpretation challenge, and then obviously communicating the results back to the patient in the correct manner and in the appropriate manner is going to be incredibly important to study. We also, similarly to what Anastasia mentioned in the newborn program, made the ethical and psychosocial implications a primary aspect of this program. To tell you more detail about each grant, there are three different components, similar to the newborn sequencing program that you just heard about. Project one is what we term our clinical study. There needs to be a clinical rationale. Project two is the sequencing analysis and informatics pipeline, and then project three is ethical and psychosocial implications. One thing that I didn't mention to you on the previous slide is that you may notice, actually, that no are in here as any particular aim about discovery. So we recognize that discovery is an important aim, but for this particular program, we wanted to focus on common challenges which are actually, I think, more important and in fact more general for the National Human Genome Research Institute to address. These challenges are not disease specific. Okay, so back to the structure of each project. So obviously, these are interdisciplinary teams. We have a management structure for each team. And then if you look at the overall consortium, I'll tell you a little bit more about these studies, but we funded nine of these interdisciplinary projects. We include our intramural collaborators from the ClinSeq program who sit on a couple of our working groups as they have extensive and long-standing expertise in this area. I'll tell you a little bit more about this, but we also funded a coordinating center to help facilitate the high-priority goals of the consortium. And then we also are fortunate to account as our collaborators a number of grants that were funded specifically to look at return of results from the LC program at NHGRI. So here is a summary of the U Awards, the kind of Project 1, Project 2, Project 3 organization that I showed you before. You can just take a quick scan here. Four of these grants study cancer. Three of them are doing actual sequencing of tumor normal pairs. Three of them are co-funded by our collaborators at the National Cancer Institute. You'll notice that we also have representation of pediatric diseases, as well as healthy individuals. So in particular, the Brigham Women's Grant as well as the Kaiser Grant are actually sequencing individuals who are not showing any overt signs of disease. Our grants focusing on return of results that I mentioned to you before are shown here. We are a combination of both sort of empiric or data-generating studies as well as normative or more philosophical approaches. Our coordinating center is housed at the University of Washington and headed by Gail Jarvik and her colleagues. We funded the coordinating center because we recognized that the value of a consortium like this would be to bring the various sites together and to identify similarities and differences, common challenges to be addressed and common opportunities to really help move the field together. I think we recognize that clinical sequencing is obviously being done in a number of centers around the United States and in fact around the world as we've heard. And so it was important to us to really figure out how best to use this critical mass of individuals. And so the coordinating center has a range of expertise. Their key activities so far have been to facilitate the working group and cross consortia collaborations. As needed, they coordinate, initiate and even lead some high priority CSER projects. They are synthesizing site-specific variant pathogenicity data and gene lists. That's one product that we hope to be able to bring forth for the community is to share what each site is doing and what the consortium is doing as a whole in terms of calling variants, annotating variants, excuse me, and then defining predetermined gene lists for each specific condition. And they also coordinate logistics and in sort of coordinating the work of the consortium help us raise the consortium visibility. So each site is responsible for achieving their specific aims for their specific disease context and patients, but we also rely on heavily in fact on the work of working groups. This is a similar structure to probably what you heard from the Emerged Consortium yesterday. We have a number of working groups in a number of areas. Some of them are quite technical such as sequencing standards or electronic reports. Others are more sort of actionability or return of results based. I think this is a good representation of the type of work that's being done across the consortium. We do have a cancer working group that's just getting up and running, so we hope to do some more specific work in that area as a consortium. So here's what the recruitment looks like as of December 2013. So far about 1,100 patients have been approached about enrolling. We've actually sequenced, oopsie, sorry, consented almost 500 of them and then sequenced about nearly 200 of them. You'll note here that we've also enrolled physicians, so it's really important I think to understand the physician perspective in terms of generating the data, interpreting the data, and then returning it back to patients. And so the project three individuals are studying the physicians quite carefully. In fact, a lot of them are doing audio transcripts and so forth. I think a good analogy is that the technical side, the genome sequencing side, is sort of mining every single variant and then some of the clinical teams are trying to interpret variants at sort of the sequence level. And the ELSI folks are really doing the same thing at sort of each sort of word of the