 Okay. Why don't we reconvene? We're not going to move to two concept clearances, both of which were discussed initially, the last council meeting deferred to today's council meeting. A lot of activity has taken place for both, including conference calls, lots of conversations, and we're going to start off with Anastasia Wise presenting the concept clearance on genomic sequencing and newborn screening disorders. Okay. So I'd like to start off just by welcoming our guests from NICHD who are with us today, Tina Irv and Melissa Parisi who are sitting in the back there. So if you have any questions about some of this, I might also refer to them at points. So as you may remember, we presented in February a concept clearance for newborn sequencing with a U-19 award mechanism. The goal of this initiative would be to stimulate research in three coordinated areas applicable to newborn screening related to acquiring and analyzing a genomic dataset, performing clinical research to advance understanding of disorders identified via newborn screening, and then related research in regarding ethical, legal, and social implications of possibly implementing this type of broad DNA-based screening in newborns. And this initiative would be funded jointly by both NHGRI and NICHD who would each be committing 2.5 million per year for a total of five years. At February council, we presented two related proposals for concept clearance. The first of these was an SBIR STTR award which was approved, and then the second concept was this U-19 award which was deferred to this council session. And to give you just a little bit of background, this has been a long process that we've been going through working with NICHD developing this concept over a number of years. This actually started at a workshop in 2010 discussing newborn screening in the genomic era and setting a research agenda that was sponsored jointly by NICHD, NHGRI, and the Office of Drug Disease Research. I followed this up with a concept clearance at NICHD's council in January as well as the presentation here in February where, though we heard in general from council that there was a lot of approval of this as a good idea in general, it seemed like everyone kind of had a little bit of a different picture as to how this initiative should be structured. We heard a number of concerns from council and we've tried to group them into five main categories. The first of these was that we needed to really focus on a clear scientific rationale for what we expect to learn from this initiative. The second major council concern was related to the population selection and that we should consider the added scientific value of broadening the study population beyond the confirmed positive newborn screen individuals. We also heard from council that the 500 gene targeted sequencing didn't seem to be enough of an advance as well as a couple of more LC-related concerns. The first of which was related more to the population selection and overall study design and the second dealing with public perception, public relations and how we would be doing the consent for the subjects. We continued this process with a series of phone calls and discussions over email with our council subgroup. We then revised the concept and sent that out to our council subgroup in April. Through a series of further revisions both with our council subgroup as well as NICHD, we have come up with a new final concept clearance to present to you again here in May and made a number of changes based on both the feedback from our council as well as staff at NICHD and NHGRI. The first concern that council had raised related to the scientific rationale for this initiative, we've identified three research questions for these applications to focus on. Applicants would be allowed to select one or more of these research questions for their research, but this would then provide a little bit more focus to the initiative. The first of these questions is for disorders currently screened for newborns, how can genomic sequencing replicate or augment known newborn screening results? The second question is what knowledge about conditions not currently screened for newborns could genomic sequencing of newborns provide? And the third question is what additional clinical information could be learned from genomic sequencing relevant to the clinical care of newborns? So this covers a couple of the different areas that we heard brought up both by staff and council members related to looking at both the technology side of what can at doing genomic sequencing add to newborn screening as well as additional knowledge related to more of the clinical conditions themselves. Related to some of the other council concerns, we've decided to broaden the initiative to include both positive and negative screen individuals, so any individuals that have no newborn screening results. We've also removed the 500 gene targeted sequencing and are requiring either whole exome or whole genome sequencing. We've asked the applicants to tailor their research to the context of the sequencing and the research questions that they are looking to answer. And so this really relates to if you're looking at individuals that had a known disorder and already had tested positive from newborn screening, you might be asking different questions related to your LC research as well as returning different results than if you were looking at individuals that had screened negative and potentially a condition that isn't currently screened for in newborns. And we also requiring a description of both the informed consent process and how the applicants would return their results within the applications themselves. And with that, I would like to thank all of the groups here at NHGRI that have been working on this newborn initiative as well as the folks at NICHD who have helped to develop this joint project. And that will take any questions. Sorry, go back to on the slides. I just on the ones where you have A, B and C. To the questions. Yeah, those. So again, I'm just trying to understand this. And I think so when you when you talk about screening a newborn now, maybe he's born, the screening is done when there's a problem or is all newborns are screened. Okay. So then you would be sequent. And so now you're the discussion about not doing targeted, but doing whole X summer, whole genome, you would sequence or at least these would be