 Thank you, Lucia, and thanks for the opportunity to present on behalf of the CSER investigators. So the title of my talk is based on a quote that's attributed to Julius CSER, I came, I saw, I conquered. And although I think that the work that we have to do is not quite that simple, I think I want to show you that our version of CSER really is helping us build the road map to victory. So what is CSER? Well, we're a multidisciplinary consortium that is united by the common theme of moving the genome into clinical practice. And we have a broad range of issues that we are trying to address. First, in looking at the generation and interpretation of genomic sequence data. Second, the challenges of integrating that sequence data into patient care. And third, examining the implications of bringing sequence data into the clinic. And although we recognize that clinical sequencing is happening outside of our consortium as well, what we really bring to the table is the ability to study and investigate the ways of doing this and different approaches and from that learning about best practices. So this is the organization of the consortium. It has external advisory committee with some of our members here today, as well as a steering committee that has representation from all of these groups as well as rotating chairs. There are what we refer to as the U awards, which are nine sites which were funded under common mechanisms. And we also include the NIH intramural program into that group. And then there are nine additional awards, which we call the R awards. And those were funded under a different mechanism, primarily focused on return of results, but have a lot of overlapping interests, primarily in the LC areas with the U awards. So all of these projects have come together to build the consortium. Our coordinating center does a fantastic job of helping us work together and integrate across these individual projects with nine working groups that are supported and represented by all of the projects. There's a lot of diversity in CSER. So our projects are focused on about seven different clinical domain areas. We have healthy adults, adults with cardiomyopathy, adults who are... I'm not sure that there's anything, it's not displaying on this computer either. Yeah. I'm going to have no problem going through my 40 slides without any support. Okay, great. Thank you. Adults who are in the context of preconception carrier screening, pediatric disease, pediatric cancer, and adult cancer. There's also some variation across the sites in terms of whether they use genome sequencing or exome sequencing, as well as three sites who do both tumor and germline exome sequencing. We think of our study diversity as a really great strength of CSER. This allows us to understand better ways of approaching clinical sequencing. I think many people would say that it's too early to really focus in on one approach to how we would implement sequencing and clinical practice, and this diversity allows us to really study what's happening. And so I want to focus on the four areas here that are influencing what kinds of subjects are in our studies. We have cases and control subjects, adults and pediatric. We study the clinicians as well as the patients in our studies. And some sites are also including families or trios. We also, as I mentioned, have different approaches to how the sequencing is performed. And finally, the last two areas are different approaches for how the results are returned. So I refer to the guided approach as those sites that use gene lists to decide before the sequencing happens what might be the relevant genes to look at for that clinical phenotype or for incidental findings. And other sites use an unguided approach where they do the sequencing first and then based on the variance that they find decide what is important to return to those participants. And lastly, we have different kinds of experts who are returning the results to participants. And so this will help us inform how to actually conduct these visits and what's needed in order to return the information to patients. So what has Caesar learned so far? We've published over 200 publications and over 700 presentations, which is about one presentation happening every other day. So the consortium has been incredibly productive. I would have to talk really fast in order to go through it all today. So I'm just going to highlight some of the areas that we've been working in and use particular sites and particular working group products as examples. But there's a lot more that's been happening. So I'm going to organize the work into three major accomplishments. First, generating new evidence. Second, contributing to professional guidelines. And third, the development of infrastructure, methods, resources and tools. So starting with generating new evidence. One of the really exciting projects that's been happening across the consortium is what we call the variant bake-off. And I think this is really highlighting the value of having us work together. So in the variant bake-off, there were nine laboratories that participated. And each laboratory was involved in calling 98 variants. They didn't all do all 98 variants, but there was overlap across the laboratories. They used both standardized criteria from the ACMG, as well as their own laboratory-based criteria. And then we did an analysis comparing those pathogenicity calls across the labs. And so about a third of the time, the labs got the same call. And about 40% of the time, they got very