 Hello, everybody. This is Lucia Hendoor from the NHGRI. Welcome to the Caesar II Pre-Application Informational Webinar. There are a number of NIH staff here in the room with me and others who may be joining on the phone, but in the interest of time, we won't be going through introductions, but rest assured that we have a number of folks here who are able to answer your questions. Okay, so I'm going to be starting off with the very short overview of the Caesar II program and its goals. For today, let me point out that at the top of the slide that I'm showing here is the link to the NHGRI page, where hopefully you found the dial-in information for this webinar, as well as the link to the FAQs that we have posted and will continue to update. As a matter of etiquette for your other fellow scholars, please keep yourself muted unless you're asking a question. To unmute during the Q&A, click the mic, and you should be unmuted. And then please remember to remute yourself after you have a chance to talk. So again, don't unmute now, but when we're ready for questions, that's what you'll need to do. Okay, so let me point out that we are all here today to discuss the Caesar II program. Our intention is to give a high-level overview of the Caesar II RFAs. I'm showing you the three RFAs here, the two clinical site RFAs, as well as the coordinating center RFA, as well as the links. Hopefully you're all here because you have some familiarity with the RFAs and had a chance to look them over. And I want to mention that even though we'll be discussing the high-level RFA goals and answering questions, the RFAs are the official source of information. So let me go in a little bit into what we intend when the NIH release request for applications. So RFAs serve multiple goals. And so when you hear us answer questions about them, we may be answering from a number of different perspectives. First of all, they are instructions to applicants as you're well aware of. They also serve as guidance to reviewers. So there's information and criteria for reviewers to consider as they're evaluating the applications. For grantees that will be funded as part of Caesar II, there are terms and conditions and expectations for grantees. And then also the high-level goals of the NIH, the NHGRI, the MCI, the NIMHD are sort of folded in, as well as a retrospective and sort of descriptive history of Caesar I, which is currently ongoing and wrapping up. I want to make a distinction and those of you who have talked with us may remember this, but distinguishing between the responsiveness of the RFA and scientific merit. So the RFA sets out a number of fairly high-level goals and program staff can help guide applicants as to whether the proposed work seems to be broadly responsive to the goals. However, program is not really the best suited for addressing very specific questions of scientific merit, such as the approaches used, for example, comparing two very technical methods. Some of those details that are more granular are left to peer review. So please keep that in mind as you ask and we answer your questions. We are looking for your best ideas. We're all very excited about this RFA and so we hope that as you read the RFA and respond to it, you'll keep all these things in mind. So one key thing I want to emphasize is that Caesar II has an important kind of fight specific as well as consortium overview. So taking a look at this picture of this orchestra making beautiful music, you'll of course recognize that there are many different types of instruments, the strings, the woodwinds, the brass, the percussion that go into making this orchestra. And of course it's very important that the violinists are technically proficient in their own way as for the other instruments. And so hopefully it's not too much of a stretch to say that each Caesar II site that will be funded is in fact part of a whole. Each site will bring its unique strengths and approaches and investigative team to this consortium. But of course the consortium itself as a whole is a critical mass of investigators as well as stakeholders that will address the key goals of the RFA. And of course the hope is that it's more than the sum of its parts. So now let me transition into the high level goals of the RFA. So I'll walk through them in turn. So the first is clinical utility. We are using the broad definition that's in this publication cited here from the ACNG, which is genomic intervention and improved health outcome. Really going beyond diagnosis and also including implications for family members as well as kind of downstream and health utilization outcomes as well as clinical outcomes. So in the most broadest sense, one of the key goals of Caesar II is to define, generate and analyze evidence regarding the clinical utility of genome sequencing. Each site will propose site specific measures and Caesar II will also come together and agree on consensus measures of clinical utility. The clinical sites will each bring 1,100 participants or more as a minimum to the table. So I want to clarify, and this is also on the FAQ, that the 1,100 is a minimum across all study design components and also including retrospective data. And then another final feature of this aim is a comparison of genome sequencing, which we've defined in the RFA to alternate modalities. The idea here is that in order for us to assess the clinical utility of genome sequencing, it's often very helpful to have a comparison approach. A second high level aim of Caesar II is research at the intersection of the domains that you see here. Our experience in Caesar I and knowledge of the field suggests that there are critical interactions among these different domains that