 Okay. So on the ICESR, which stands for Investigator-Initiated Clinical Sequencing Research, which we're proposing as a program announcement with Set-Aside. So the motivation for ICESR is to follow up preliminary and intriguing CESR findings and settings that have a conceptual link to CESR, too, that are best done independently. This, as Council will recognize, is a timely and straightforward way to stimulate investigator-initiated research in genomic medicine and bring into the NHGRI tent maybe some different researchers that we haven't seen yet in the consortia research. ICESR research would focus on investigator-initiated questions and approaches by definition. However, we might expect that the research would fall under one of three broad aims. First, to understand whether and how clinical sequencing impacts disease diagnosis or treatment. Second, to integrate and analyze multiple data types to improve use of genomic information in clinical care. And then third, to investigate function of variants from CESR or CESR, too. So this conceptual link to CESR really results in examples of research topics that could be proposed, and I will mention that these are just examples I think we'd want to let investigators come forward with their best ideas as well, but just to walk you through some potential examples. Under studies that help us better understand the impact of clinical sequencing on disease diagnosis and treatment. Disease could be those that investigate diseases with a high diagnostic yield. So as you saw in Dan's presentation, CESR investigators report a wide range of diagnostic yields and studying those that are associated with a high diagnostic yield might help us understand better why and how clinical sequencing has been more successful in those diseases. Or another example might be examining factors influencing the phenotypic spectrum. For example, subtle findings may have been initially overlooked in the initial clinical sequencing study. For the second broad aim, integrating and analyzing multiple data types, those could include computational and health economic approaches to identify diseases that are likely to benefit from clinical sequencing or integrating other data types such as family history, environmental or other omics data to improve clinical validity. Under investigation of function of CESR two variants, studies might include the annotation of existing functional data to improve interpretation in the clinical workflow or elucidating function of variants identified in CESR or CESR two. We spent a little bit of time talking about the distinctions between investigator-initiated and CESR two, so I'd like to talk a little bit about that. So compared to CESR two, we envisioned that ICESR would involve smaller, responsive and more flexible research settings. In studying targeted projects relevant to clinical sequencing, we would expect investigators to be able to describe their relevance beyond the specific genes or diseases proposed. Such research would not require substantial infrastructure and the consortium-wide approaches that would be needed for CESR two. In fact, we would expect the ICESR to operate largely independently of the CESR two investigators and their institutions. We are proposing that ICESR grantees meet once a year amongst themselves. The attendance of the CESR two meetings would not be required, but they would be invited to come. And compared to CESR two, the ICESR would not focus as much on LC as those topics are supported by an existing and separate program announcement. So the ICESR is proposed as a program announcement with set-aside using the RL1 mechanism. We envision a one-time PIS timed with the CESR two concepts. Each award would be encouraged to come in with up to a 300K direct cost limit. This is the size of an average RL1 for up to a four-year project period. Up to six awards are proposed for funding with review done by the Center for Scientific Review. We're also talking with SBIR staff at NHGRI to see if we might be able to coordinate with their program announcement with review or PAR. This is the small business grant mechanism for which we have already an existing set-aside and we could also leverage the same panel as the existing RL1s. So this was a shorter presentation because we wanted to give you sort of the broad strokes of what we envisioned as aims. The investigator-initiated ideas would obviously come forward as investigator-proposed ones. But we did want to point out then in discussing how best to implement the stimulating R-Investigator-Initiated portfolio. We had an active discussion among staff and there were a number of alternative options we could have pursued. So we would appreciate your feedback on things like the scope of the suggested topic areas, the relationship to CESR and CESR II. We've proposed this as a PAS that's specific CESR II, but I know a couple of you have already raised the possibility of having a broader genomic medicine, funding opportunity, comments on logistical aspects such as single versus multiple receipt dates or the size and the length of the grants would be welcome. Carol raised the idea of having planning grants for investigators to have kind of a smaller limited time to plan for potentially larger efforts afterwards. So I think that might fit well here with ICESR. And then as I mentioned, the small business mechanisms is one area that does not actually require a formal council vote, but which we felt was very easy to coordinate with our existing efforts. So we have the same four discussants, Lucila, Shanita, Dan, and