similar calls. So that would be something like likely pathogenic in one lab and a variant of unknown significance in another lab. But you can see that about 25% of the time, there was a little bit more discordance between the laboratory calls. And investigating what's going on and understanding what's different across the different laboratories helps us understand how to improve our methods. And so this is just an example of one of the variants where there was a lot of discrepancy across the laboratories. And you can see that when we looked at which particular criteria in the ACMG criteria were used, that also varied across laboratories. And the labs have spent about the last six months going through each of these 98 variants one by one and understanding what the discrepancies are and why they differed. And I think this is really going to help us improve our methods as we go forward. Another example that really highlights the strength of our consortium in having diversity is from the sequencing standards workgroup. And this example, they looked at all the different platforms that are being used for generating sequence to identify poorly covered regions across the genome. And so they identified about 114 genes that occur in these poorly covered regions. And of those 49 genes were commonly missed by all centers. And so this analysis has also been expanded to include other sites as well. But I think it really highlights the strength of having diversity across the consortium and not all doing things exactly the same way. We've been collecting metric information across the consortium and this is a combined table looking at the germline findings that are reported back to participants that are related to the clinical phenotype for those participants. And so one of the interesting areas of doing this is looking at how these yields differ depending on phenotype. And I think this is also a strength of having us look at different clinical settings and helps us to understand how does the use of genome sequencing differ depending on the particular clinical scenario. So you can see that the return of pathogenic or likely pathogenic variance for instance varies from 6% for all of the cancer phenotypes compared with 42% for the ophthalmology. Because we have so many sites that focus on cancer we're actually able to look at subtypes within that group. And so again this is focusing on the germline findings here but you can see that 6% of subjects who have a pathogenic or likely pathogenic result returned actually varies also depending on the type of cancer that they have. And so I do want to just point out that this breast and ovarian result might be artificially low if those subjects are selected to be individuals who did not have a BRCA finding. We report on other findings as well. So primarily these are looking at incidental findings and one of the important findings from the consortium is that our rate of incidental findings is fairly low around 1.7%. And this is an important benchmark for the community that other laboratories can compare themselves against if they're finding a much higher rate than they may be doing something that is different than how other laboratories are analyzing the results. Many of the sites are also returning non-ACMG incidental findings but again that is a relatively low proportion of subjects. The pharmacogenomics findings, you can see there's a range from 0 to 95% of subjects who have results in that category and I think that reflects the different approaches that the sites have to what kinds of variants they're returning how many genes are being returned for pharmacogenomic variants and an important area of diversity for us to look into further. For the carrier genes we also have a really broad range and we've been doing a study across the consortium to try to understand better how our approaches differ. Some sites report as few as 3 to 10 genes for carrier status other sites report thousands of genes and so that's a major difference in how we decide what kinds of carrier results to report and how many findings you're going to have. And then the last row the potentially clinically relevant variants are from the tumor exomes and there you can see across the sites that are doing tumor exome sequencing they have an average about 58% of subjects have a finding to return. Following up on that last row this is a particular example from the Michigan site that was recently published in JAMA and they had 102 participants in this study 89% of those subjects had adequate tissue to do both exome sequencing on the tumor and the germline of those subjects 46% had potentially actionable findings and for a quarter of them the treatment plan was actually changed for the management of that patient. For about nine participants or 10% they achieved partial or complete remission for at least six months and another nine subjects had variants that were germline variants suggesting a heritable cancer condition and so they followed up with family screening in their relatives. So this just gives you a sense of the yield in this particular study. All of the sites have been focused on different approaches to return of results and this is an example from the NC gene site where they developed a semi-quantitative metric and what's really exciting about this is the metric has now been used by the ClinGen consortium by the Actionability workgroup and implemented for all 56 ACMG genes and that poster will actually be presented next week at ASHG. I think something that everyone in the consortium