influence implementation of clinical genomic sequencing. So applicants will describe how their proposed research takes advantage and proposes to answer questions related to these domains and how their proposed research might generalize to other sites or settings. It's important to recognize that we are starting to get handle on a number of two way interactions. So for example, the interactions between patients and practitioners, but going beyond those two way interactions for the next four years of Caesar II will be critical, as will the tie in of these domains to diversity goals, which are described in the RFA as well as health disparities. A third aim of Caesar II is addressing real world barriers to integrating genomic clinical and health care utilization data within a health care system for the purpose of clinical decision making. So in our concept clearance where we presented the high level goals of this concept to our NHGRI council, we described a number of areas which you see here represented in the figure of genomic clinical and health care utilization. The bullets are examples. And what we did was we sort of described how these data types tend to be siloed. So for example, it's very difficult and challenging to link genomic to high quality phenotype data. So addressing these real world barriers and addressing the data integration as part of Caesar II will be critical in making sure that Caesar II data contribute to an evidence base that will be helpful for clinical decision making. And so we're envisioning this aim as somewhat of a pilot. So we recognize that there are different challenges and advantages of doing so in different settings. And so the RFA describes a little bit about what we expect in terms of this pilot. And as part of part of that, you know, this aim has somewhat of a many flowers bloom approach. And I think, you know, different groups will come up with slightly different approaches. But we will encourage interoperability of processes, standards and best practices across Caesar sites and with external health care systems is feasible. And I also want to mention as part of this goal, we anticipate that Caesar II will be in a great position to contribute to existing resources that are doing similar work such as ClinGen. I'm going to now turn this over to Dave Kauffman to talk a little bit about the LC expectations. Thanks, Lucia. So as many of you know, LC stands for the ethical, legal and social implications of implementing clinical genomics in this in this case. And so the Caesar II applications must address some of the LC research some LC research questions, simply addressing human subjects concerns that come up in the in the other objectives that that Lucia described will not be judged to be responsive. But you know, we believe that there are tons of great LC research opportunities across all three aims. We think there is some flexibility in the degree to which applicants emphasize the LC within each of the aims. And for those of you who are aware of the structure of Caesar I applications, LC sort of had its own separate project there. And that structure is not being required. You don't have to write your LC as a sort of separate part of the application. On the other hand, you certainly can do that. We expect that LC research will in Caesar II will go beyond issues of consent and the return of research results and measuring sort of psychosocial outcomes of returning results to people. And of particular interest to us is research that will help ensure the utility of genomics as it gets implemented in diverse populations in healthcare settings beyond academic medical centers and in ways that address and don't exacerbate health disparities. You know, and with respect to this last bullet point, you know, some of this work may indeed be oriented towards identifying problems that exist as we implement clinical genomics more broadly. But we do hope that some of the work will be oriented towards some problem solving to sort of, you know, try and get at some some of those issues. Back to you, Lucia. Okay, thanks, Dave. Sure. So that was I'll see another important component of Caesar II will be getting input from key stakeholders, which we've described in the RFA is including professional societies, payers, regulatory agencies and patient groups. And this is this is, you know, a somewhat expanded and more focused effort in Caesar II to engage these stakeholders in helping define and be responsive to metrics and clinical utility and really any issues that come up related to genomic sequencing and integration of it into clinical care. So I think we recognize that today in 2016, we may have an idea of what the landscape may look like in four years. But we may not, you know, be able to recognize everything that comes up. And of course, we want to position Caesar II to be responsive to evolving needs for data and evidence. After all, this will be the clinical sequencing evidence generating research consortium. And so applicants will be expected to develop site specific stakeholder engagement plans and describe their potential contributions to a Caesar II wide engagement plan. The coordinating center RFA describes some expectations for the coordinating center to help facilitate the development of this consortium wide engagement plan. And then important thing to keep in mind as you think about these plans is to consider the value of engaging stakeholders throughout the entire research process from the study designed to the implementation of findings. Okay, so that's basically it for our short overview. I want to remind people that we do have this FAQ up. I'm at this webpage. It's the same page that we cited in the notice and the NIH guide. The