interview. They're really trying to look for themes and commonalities in terms of what physicians want and how they respond to information and how they best communicate results back to the participants. So I will just mention that we still have a lot of work in progress. We are, I think, learning that one size does not fit all. And I think, you know, while we hope to bring forth some best practices for the community, we're discovering that there are a lot of different and equally valid approaches. For example, six of the initial sites that were funded were asked about their practices of reporting incidental findings. And you can see here that all six report the incidental findings. Half of them include the incidental findings in their primary indications and half actually have a separate report. And these decisions are also made by consensus, generally made by consensus among the clinical teams. So there are many perspectives. Half of the sites actually allow patients to opt out of receiving medically-actional incidental findings again for very site-specific reasons and well-justified ones as well. So you can see that there's some variability here. And we're working to understand sort of why people made these decisions, who makes the decisions, are there, is there a clear way going forward that we can recommend to the community? Or is it more of an issue of kind of defining what factors each group needs to consider in terms of making their choices about how information is returned? Groups are also displaying some heterogeneity in terms of how they return variance. And obviously I think one big challenge for the field as well that we're hoping to address within CSER is what is sufficient evidence for pathogenicity? I think this is really a critical area that is not unique to CSER and we are eager to collaborate with others, I think, in this regard. Some examples of recent work from our consortia. There have been two recent working group papers, one focused on summarizing the similarities and differences in defining challenges in terms of identifying actionable genes within the consortium. So this is a summary and descriptive paper from the first six CSER sites in terms of actionable genes. There is also a working group paper on approaches to integrating genomic information into the electronic healthcare records. We have a number of other papers that are published or co-authored by subsets of the consortia or individual sites, and I'm just highlighting if you hear there was an article written by a number of folks in response to the ACMG recommendations on incidental findings. A exercise to actually annotate incidental findings in the NHLBI exome sequencing project. And then one example of a discovery study in cancer where a whole exome sequence, sorry, this is describing the clinical pipeline, clinical sequencing pipeline from one of our sites that has extensive experience. And then here's the discovery study identifying several ESR mutations and hormone-resistant breast cancer. So we are doing some critical discovery as well. So I could not give this talk or not for the contributions of numerous people. I'm showing you here the U grants, the first phase that were funded, the three that were funded in the second phase, as well as the PIs of our grantees. Also, I'm fortunate to count among our collaborators a number of people NHGRI that have helped us really lead and championed this effort, in particular, Brad Ozenberger, who is now at Washington University in St. Louis, and then our collaborators at NCI as well. I'm happy to take any questions at this point. Thank you for your time. So how does this, how does your study differ from the TCGA? So my understanding is TCGA is, they're collecting samples from a number of cancer individuals in cancer, but it's not in the setting of their routine clinical care. And the purpose of CSER, first of all, is much, it goes beyond cancer. It's not, the lessons are not cancer specific, although we do have cancer sites. But it's really to figure out how to generate the information, how to interpret it and return it within the context of the clinical workflow. So I don't know if anybody else from NHGRI wants to comment. Yeah. It's all right. So it's all discovery. Maybe any impressions or data on patients and providers and how adaptable sequencing has been to, well, to the provider community in particular. And I don't know if there's a little discordance between the number of people, why people haven't agreed to do this, if there's any insights into that as well. So maybe the acceptability of sequence to physicians and how readily they are really prepared to actually utilize it in their practice and what do we need to do to really facilitate that. And also the patients, what are the most common reasons for them not to want to participate? Okay. So I think in terms of the physicians, we're fortunate to have a pretty big diversity of, I think, clinical domains represented within the CSER consortium. And some of you that are involved in CSER may want to comment on this. But my understanding is, you know, it really depends on not just the clinical community in terms of cancer versus pediatrics. It really depends on one's institution, what sort of the climate is for being receptive to clinical sequencing. So NHGRI's visited, we've had the fortune to visit a number of CSER sites. And many physicians really are on board because they see this as sort of the next sort of step in personalized healthcare. Many of them, I think, recognize that there are challenges, like really, really critical challenges where they don't have a lot of time. The clinical utility perhaps is not as evident for genomic sequencing yet. But I think, you know, for these nine sites, at least there's a lot of promise