 We're about to embark on the Caesar concept clearance. Now that's going to be a long discussion. I'm looking at Lucia. Do you want the workshop report to go and then take a break? Would that be OK to not till four? But we don't want to try to go all the way through the concept. So would it be logical to do the report on the workshop and then come back? OK. Dan, you're up. So September was a busy month. Not only was there the round table meeting, but also there was a workshop that was organized called Integrating Genomic Sequencing into Clinical Care, Caesar and Beyond. Dan Rodin, a council member, was at that workshop and was pretty instrumental in the organization of it. And he's going to give a presentation based on the report or the outcomes of the workshop. And that will be a preliminary to slide into the concept clearance. Thank you very much. I am the mouthpiece and not really very much more. I have lots of titles. And for those of you who don't know, I come from Vanderbilt. I decided not to put that title on there because it's not relevant to this. So in addition to sitting with you all every four months, I also come and visit with the Caesar group as a member of their advisory panel. And I was part of the planning session for the workshop that you're going to hear about and that forms the basis of what you can hear about from Lucia. So the talk is divided into two parts. The first part is just to talk a little bit about what Caesar has done so far. And then the second part is these other two bullet points. I'm not going to bore you by reading them. I'll read you enough slides later. Caesar is 21 institutes, one consortium, 377. I'm not swearing to the accuracy of that number. Investigators at the sites that you see. And in my mind, what Caesar is doing is taking the art or science of genomic medicine down to the level of the individual patient. And that really sort of highlights the focus. The focus is on what do you do with an individual patient with a genomic variant? How do you find them? What do you do with them? So the domains are in technology. Sort of remember this program started several years ago. So how do you generate and interpret genomic sequence in a broad range of clinical contexts, which I'll outline for you in a moment. The clinical care, studying the challenges involved in integrating genomic information into care, and then focus on outcomes and a focus on the LC issues, which become particularly problematic or assume particular importance as you start to move this information into the clinic and start to engage patients with their own variant information. So there's a series. I think the word diversity is probably sort of a provocation here because we've heard so much about different kinds of diversity all day long. But I'll stand by it nevertheless. So there's a wide range of clinical scenarios that CSER investigators have engaged. So the idea was that at each of the sites, there is a focus on a particular therapeutic area or a particular problem in genomic medicine, ranging from adults with cardiomyopathy all the way up in this corner here down to a series of studies around cancer, both in the germ line as well as in the tumors. And then there are sort of a set of focuses on germ line genomic issues around healthy adults, adults with cardiomyopathy. There are developmental and intellectual delay projects. There are ophthalmology projects, and I'll show you more about those in a second. The second is diversity and ancestry. And I think given what we've just discussed, you can appreciate that this is not optimal, but this is the CSER participants as of when this slide was made up last week. So 75% European-American and the remainder as you see it. And then there's a wide variety of approaches that have been used. And again, I won't read you this, but you can appreciate that there are both adult and pediatric. There are patients as well as healthy participants. There are genomic physicians who inform patients of their results. There are primary care physicians. There are patients who are screened because of a disease. There are patients who are not screened because of a disease who are just screened. So there's a wide variety of study designs. The intent being to figure out in each of these contexts and broadly across many contexts, which are the optimal approaches. And I'd say approach is not approach. So I'll give you a couple of examples of the kinds of things CSER investigators have done. One of the issues that came up in their deliberations was this guideline issued up here by the American College of Medical Genetics and a pathology group. And that basically proposed guidelines for how to interpret genomic sequence data. They implemented, the CSER investigators implemented those guidelines across nine CSER labs and found that there was very little concordance across the lab sites. That's a depressing result, so 34%. They put their heads together, spent a lot of time trying to understand why there was such low concordance. And within the last week, the paper that describes what they did to increase the concordance across labs was actually accepted for publication. So again, they've now increased the concordance to 71% across all labs and describes the way in which that kind of activity can help their labs and, of course, by inference, other labs doing this kind of work. Another activity has been to look critically at genes that they have targeted, either because they use panels or because of whole exome projects, to look at the coverage. In other words, to look and ask the question if there is a rare variant that might be important in this gene, what's the likelihood that I will miss it? And that's a very important topic for people who want to do genomic medicine. I just have to highlight the most important gene on this list is this one here, because it's an ion channel gene and everybody knows that those are the most important ones of all. But the ones in blue are the ones that are particularly problematic because there are regions in those genes that are missed across all the sites. These are whole