archive of this webinar will also be posted there for colleagues of yours or the community who aren't able to make it today. So there are three scientific contacts listed in the RFA. I'm one of them. I also have colleagues from the NCI and I aim MHD here. And I just want to give them a chance to say anything if there's anything they want to chime in with. I'm Charlie and I'm based in NCI's epidemiology and genomics research program and we've been very fortunate to be part of Caesar I and now Caesar II. So everything that for all cancer projects, everything for Caesar still applies. But if you have cancer specific questions, it might be best to get in touch with us for your concern. Thanks, Charlie. So I think we are coming to the end of our overview. I do want to go through a couple of questions that we received in advance as you are gathering your thoughts. As you're preparing to ask questions, however, if you could try to keep them as general as possible to allow for as many questions as we can to get answered today, we recognize that people may be interested in sharing the details of their study designs. And you know, that's that's appropriate to some degree. But if people have very, very specific questions, they may want to consult with us offline so we can answer those specific questions. Okay, so one of the questions that we have gotten is whether clinical utility, the clinical utility aims should focus on a single disease entity or multiple disease entity. So what is the best approach? And I want to show people a link to the the FAQ. Let's see. Can we get that up? Definitely ask. Okay. Where we've started to address this. This is a question that we've heard. So for those of you who are on the webinar, you can see this question to here. So the RFA does have some language in there that applicants should obviously justify the proposed clinical clinical conditions that they plan to study. NIH is relatively agnostic about, you know, one versus multiple conditions. And so, you know, we recognize that really this is a judgment call on the basis of the investigators. The optimal balance, of course, needs to be considered in light of the scientific questions that your investigative team is most uniquely poised to answer. So that's one example. I will just sort of scroll down and let people know that we have additional clarifications on the sample size. The data integration aim. And then we have some very specific questions about the stakeholder engagement plan and whether they need to be formally included. And then some other questions about applicants who are interested in applying for the clinical site and the coordinating center or who are currently new investigators. So I'll stop there. This is a time to unmute your lines if you have a question. And we'll do the best we can to allow one at a time to speak. Any questions? Okay. Can we provide an example of a stakeholder engagement plan is one question that a participant's asking on the chat. So, you know, I unfortunately, I don't have a plan ready to share with you. One thing that I would encourage people to do who aren't as familiar with these, we have been having conversations with PCORI and they have been extremely helpful in sharing examples of stakeholder engagement plans. They are, of course, for a different purpose, but one thing we can do is provide a link on the FAQ so people can perhaps consult those and determine what features may be related to their specific aims. Yeah, I would just add Lucia that if you do go to look at PCORI's plans, they are much more in depth than we acknowledge that we will be able to do and we expect you all to do. They do engagement at every turn and we're not expecting that level of depth, but at least some of the sort of topics and sort of methods I think are there. Good point. Other questions? Hello. Go ahead. Can you hear me? Yes. I have a question regarding what I consider somewhat of a gray zone where obviously evaluating the clinical utility of, in our case, potentially clinical whole exome sequencing. And of course, this is done in clinical practice and we're looking to see the impact of this on clinical utility. But the question I have is regarding the budget and kind of what is covered by what. The research itself is in fact investigating this use of a clinical tool, which in and of itself is something that is considered a billable process. I'm just wondering if the NIH has any sense of whether all efforts in these initiatives should be covered by the research budget or is it appropriate to use clinical resources and redirect the budget if you will to assessing downstream of that. Okay. So that's a good question. So the short answer is costs that are needed to generate the data in a research setting or a clinical setting are allowable. An approach in which an institution, for example, already has a process that they may be able to use to generate data for CSER2, of course, may not need to request costs in the CSER budget. And so if you have an existing process by which you're going to generate data, make sure you describe that in your application. You know, people who aren't in that position who need costs to generate clinical sequencing data or require and investigators on their team to generate the data should obviously budget for those costs. Does that help? Sorry, I went back to mute again. It did clarify things. Thank you. Okay, you're welcome. Can I have a related question? Sure. So sort of converse to that is data that is generated in a research setting so would still be considered to be responsive in terms of assessing clinical utility, even if it's not done in a clear certified environment? Okay. So I'm going to actually just respond and