Bob. So why don't we start with Lucila? Yes, I guess I advanced my comment before. I think from the questions that you raised here, it seems to me that the size is a little bit on the small side, that it could be bigger even if it's at the expense of funding one less on the CISR-2. You're talking about the 300,000 caps? Yes, 300,000 seems small because depending on what you're going to do, this thing might get more expensive. And again, reiterating what I said before, I think it should be the broader genomic medicine instead of a linked CISR-2 necessarily. Thank you. Shanita? I think it's important to include the option for it to be a planning grant because I think that there are institutions that have nascent programs that could use this mechanism to develop the plan for larger applications. I think that's really important. But overall, I'm enthusiastic about it. Thank you. Well, I think I really said what I thought before, so I won't repeat it to say that. Well, maybe I'll just say that we're at the point now in this field where there are lots and lots and lots of good ideas. And I don't have a strong feeling about whether this should be ICSR or a much broader program announcement. That's not me. If it's ICSR, then the advice to staff would be to keep a very, very close eye on the kinds of applications that you get. And if it turns out you get lots and lots and lots of wonderful applications, then that would accelerate the pathway towards a much broader program. And it's possible. Great. And Bob? The only thing that I'd like to just affirm that having an ability for people who are not necessarily in the field to bring in their ideas but with those ideas somehow fused with or at least interacting with that of the current CSR so that we get new ideas without them being completely unlinked from the overall program objectives. But I would love to see new ideas of people that we don't know about or things that people haven't thought about because as my neighbor said so, clearly the best idea they're not necessarily going to be coming from the people sitting around this table. Other council members? Yeah, so I concur that I would go with fewer awards and more funds per award. I think that's a really important suggestion that just came in. And I also like having the PAB broader genomic medicine but making sure that these investigators are included in CSR. So I don't know if that changes what you call it or just make it clear in the ICSR announcement this is really to be broad, but I really do think it's important to have investigators funded under this be integrated somehow into these other initiatives. I think that's key. Yeah, so I do want to comment that I don't think one precludes the other. This was our way of kind of envisioning getting some investigator initiated research funded quickly. We could imagine a companion one later on. So it wouldn't be necessary and usually exclusive but I think that's good feedback. And planning grants don't need to be as much, right? If planning grants actually gets folded into this, you would want a different cap, I think, for planning grants versus R01 style grants. Yeah, just real briefly, I just wanted to make sure if this goes through and the program announcement goes out for the ICSR, I would just take great pains to try to specify that these are examples, right? Because I think that if we do, which I'm very much in favor of, if we want to harness the brilliance of the community, because like Bob says, we don't know enough. We have to make sure they don't feel constrained to submit something that they think needs to be pounded into this. So, Les Val, I think I'm arguing a different point. I'm completely supportive of the investigator initiated approach. And so it's not a question of whether to do something along those lines. It's whether the expectations are aligned here. It just seems to me as I read the objectives here is to Dan's point. These could be CSER or any clinical genomics program. They don't really seem to align to CSER. That may be fine, but that is how it reads. And people could easily go off and develop methods that don't capture the richness of the patient-centered approach to CSER. It just seems to me that that's whether it's eMERGE, CSER, or something else. And I think you were going the same place. And again, it may be fine. That's point one. Function slipped into this. And we haven't talked about function in the context of CSER. And so I'm wondering where that's coming from. I think it comes from a number of discussions. We've had not just as part of CSER, but it's evident that from CSER there have been a number of pathogenic or variants of uncertain certificates that could be followed up for function perhaps as they relate to therapies or other diagnostic implications for patients. Is that what you mean? I completely agree with that. But we're straying from CSER, right? So we're broad-minded. Where's the tie into CSER? We're not going to initiate wars in general for clinical genomics, which is fine, but it's not CSER. That's true. I think what the tie into CSER was the identifying function of variants identified in CSER. So I just concluded that. Isn't the solution to this, sorry, isn't one way of thinking about this is to make sure that the language in the RFA clearly ties this particular part of the genomic medicine portfolio to CSER and its overall goals in the CSER program. And that's not to preclude other investigator-initiated grants under other mechanisms. And I'm not sure where those other mechanisms are and how well-funded they are. So I think