research projects that then sequence newborns, regardless of phenotype. And it, right, whether there's a problem or not. So the applicants could propose a research project that was related to a specific phenotype, or they could propose to look at individuals that didn't screen positive for one of the no newborn screening phenotypes. And that could be that there's another phenotype that's very relevant to newborns that they are interested in looking at, or it could be individuals that are expressing a phenotype at that point that they want to learn more about. Okay. Okay. I see. Yes. I just had one question. It as the concept clearance reads in what was distributed, I think very appropriately the LC component is put forth as a necessary component. I just want to make sure everybody knew that in your presentation, it's not as clear that my own feelings are that it's not at all clear whether newborn screening using whole genome sequencing will actually be useful. But that's what we're going to ask the community to come up with ideas about. I do think it's such a special population and such a vulnerable population that the RFA itself needs to make very clear that that needs to be a prominent component of any. Yes. All of the applications would be required to do research in all three of those component areas, the genomic sequencing, the clinical research as well as the LC research. And then these questions are more to focus the different types of research projects. Correct me if I'm wrong, but I think we will use similar language that we used for the CSER program, where it was pretty clear that in fact that you didn't do well in all three or all the areas that's good, because I could see that as a primary research question, right? The LC issues and that doesn't come across as much. And I just think that's really. Wait, are you saying that that you might have grants where they have only that component? No, they have to have all three components, all applications. Okay, so one way to avoid people tacking that on as a paragraph at the end of their grant, which they certainly used to do, I don't know if it happens as much, is would be to put it as the first thing that they talk about, because if you think about it, when you're, if you're going to do this, you better have that figured out before you even start. So maybe make that more critical by putting it up front. That's a good suggestion. Although I could see the value in new board screening for Mendelian disorders with high penitence, I think I have some concerns about when you're going to find variants, especially in whole exome that give rise to conditions where the outcome is not certain. So they could increase risk for learning disabilities or autism, for example, and you stigmatize that child and think about early interventions. And I think some work needs to be done on the LC side and also the clinical side to understand the balance between wanting to do an early intervention, which may help a child versus the ethical issues related to stigmatizing a child who may be perfectly, have a perfectly normal outcome, because it's only a risk, not a certainty. And I think that's part of the reason why we really wanted the researchers to choreograph their LC research and their clinical research as well as what results they're returning based on what research question they're asking and the particular tailor that that research to that question itself, because depending upon what phenotype they're looking at, what results they return may be different and what's appropriate may be different depending upon what questions they're asking. Is that a concern of yours or you're raising this as an important area that might be investigated by an application? Since it is a concern, it should be investigated. The problem is you don't know the outcome for many years. So you almost have to do longitudinal studies to really understand and understand talking to parents, whether they want, how do they balance their child being stigmatized versus having an early intervention, which might help them? The problem is those kind of studies you're going to take, they're not something you can do in a short period of time. Rick, I'm not sure we figured that out for Mendelian very well, right? I mean, we need, even, I'm saying it's even, it's even hard on the simpler ones in the sense that for an adult onset disease like Huntington's, I just, you know, even way back when you don't, I mean, do you want to do that and know that information when there's not much you can do about it and then the stigmatizing. In some of these cases, there are things you can do. There are interventions which can help and you're going to find these things more frequently because they're common disorders. So what I would say, Tony, in my own opinion is that this concept clearance would hopefully attract applications and research proposals that would start to look at whether we'd have to evaluate whether they would be too long term. I mean, I think there's a lot of details we worked out, but what you led with, I completely agree with, are some of the LC issues associated with it, which one of the things I think we as an institute would uniquely bring, and I think Child Health would echo that as the partnership of having sort of a cadre of researchers in the LC community that we have fostered, that getting them involved in some of this and partnered with Child Health where they bring this incredible expertise around newborn screening more broadly, that I think is sort of the kind of uniqueness we saw with this partnership that made us enthusiastic. Pearl? Is there any way of partnering with the return of research results initiative, which is looking at pediatrics, you know, pediatric emerge, et cetera? I mean, it just seems like that might offer some additional... We would really like to have these groups meet together and discuss those issues, yes. Anyone else on council? Child Health folks, since you're here, is there anything you want to add to this? Because I know you're fine. Good. All right. I just wanted to make sure we'd like to give you a chance if you want to say anything. So we require a vote for this. I'm looking for a motion. Move approval. Is there a second? Second. Any additional discussion? If not, all in favor? Opposed? Abstentions? A couple of abstentions. Okay. Several abstentions. All right. Thank you. Thank you and a thank you.