quickly try and tease out two components. So, you know, obviously research data is part of this research consortium. So, you know, NIH funds scientific research. And so it's completely appropriate for the data that's generated as to Caesar from Caesar to be considered research data, clinical research data or research data. Now, I sort of heard a question about whether the research should be generated in a clear setting. And, you know, I think given the given the goals of the RFA, I am finding it difficult to think of a situation in which you would not generate research findings in a clear setting. I think, you know, interpreting variants and returning them to participants, the standard of care currently really is clear. So I think you'd have to have, you know, a very strong justification for not using that approach. Okay, thanks. So we'll take a question that came in via email for cancer focused applications about RNA sequencing and is that allowed? Okay, so just we want to say that with the RFAs, we're encouraging the comparison of genomic sequencing approaches to alternative modalities, but with the preference for established modalities such as standard of care targeted gene sequencing panel. So we know to the extent RNA sequencing is already being used, and it's perfectly fair to have that as be one of your comparators with genomic sequencing. The inclusion of other genomic approaches generally is permitted as long as the justification relates to the genomic approach to a specific aim in the RFA. And then the second part is somatic and that sequencing allowed. So a somatic only sequencing. So we would encourage in the RFA is germline, germline sequencing. So germline somatic integration is something that we put in our anti-priorities. For somatic only, I think you'd have to have a very strong justification. And so we would prioritize germline and somatic over that. Yeah, I think there are. This is Dave. I mean, in terms of LC issues, I think there are some interesting ones as we think about differences in both physician and physician laboratory and patient treatment of an understanding of germline versus somatic findings. So there may be a lot of richness there if you are thinking about doing both. And just a quick clarifying. So we would prefer germline somatic that isn't to devalue just germline sequencing. So we would accept that. But again, for any of these projects, really, they need to be scientifically strong and justified and scientifically justified as and responsive to the RFA. So if you have specific questions, we're more than happy to talk to you about your particular project. I have a question regarding particularly in pediatrics populations. How the NIH might view the appropriateness of whole genome as opposed to whole exome sequencing in a clinical context. This is clearly something that is starting to emerge, but is probably not considered mainstream by any stretch in this setting. Is that something that you would consider reasonable? So if you look at the definition section in which we describe what we mean by genome sequencing, you'll notice that both whole exome and whole genome approaches are included in that definition. And so, you know, I think this is another one of those cases where I think it's someone of a scientific judgment called depending on what specific disease focus your group is planning on setting, there may be settings in which one of them is, you know, more valuable than the other, perhaps, you know, what was probably more likely that one is more cost effective than the other. So, so, you know, I think for as a broader statement to all applicants, please, you know, do read the definitions and make sure you understand what we consider to be genome sequencing, but really the choice of technology is a judgment call on the basis of the PI and his or her team. Okay, so three second rule of silence here. Let's go ahead and go to another question that we've gotten via the WebEx regarding the data integration aim number three, what scale is referred to for a health care system? So for example, as a single site community health center would that constitute a health care system? And so I think the answer there is, yes, I think you as long as you can sort of relate it back to the goals of the RFA, the exact health care setting can be fairly broad. And in fact, we are encouraging folks to think beyond specialized academic medical centers in terms of evidence generation for Cesar two. And in in objective three, you'd need to be able to show that you've got in that community health care center that you've got some, you know, some data integration issues that you're going to try to address. So then we have a question. Does the reference to clinical laboratories refer to routine diagnostic testing as opposed to clinical sequencing laboratories? In objective two, and in objective two, when we're talking about the intersection between the providers, the family, the patients and their families in the clinical labs, we were primarily referring to the clinical sequencing labs in the in the context of that. If you have other routine diagnostic testing that plays labs that play an important part in your specific application, then that would be something that you would want to also include in that. Really, it's like who are the main players that are involved in the that clinical interaction. One says in clinical domains where XM sequencing is already moving into clinical care, is it responsive to compare alternative approaches to XM sequencing or is it necessary to compare sequencing to non-sequencing modalities? So I think the expectation in the RFA is to have one or more sequencing modalities compared to alternative modalities. So the