that, yeah, you do run a risk if you're starting to propose, you know, a wide-scale mutagenesis in zebrafish to just try to decide whether, you know, variants that you've identified are functional. That's probably not part of this program. Yeah, I think it's a very important initiative, but it's probably not part of this program. So I think the answer is just to write the RFA in a way that would sort of allow you to say, well, this particular activity is CSER and it's offshoots. And in order to qualify, you have to meet these kind of criteria. And I hate to say that staff should decide whether something is responsive or not, or the study section should decide if something is responsive or not. But there is this element of responsiveness and somebody comes out of the left field. It's clearly unrelated. I guess you could use that as an answer. But it depends on the language. Yeah, so I think you're hearing different recommendations because mine was to actually make it less CSER and you are to make it more CSER. Well, I think whatever it is has to be explicit. I think that's my recommendation. If we decide that we want to have a broad program in genomic medicine, you know, RFA, that's not the discussion we're having, but if that were the way we would do it, then the RFA should say this is a broad program that will entertain zebrafish mutagenesis and individual patients and what have you. And then you can write it the way you want to. It's still clinical sequence, so it will be more human-based anyways. But I think just making it too specific to CSER kind of limits and you might not even get enough good applications. The other way you can have both. Maybe I could just comment. The discussion that you're having is a discussion that was mirrored within the staff and we went around a lot about should this be a general program for investigator-initiated research in genomic medicine or should it be more specific. This is the first one of its kind that we have done and we really need to get some experience with it, I think, before we go much more broad. And so this was an opportunity to really try to say, gee, there are some, you know, clear things that have been identified here that could be followed up or pursued or expanded abroad in investigator-initiated research. That's where the function came from and we hear you that that's not as much clinical sequencing and so we have lots of programs that are exploring function, we can take that out. But I think it would be very helpful to us to sort of dip our toe in this water first and see what we get for something that is a little more related to one of our specific programs and then see how that comes out. If we get nothing, you know, that'll be an answer for us as well and we can go broader than on the next one. We wouldn't have an eye-emerge and an eye-ignite and, you know, eye-separate ones. But I think we do need to try one that's a little bit on the small side just to see what we get. So that's sort of where we've come down. So I'm just thinking off the top of my head here that's hadn't occurred to me until this discussion. I think it is too narrow to have one of the aims, the investigations of function-initiated pathogenic filming variants that are unified in those. But I do think that given the magnitude of the problem of how to determine variants and whether they're deleterious or they're pathogenic, one could just broaden that to say investigation of the pathogenicity of the U.S. Something along those lines, because that is a central challenge if not a central challenge for genomic medicine and it would be, you know, people might come up with approaches that look at these variants that don't just rely on function. We wouldn't want them. Could I get comments about eligibility requirements? Should this be wide open? Anyone on the slide? To restricting it in any way. Should we have CSER funded investigators apply to this as well? I understand that. I wanted to counsel the comment on it because we hadn't heard anything about that. Could I hear something? The whole intent. I think everybody from all 49 states except North Carolina should be allowed to apply. Well, you know, he started. No, I think the whole intent is to broaden the page. I'm not hearing the answer to your question. So can we ask, counsel, because programmatic balance is something that we always do consider, are you comfortable with if we had, you know, 12 applications from some unnamed university in North Carolina, that we might not fund all of them. And we usually put some, you know, issue of balance or geographic dispersion. Intake would be wide open. Especially for this program. I mean, despite what Jim might say, it's not totally representative of all 50 states. Don't you think CSER investigators are going to have a distinct advantage in the review process? So would you propose a mechanism that if you have a CSER site, actually, but you won't have a CSER site because you're still competing for the CSER 2. So you won't even know if you're a CSER site. So what we have done in the UDN and other programs is to say you can't be awarded for more than one RFA. So one institution would not have a general site and a diverse site. One institution wouldn't have one. So the UDN was set up so that it couldn't have the same PI, but multiple sites could be awarded to the same institution. So one way of trying to ensure this is wide open, which I think we all agree, it should be. In three, and I had suggested broadening it to investigating determination of pathogenicity. You don't have to say identified in CSER