there. I think many individuals sort of see this as a research endeavor, which it absolutely is, it's clinical research. And I think we're learning the lessons in order to sort of move the field forward. So I have to say that at least in the nine sites that we've heard about so far that we fund, you know, the physicians have been receptive. I think it does take some effort to recruit patients in light of their busy workload, but many of them are wanting to do it. I can offer one particular example, the pediatric cancer study from Baylor, for example. The physicians there are used to enrolling their patients in clinical trials. And so, you know, the value of clinical sequencing in that context I think is seen as much higher. And there are similar examples throughout the Caesar consortium. And then in terms of patients not participating. In general, actually, we have heard that a lot of patients are really receptive to this. I think that once they get past the idea that, you know, you're sequencing the human genome, you're sort of actually learning about an individual at sort of the, you know, the nucleotide level. Once you get past that scientific explanation, a lot of them really do see sequencing as perhaps an end to their diagnostic odyssey. Some of these individuals have been going from visit to visit, test to test, trying to get an answer to, you know, what is causing their condition. So that's one example. I think we haven't seen so far people decline participation due to the fact, due to return of results. Actually a lot of them, or results being placed in their medical record. Once people, once the researchers explain to them what the value of the information potentially is and how it will be interpreted. Many of them really don't see many concerns with that approach. So, so far early signs are that it's reassuring. Yeah, but you had fewer than half of patients approached in role. That's true. That does seem low. That's, so we do have a pipeline. I think what I'm showing you is that there is a process by which people are consented. They're put in the sequencing pipeline. They have to come back to have their results returned. And in fact, and the other important thing I want to add is that in the early days, especially at each site, there is a process for determining which variants to return, right? That's not a trivial process. And I see Heidi back there. So maybe she can comment on really how long it takes to actually call a variant. But I mean that, that is a process that takes a substantial amount of time. I think it's shortening, but that has to be factored into as well in terms of who actually gets sequenced and results returned. And I just do want to comment that we have had patients decline because they do not want their results in the medical record. So, so we do have a proportion of patients that upon enrollment, once they go through and find out that a criteria for enrollment is that their results will be placed in the medical record, they have declined for that reason. Not, you know, the majority do continue to enroll, but I just did want to make that clarification. It's not universal. Yeah, that's a good point. On the physician enrollment side, they're required to undergo six hours of training, two that are didactic, and then four hours of self-study case modules that they have to take quizzes on. They get CME credit, but there is, you know, the time commitment that is the major barrier for the physician involvement, though I think it's usually mainly just a time commitment question and not interest in general in the topic. So I guess what is returned at one site might be considered incidental to the phenotype of interest at another site? So each site does make their own decision about what constitutes an incidental finding. So you could, you could find your, you know, there are differences in terms of what's returned. So it's possible that one site that considers a variant crucial for a primary phenotype is considered an incidental finding in another study because they're not recruiting patients from the same phenotype. And I guess you're not trying to make people harmonize their procedures at this point, but are they at least keeping track of which findings are returned and which genes are considered incidental in some public place where we could access that information? So it's not yet public. We've just now started to collect the gene lists that are actually the diagnostic gene lists as well as the incidental findings. So I think, again, I think it remains to be seen whether or not, you know, there is a consensus. I think there are also plenty of other organizations and societies that want to weigh in that are probably more appropriate than this research consortium. But certainly we are looking at that very critically and plan to share that information as well. Yeah, as a participant in the Philadelphia site, I can answer Mary by saying, you know, if you've seen one Caesar site, you've seen one Caesar site. They're very different. And hopefully the working groups will amalgamate some results. I just want to emphasize a couple of points that you've mentioned. We are very concerned about why people don't participate and are screening them, querying them as carefully as we are the participants. And the second thing is we found that one of the reasons the parents opt not to participate is that this is not a substitute for regular medical care. And so our patients with congenital hearing loss, let's say, are getting cytogenomic arrays and full panels of known hearing loss genes. And then this is an add-on. And oftentimes parents say, look, you've done what you can. That's enough. We don't want to invest the additional time. So the extra time burden of participating. Thank you. Okay, thank you.