alternative could be another genomic modality or it could be a non-genomic or non-sequencing modality. I think that's a judgment call on the basis of the investigative team. With studies that explore the utility of clinical genome sequencing and risk assessment and prevention be eligible. I think so. I think whoever asked that question may want to give us some more details or contact us. But I think more broadly, yes, I think as long as a study addresses the goals of the RFA and makes a compelling case that understanding clinical utility is important in that setting, I think risk assessment and prevention could be relevant. So the next question asks whether or not hospitals or groups partnering with a commercial genomic sequencing company to do the sequencing would be eligible or responsive? Yes. So the answer is yes. You'll of course need to describe the site that will do the sequencing and then in the RFA address a number of specific metrics that are related to the genome sequencing costs. But yes, it would be permissible to allow a private commercial company. OK, we have one technical question. Will the slides from today be made available? Yes, they will. The slides and the webinar with the audio will be made available. For diversity sizes, ancestry marker testing required or expected? We did not have any explicit requirements. I think you'll want to, if you are proposing this, you'll want to describe the use of it in the rationale. Given the definition of sequencing in the RFA, they do the diseases or phenotypes need to be associated with one with more than 100 genes. So, you know, in the definition, we really were basing the genome sequencing test strictly on the technology. So I don't think we said that they had to be linked to an individual phenotype that was associated with more than 100 genes, if I'm understanding the question correctly. But the sequencing technology used, if it is a targeted gene sequencing panel needs to include 100 more genes. And I think more broadly, this what is not going to be responsive or in scope is if you were planning a project where you're sequencing component, only sequence one or five or 20 genes. We really need one of the two arms and the comparator to do a broad look at the genome, be it a genome, whole genome sequencing, whole exome sequencing or a large gene panel, which we use the 100 genes as a somewhat arbitrary but important distinction to help determine what is meant by a large gene sequencing panel. Let's pause and see if anyone else wants to chime in with questions. We have a number of other questions that have been asked. Okay, moving on. What are the distinctions for C02 versus eMERGE and IGNITE? So some of you may be aware of other NHGRI funded consortia and this question has to deal with deals with the scientific overlap between among them. So just to sort of a very high level summary, these are two is focused on studying the clinical utility of genomic sequencing, performing a research around the clinical encounter between patients, physicians, families and labs and addressing barriers to integrating genomic clinical and healthcare data within healthcare system. So that's what we just discussed. Hopefully that will sound familiar. IGNITE is focused on demonstration projects for clinical tests with established clinical utility. So the programs working on incorporating genomic information from these tests into the EMR and developing clinical decision support for implementation of again these tests that have established clinical utility and they're also focused on dissemination and ways that are complementary but distinct to C02. And then eMERGE and its third phase is focusing on assessing the penetrance and phenotypic implications or rare variants clinically relevant genes, integrating gene variants into EHRs and creating community resources. So that's the high-level overview. And then one more comment is that, you know, we recognize in these large interdisciplinary grants, there may be people that are thinking about applying who can leverage when a more data sets, whether they're from either of the consortium that I mentioned or not. And I do want to point out that it's important in your application to distinguish what your research that you're proposing for funding, how that would differ from research that's already funded. And if you're proposing to use data that have been generated through other consortia, make sure you take a look at the section on using existing or retrospective data. We have a number of items that really should be addressed to help reviewers evaluate whether the data can be useful for use in C02. Another question that was written in for the ethnically diverse sites, is it enough to be doing the research in a diverse setting? Or is it expected that implementation in a diverse setting will be a central focus of the research itself? That is, versus looking at genomic, just the genomic diversity of the patients. I think that we would while we can't require that an application focus on the implementation in diverse settings, it is a very strong interest and we would, I think, are going to be inclined towards studies that can do both and not just check the box of recruiting and sequencing people, but learning how to do this in another population. And as you look at the description of some of the discussions about LC related issues around the in the diverse diversity enhanced RFA, you will see that those wouldn't really be able to be addressed if the implementation as well, if the implementation was not happening in that context. Yeah, I mean, it would be a really a lost opportunity if you were doing research in a diverse population, not to really use that to address the LC