and CSER 2. We've got public databases and we've got variants. There's ClinGen out there. There's all kinds of people doing stuff outside of CSER and CSER 2. It sure doesn't have to be within CSER 2. So I feel like I don't understand what the feedback was on the last point. I feel like a discussion, I'm going to say I'm going to ask explicitly, do people think we should restrict either at the investigator level or the institution level who can get more than one of these awards both across the three CSER RFAs and also considering this investigator initiated thing? Do people have strong opinions on that? I was in favor of restricting. I think we talked about that before and I still believe that we should be trying to encourage people to apply who are not part of large CSER consortium just as long as they will meet with them if awarded and that will have some interaction. Wait to clarify Bob, you mean restricting by excluding them. In other words, if they get an award for one of the main CSER, they are excluded from getting an I CSER award. I disagree. I think it should be everyone. And then the reviewer should be told just select what's best. Then you do your programmatic afterwards, but I don't think it should be restricted, especially by institution. It could be someone else. Yeah, I guess this is getting complicated. I think we all agree it should be wide open for people to be able to apply, but I think we could run into real trouble if we don't exclude awards. You might end up with one institution with like four of these, which would be kind of crazy. Jim, that discussion is kind of premature. Who's getting in the doors? Two different opinions, which is fine. Anybody else want to offer? It seems reasonable to me to exclude the CSER people, because they already have funding in this general area and presumably a big advantage, but it seems to me a mistake to exclude other people from the same institution from applying. You know who has a CSER award before you decide the law comes at the same time. I think from a perception point of view, I think if you don't say that you can only get one of these RFAs, then the people that you probably want to try to get one of the investigator awards are going to say, you know what, I'm not going to have a chance for this. This is all going to go to the people that are already embedded in this program. So, I mean, that's an unfortunate reality. Ideally it should be open to everybody, and it's the best ideas when I agree that's the most wonderful ideal way to do it, but I think you're going to discourage people. I agree with everything Bob says. Bob, anything else? How do you like Tchaikovsky versus Shostakovich? So, I think there was language in the recent encode RFAs that, because there were five that went out. It said something to the effect of anyone can apply, but funding will take into account whether PIs would be funded under other RFAs. So, it's not necessarily excluding people from getting funded, but it's sort of leaving that opening that it's not, they don't have a necessary advantage. But in this case, I mean, we already said we're not going to let the same PI get grants from more than one, but here the uncomfortableness had to do with institutions. So, I guess the language then would be anybody can apply, but we will be looking for institutional diversity. Not institutional diversity. Well, then we would just, then that's fine. Then we just adjudicated when it comes in. I'm wondering about the size of these things. Where did you come up with the 300K cap? That was the average cost of an NIH grant. We felt that was a reasonable one. What would you suggest? I'm just wondering if you took into account how many patients you could sequence with this or things like that. No. The expectation isn't necessarily that they would be doing a large amount of sequencing in these grants. They could be doing a whole host of things, building on that kind of research being done in the fall season. Mark wasn't the only one that was concerned about the size of these grants. What was your concern? My concern is if the intent is to get a whole lot of people to apply, then you have to have a good reason to go for it. And sometimes it will cost more than 300. We know that. I think by the same rationale, you would be limiting the people who will apply or the kind of ideas that will come up. Actually, I wanted also to clarify. I wasn't saying we should have fewer than this. I think we should have more R01. We could have one less of the season itself to make up for those. I would agree that imposing a 300k cap seems low. You could sort of indicate that the target mean is around 300, but I think giving people flexibility is good. That's a relatively modest size grant. I agree with that, especially with regard to how expensive it is to interface with clinical facilities. I thought Jonathan's comment was you could say that we expect the median to be at x, but it would accept proposals of... What's the current cap? Is it the current cap of 500? Yeah, so why not just... Over 500, they have to get programmed. I know, I know. Understandable. I think we've got a good discussion. We've heard diversity of opinion and staff will take that under advisement, but it's time to vote. So can I get a motion to accept? In a second. All in favor? Any opposed? Any abstentions? Thank you very much. I just make a comment that I think this will be embarrassing. I think we'll see it did a really good job. The pre-counsel meeting is very well prepared, very clearly written, compared to some of the previous exposure.