 Okay, so now we thought we would take the last part of our program this morning, as I mentioned earlier, to highlight a few of the initiatives that NHGRI has supported that are in the implementation science space. And as we mentioned yesterday, a lot of our discussion was devoid of young kids and even younger kids. So Anastasia is going to talk about the newborn sequencing program. Great. So first off, I'd like to thank the organizers for having come down today to talk to you about this program. And I'm going to talk to you about just a single NIH program that's a joint initiative between two institutes at the NIH. So this is a program that's been started recently between the Unistriver National Institute of Child Health and Human Development and NHGRI, the Human Genomics Institute. And so what I'm going to do is talk to you rather than focusing on the specific grants themselves, but a little bit about the process of starting this genomic medicine project and some of the challenges that we've faced while developing the initiative. So as many of you are aware, the cost of sequencing has been dropping very rapidly, and this has allowed us to start considering using sequencing in a clinical context, as the cost of sequencing is now starting to be very close or similar to the cost of doing individualized genetic tests. In the United States, the newborn screening public health program captures most of the population. Over 99 percent of infants are tested and screened as part of the newborn screening program in the United States. This is their first testing that's done, and it's the most common genetic testing that's conducted in the United States. However, most newborn screening testing is not done using DNA or any form of sequencing. However, what we've learned from the community is that this might be one of the first groups that would really be interested in applying sequencing in more of a clinical context, and it could potentially reach a large number of the U.S. population. So to begin looking into this, we held a workshop back in December of 2010, this workshop, Newborn Screening in the Genomic Era, setting a research agenda. And there's more information that can be found online about this workshop that we held. And what we really heard at this workshop was a call to do pilot studies, to look more into what sequencing could add both to newborn screening as a public health program as well as newborn screening more in a genomic medicine context. So the first thing we really heard from the members who were present during this conference was that we needed to look at the public health context and could sequencing provide the same type of data that these biochemical tests that are currently being done provide, as well as if we did sequencing in newborns, could this information be used throughout their lifetime for genomic medicine and care throughout their life? There were a number of questions that were raised about needing to explore the ethical, legal, and social implications of this type of research, especially since we were talking about newborns and providing their sequence information and potentially using it for their care throughout a lifetime where they wouldn't necessarily be the ones who were then consenting at birth for the sequencing to occur. There was also a lot of questions about the clinical validity and utility of this data and that we needed to focus at least at first on some higher risk individuals, such as infants that were in the neonatal intensive care unit or NICU, and incorporate the longitudinal data so follow some of these individuals over time and see how the information could be used in their care. We took this information and started putting together some ideas for what this initiative could look like between our two institutes and presented this to our councils at both NICHD and NHGRI. These councils serve as advisory boards for us to be able to present information and to be able to provide feedback and recommendations for new initiatives that we're developing. Some of the concerns that we heard from both of our councils was that they had some real ELSI concerns about the ethical, legal, and social implications of this research. They wanted to really think about the populations that we were selecting, whether these were going to be healthy or sick newborns, and the study designs they thought should really be based upon what that population was. There was also some concern about public perception and public relations, because at this point in time there had been some highly publicized articles that had come out about newborn blood spots being used in research and the need to be able to consent parents when those blood spots were taken for doing newborn screening for research use, if they were going to be used in that context later on. So we really heard from our advisors that if we were going to develop this type of initiative, we either needed to collect samples that were different from the newborn screening sample and have them be specifically consented prospectively for this sequencing study, or that the samples that were being used that were from the newborn screening program needed to be specifically consented for research use. So as we started putting together this initiative, this is the general purpose that we came up with, which is to explore in a limited but deliberate manner, which really captures that pilot project idea, the opportunities to use genomic information for broadening our understanding of diseases identified in the newborn period. This is intentionally a very broad mandate and a purpose, and that was intended to be able to cover both the public health setting as well as the more genomic medicine context, so that the researchers would really be able to look at questions that related to both of these issues. We also laid out for the researchers three questions that the grants had to address. They had to address at least one of these three questions in their research proposal. The first of these questions was to look at disorders that are currently screened for in the newborn screening program and determine whether or not genomic sequencing could replicate or augment those results and be used in the newborn screening context. The second of these questions was to look at what knowledge we could gain for conditions that are not currently screened for in the United States as part of the newborn screening program and see what genomic sequencing could add to other conditions that might be relevant to the newborn period. Then the third question was what general additional clinical information could be learned from doing genomic sequencing in the newborn period that could be applied to clinical care. We also required that each of the applicants perform three different components to their research studies. The first of these was they had to have a sequencing component. The second was they need to perform some sort of clinical research addressing one of those three questions. And then we really wanted the ELSI ethical, legal and social implications research