questions and unique issues that may come up with diverse populations. And I mean, I think just looking in objective one and objective two, I mean, whether clinical utility differs in other health care studies in other populations would be interesting and important. And whether the interactions between family members, providers and laboratories in these settings is at all different and needs and needs additional work, I think would be a rich area to explore is our whole. Yeah, I completely agree. At the same time, I just want to point out, I think implementation is sort of a spectrum and we don't want to discourage. So, so, you know, I will say, I think there is sort of a niche that needs to be filled in terms of recruiting participants and investigators from settings in which, you know, we don't see a lot of participants currently. And so that shouldn't discourage people from trying to take, you know, collaborate in those settings and recruit patients from the settings. But we do want to emphasize that the focus is implementation. And so make sure that, you know, if you're initiating a collaboration in one of these kind of more novel areas that you tie it to implementation. I mean, I think with that said, we don't want to discount the value of learning more about the genomic diversity. Yeah. You know, that is clearly an added benefit as well. And so that is something to speak about. I like what you said, Dave, about sort of going beyond sort of the checkbox diversity approach. So other questions? So we're scrolling through all the questions that we've gotten submitted via the WebEx. I think we've gotten through all of them. If the questions flow down from the group that's called in, I think what we'll do is the NIH staff will stay dialed in for another five minutes or so in case people haven't to think of questions. If you do have questions or thoughts, please share them. OK, thank you. Thank you very much. OK, one more question. About the the definition of diversity, to establish diversity does self identification as a specific race, ethnic, etc. group count. So can any way to make that bigger, Christine? So I do want to point out in the RFA, we have a definition section, which is highlighted here in yellow. And we do have a very specific definition of diversity. And I want to point out this is extremely relevant for those of you who are applying for clinical sites, because the 25 percent and 60 percent minimum thresholds for recruiting diverse participants will be evaluated in relation to this definition. So you can see here that those patients can be defined according to racial or ethnic minority populations under served populations, which relates to the definition immediately below this one, or populations who experience poor medical outcomes. So just keep in mind, you will have some number of patients that you're planning to recruit for Cesar to either 25 percent or 60 percent of those participants, depending on which RFA you're applying for, need to meet this definition. So there's been some general questions about the relative emphasis of cancer versus non cancer or the number of cancer applications that we would expect. And we're not coming into this with any quotas or specific expectations for different disease types. We will, of course, take into consideration programmatic balance. We don't want to wind up with all of the sites focused on the same type of disease or broad category of disease. But I don't think that the only reason we would potentially be considering cancer differently than we might consider cardiovascular disease as a group or infectious disease as a group or whatever disease group you want to choose is because we are partnering with NCI. And so that opportunity of cofunding does give, you know, as opportunity to consider bringing NCI in as collaboration. But the NCI cofunding is not 100% directly tied to the number of applications we would fund. And it will be dependent on what quality of applications we get and the diversity of different disease types that wind up being submitted and reviewed and hitting the other programmatic criteria. Okay. I think there's a request for clarification. Can we rely on participant self-identification as Hispanic, AA, et cetera. There are other approaches. I think that's allowable. I think, yeah, we recognize there are different approaches. Yeah, again, I mean, I think, you know, recognizing the limits of self-identification and, you know, the need for for care in the way that you ask those questions. But Okay, we're slowing down with questions here. So maybe this would be a good time to point out that we are requesting letter of letters of intent by July 5th. These are not obligatory, but it does help us plan for the review. So please consider sending one in if you plan to develop an application for any of the RFAs. And then the application due dates will be August 5th, 2016 by 5 p.m. local time of the applicant organization. We do have a separate application due date for AIDS applications. If you are planning on submitting an AIDS application, please contact me offline so that we can discuss your application and that AIDS due date will be September 7th. Okay, so I think unless we get questions in another minute or so, we will start winding down the call and get ready to sign off here. Last call for questions. Okay, I think we'll wind down the webinar. Thank you to everybody who dialed in. We're very much looking forward to hearing and seeing the idea is that the community comes up with. We're all very excited about Caesar 2 here and we hope that you are too. Thanks again and feel free to reach out with additional questions and we'll update the FAQ. Okay, thanks everybody for joining. Bye.