really values is the case studies that have been presented on our conference calls and in-person meetings and this has really given us a really rich discussion about what kinds of findings, how people are reacting to those findings and the genetic counseling workgroup took some of these illustrative cases and developed a paper on lessons learned that could be disseminated to the community. This is a particular example from the NC gene study of one of those case studies where this woman was a 36-year-old when she enrolled in the study. She was diagnosed at age six with hereditary spastic paraplegia which caused significant morbidity in her lifetime over decades. The exome sequencing identified a variant and a diagnosis of DOPA responsive dystonia and she was able to begin treatment which resulted in a dramatic response where she's now able to walk without crutches and free of her painful daily symptoms. Many of the sites are also looking at cost analysis and utilization studies. These are two examples from the next medicine study at University of Washington that have been published and this data is just beginning to emerge also across many of our sites as our studies are maturing and we have now accumulated the information about what patients do with their results and so the MedSeq project and the NextGen project will be presenting posters on these topics at the ASHG meeting. The Outcomes and Measures workgroup has had a really hard job of looking at all of the psychosocial and behavioral outcomes that are being collected across the consortium and I think this is one area where our diversity has made things challenging for us because the sites are collecting different kinds of outcomes they're collecting those outcomes using different instruments and so it's been a little bit of a challenge to figure out how to do analysis of these outcomes across the entire consortium. They were able to build this framework and identify domains that are being assessed by many of the sites and they are going to focus on the psychosocial impact looking at anxiety and depression as their primary paper that they'll start working on to combine outcomes across the consortium. We've also had many normative and legal analyses that have been conducted across the consortium including looking at liability risk, distinctions between research and clinical care, looking at genetic discrimination, regulatory rules by the FDA and also looking at disclosure of results in pediatric cases and this work has been conducted by the Pediatrics Work Group as well as many contributors from the UNR award sites. So now I want to move on to the contributions to professional guidelines. There have been three major publications during the course of CSER that have been major guidelines from the ACMG and while I don't want to suggest that these would not have happened without CSER I think CSER has had a major influence on the final outcome for these guidelines and as you can see there are many CSER investigators who've contributed in many different ways to these guidelines. So for instance some of the CSER sites had developed their own gene lists for incidental findings that were shared with the committee that was developing the ACMG guidelines and developed the ACMG56 list. And the CSER variant bake off we had a first round that I didn't mention before that was ongoing at the same time that the pathogenicity guideline was being developed and contributed to the thinking of that guideline. There have also been many responses to the ACMG guidelines when they came out and I think this is a particularly valuable part of our consortium that we are bringing so many diverse groups together and that we are trying to prevent being polarized in our thinking by having these discussions and really being able to understand the perspectives from a variety of different disciplines and I think that's really a strength in bringing us together. Finally I'm going to talk about the infrastructure methods, resources and tools that we've developed and I'm going to just really briefly hit upon several examples but I really hope that you get the sense that we are working very hard to share these resources with the community and also that they're having an impact on the community. This is an example from the Michigan site. All of the sites have had a real challenge in developing the analytic pipelines. The Michigan site has gotten their pipeline down to about a two-week turnaround time. I think across the consortium that's about 16 weeks. This is an early example from the Actionability and Return of Results workgroup where we've had processes that have been developed by all sites and how to develop gene lists or decide what to return and they've disseminated those results to the community. All sites have developed gene lists and those have been deposited into an NHGRI website that includes not only CSER but other consortia. We've all developed consent forms and those are available publicly on our website or sorry, informed consent and governance workgroup has thought about recommendations and what is the same and different across our consent forms. We've had really good examples of clinical reports such as this one from the MedSeq project which has been also published by Vassie and McLaughlin and these report templates have also been posted on our website. The EHR Integration Workgroup has worked together with the Emerge Consortium and conducted two surveys about how the sites are integrating sequencing information into the EHR. We've had