exome and whole genome sequencing sites and they are particularly important because you might miss something in those genes. And then the evidence base. So, again, the projects, the specific projects, these are all germline projects now, are down the left-hand column, developmental delay, intellectual delay, ophthalmology projects, cardiomyopathy projects, other cardiovascular projects and all other projects. And then, sedrobic intellectual delay, autism. And the cancer is the germline cancer, not the tumor genome. So you can see that the yield for pathogenic or likely pathogenic in green varies from 5% to about 39% depending on which kind of patient you're screening. And then there's a large number of other or variants of uncertain significance. There's a small number of patients, two to 4%, that have incidental findings, so-called incidental findings, according to the ACMG list or an expanded list beyond the ACMG. And how each site dealt with those is how each site dealt with those. These are a series of representative publications in both the genomic literature as well as the more broad medical literature you've heard about some of them and I won't go through them. Again, summaries of the experience across the network, summaries of approaches to disclosure of the information, summaries of how this affects cancer management and illustrative cases. You saw the numbers from Eric, I think I had the same numbers, although I have 14 working group publications and Eric had 13 in his report. And then the other activity that has been very, very important across the entire activity has been the contribution of CSER investigators to generating policy and guidelines across genomic medicine. So policy for return of incidental findings, policy for interactions with FDA over how tests are regulated, policies for laboratory management. And the investigators that are highlighted in red are the investigators who are part of CSER who contributed to these kinds of guidelines. There are no investigators in red here because they're all CSER investigators. So that's a very, very brief overview of what CSER has done in its first round. Now the workshop that I'm going to just tell you about in the next few slides had two aims. One was to prioritize the scientific opportunities for the next five to 10 years and the second is to identify features of a program that you'll hear more about from we'll see. So the topics, I don't think I want to read you these topics in particular because these are just the six sort of breakout sessions or the six, we didn't have breakout sessions, but the six working groups that we formed, we each had, each of these topics took about an hour to address with short talks and then a lot of discussion. So facilitating development of shared evidence base, I'm now having said I'm not gonna talk to you, I'm not gonna read them to you, I will. Interpreting variants and action ability, assessing clinical utility, patient-centered research from consent to outcomes, increasing ancestral and other kinds of diversity and healthcare utilization, economics and value. So those are the topics that were covered and the kinds of approaches that were developed within those topics and across topics were the kinds of things that laid a groundwork for what Lucille will talk about in a moment. So create framework for assessing clinical utility of genomic sequence beyond the narrow definitions that we've used today. Make interpretation and return of results efficient and accessible, improve standards for variant classification, characterize the impact of genomic results return on the patient and the family and then develop, implement and disseminate site-specific models for a shared evidence base. That captures both phenotypes and long-term and short-term healthcare outcomes. That's a tall order, but that's what it is. So the principles that you'll hear about in the next round are to focus on clinical encounters. That's where CSER strength really is, interactions among patients, family members, practitioners and laboratories. That's the activity that CSER pursues and that other programs within the genomic medicine working group or the genomic medicine area in the Institute have less of a focus on. This is the real focus of CSER, increasing ancestral and socioeconomic diversity, continuing to pursue the ethics and other issues. The idea that the whole is greater than some of the parts, the consortium issue and then collaborating with stakeholders like professional societies, payers and regulatory agencies and that's a collaboration as well as sort of an educational mission that goes beyond CSER, but CSER has embraced as well. So you can look at it, this is one way to think about this. CSER has to date accomplished these sort of in broad terms these four bullet points. Implementation of clinical sequencing pipelines, interpretation and return of genomic results, patient physician and physician lab interactions and patient centered outcomes. What do you do with the result? How does the patient respond to that result? And what CSER 2 will be doing in very broad brushstrokes and this is the proposal of course is to continue to assess clinical utility, to continue the focus on interactions among patients, families, physicians and labs, build alliances with non-traditional entities. This is pretty open-ended, you'll hear more about it but there are many constituencies that have not traditionally been engaged in this kind of activity that we think can be engaged in the upcoming activity and then obviously be responsive to the rapidly changing need for evidence. That is my report and I'll be happy to take questions and relay them to Lucia for her to answer. Questions? Comments? For coffee or the concept, one or the other? Yeah, I think both. I'll pose the five second rule, I haven't seen any hands go up. Thank you very much, Dan. Let's take a break for, if I say 10 minutes, we will come back in 15 minutes. Let's say 10 minutes, run upstairs, grab some coffee and we'll resume with the concept presentation from Lucia, okay? I've done this before, Jim. Yeah.