over 1,100 sequences deposited into DBGAP and CSER when combined across all the sites is one of the top 10 groups that have contributed to the ClinVar database and then many of the sites have developed tools that have been deposited onto our website and are available to others. This has had an impact on many different groups and again we recognize that other people would have been doing clinical sequencing anyway but we believe that what we've done has influenced how they've implemented clinical sequencing and accelerated their plans. Just want to briefly remind people that they're still ongoing work in the consortium through the end of June 2017. There are several different projects that will be happening across all of the sites and these are the areas that we're focusing on and the CSER individual sites have also identified areas that they're still working on and where important findings are still yet to come from their studies. In summary, CSER has had an important influence on how clinical sequencing has been implemented. We're learning important lessons and the whole is much greater than the sum of the parts by bringing us together as a consortium we're really able to learn a lot more than if we were doing this in isolation. I'm not going to dwell on the future but just to say that in your background materials these items that we came up with as a consortium are described further and also will be talked about more during the day and say thank you to all of my fellow CSER co-PIs and everyone who's contributed to CSER. Thanks. Thanks very much, Katrina. We have a couple minutes for questions. Are there questions from the group? Katrina, can you go back like one slide which is there? What is it that you think CSER should be focusing on going forward? Dan, could you use the mic? What is it that you think CSER should be focused on going forward? Thanks. I guess that's the question for the day. I didn't want to dwell on this too much myself because I know that many of the other CSER investigators actually have presentations that will be happening later in the day that they are going to go into these topics further. What I wanted to point out here is that we went through a process as a consortium over the last six months where every site first identified for themselves what they thought were the most important topics and then we came together, discussed those ideas and came up with this list that we felt were the most important things as a consortium and so what I really thought was interesting and maybe not surprising about this list is that it really follows the agenda for today and so I think there's really a lot more time for discussion in some of the other sessions about those topics but that was our process. Bob, did you have a question? Yeah, I did. I wanted to ask you to comment a little bit on one thing that struck me and that is guideline development and the impact of this work outside of genetics community. These guidelines you showed were all published in genetics and medicine. They're all ACMG guidelines and it's been my unfortunate experience to deal, for example, with third-party payers who have told me essentially they don't pay any attention until the American College of Obstetrics and Gynecology and the American College of Physicians, the American Heart Association, et cetera, published guidelines in support of some point that I've been trying to communicate to them. So what I'm wondering is does Cesar have ideas on how to expand their impact beyond the genetics community or are we relying on a... it's not trickle up and it's not trickle down so I guess it's trickle out from our group. So I think that's why the evidence generation is so critically important because I think those other groups really need to see the evidence before payers would decide to implement this within their systems. I know that all of us have that experience within our own organizations and also when we go out to talk to other organizations that they really want to see the evidence and so I think that is the way that Cesar is really going to be able to contribute to and move other groups forward is by providing the evidence that they can base those decisions on. Sharon, we're going to follow on that. One might view it as a negative example but an example of what you said so one of the papers you showed was at a group of the cancer investigators published in the major cancer journal JCO an article saying we did not agree with the ACMG guidelines for incidental finding in tumor sequencing and last week ASCO came out with their new guideline which cited our paper and which says they don't agree with the ACMG guideline for requiring the reporting of incidental findings in tumor sequencing so I think it is important for us to publish internals that are not only genetics journals in order to kind of get our voice out. Great, thank you. One more question from Eric. The papers continued today. If they could address, for example, how is the patient-centered research different than what Cory's doing? How is the first bullet different than what the UDN project is doing? How does increasing diversity differ from I forgot the acronym of the study that's supposed to be serving under served communities? Is it insight? Isn't it insight? Ignite, that's it, ignite. But anyway, if that could be addressed and also I guess with Jeff Schloss's comment how Cesar is going to interact with the other programs in NHGRI just more broadly, I think it would help clarify a lot of it. Great, thank you. All right.