to be integrated as a part of these projects. And so each of the research projects also has to have an ELSI component that's related to the clinical research that they're doing and really looking at the social and ethical implications of this research work. Since there had been some concern as well about how this was going to be received by the public, when we put out the announcement for the four awards that we made in September of 2013, we also did a telebriefing and press release in order to be able to bring a group of press officers together and really explain to them what our thoughts were behind the program, what it was we were trying to address, and a little bit of information about each of the four grantees that we were awarding. And this really did help with the press that came out from the announcement. As you can see, a number of these headlines came out very positive, NIH studies explore promise of sequencing baby's genomes, researchers study the value of DNA analysis in screening newborns. And some of them still came down to that question of, is this good medicine or too much information? What happens if you screen all of a baby's genes? So we think we were able to then capture a lot of what the program was intended to study, which is really how can sequence information add to the care of newborns, both in this more public health and genomic medicine context. As we move forward with the program, now that we've made these awards, there have been additional other challenges that have come up. We found that we've received some questions from the FDA and we are looking into the need for investigational device exemptions for these research projects because they are using sequencers that have only so far been approved for use in a research context and potentially using that information for clinical care. The FDA has looked at this from the perspective that even if we are doing the sequencing in a CLIA or CAP-certified facility that that's really certifying the process and they're very interested in whether or not the actual device itself. And that includes the entire pipeline from processing the initial samples through the sequencing on the machine to the analysis pipeline itself, whether or not that has been approved by the FDA as a diagnostic test. And they've had some concern over both the sequence data being returned for clinical use as well as the data being placed in electronic medical records for future care. So not just have the results been Sanger validated for being used immediately for these newborns, but how is this data going to be used in the future? So we are working currently with our grantees as well as the FDA to be able to address these questions, but I think this really shows how even as we start looking into these areas and putting forward these new initiatives, it's a changing regulatory landscape and we're hoping that what we learned from these first initial four ways into newborn sequencing can teach us something about genomic medicine initiatives for the future. And with that, I would like to thank all of our supporters, both at NHGRI and NICHD, especially Tina Erve, who is the program director at NICHD, my counterpart there, and ask if you have any questions. Thanks. Great. Questions, Mark. Mark, I'm from Winston, Brussels. Thank you very much. This opens fantastic perspectives, but I also have a few concerns about, if you take, for example, those disorders for which we already screen using the phenotype. That means knowing what is happening in the baby. If you shift to the genotyping, what are you going to do with all the variants of unknown clinical significance? Are we ready to handle these? And that's one of the questions that these grants are really looking to address. So, for example, one of the projects is actually specifically looking at, like, sensitivity and specificity of the genomic sequencing results and trying to see can we get results that are equivalent to what was being done with more of those biochemical, phenotypic tests that are currently being used for newborn screening? And can we replicate that same kind of information? Is it really producing the same type of information, or is this more of an additional type of information that could be useful in some context, but not necessarily in others? And if I may have a second question. Do you, about the same issues of neonatal testing for those conditions which you can act upon, what are the really new ethical, legal, and social issues? And you might argue that testing for MSUD, using biochemical testing, has exactly the same questions. What do you see as new questions in that range, the A column that you mentioned on your slide? So you're asking what are the new issues with testing newborns beyond what was already a concern with doing the newborn screening testing? So part, one of the ethical issues that came up with this initiative was the fact that we were looking not only at testing sick infants, but also healthy infants. And whereas screening is looked at as being part of the public health paradigm, where these are conditions that you really know how you're going to act on them. And because of that, doing that screening can be justified. If you move to doing sequencing, that we don't necessarily know how to act on all of that information. So there was some concern about the ethics then of returning that information to the parents if we aren't necessarily as certain of the information from the sequencing as we are for the standards that a screening test would have to meet. And so that's another question that some of these studies are looking at. So if you discovered one of these cancer-causing genes in these newborns, what would you do? So the studies are looking at that in different ways. We did not lay out for the grantees what results they needed to return or how to handle return of results. And that's actually a question that they're looking into. So for example, one of the studies is looking at returning medically actionable results that are medically actionable in the newborn period and then asking the parents about whether or not they would like to receive other types of information in different bins or categories of information and trying to study what is it that people really want to see and is that useful both to the parents as well as the clinicians? But you have guidelines at the moment published guidelines that you should inform the... In the clinical setting, not in the research setting. Yeah, that's in the clinical setting, yeah. Correct. Yeah, so again, just to clarify that point, the ACMG guidelines do not, they do indicate return for children if sequencing is done in children but they are only for clinical application of exomegene sequencing and they are specifically excluded from research for the very purpose of trying to answer some of the questions that are being raised by this. I wanted to come back to the point that Mark Abramowitz raised and even though the focus of this medicine, of this meeting is genomic medicine, I think it's really important to not get tunnel vision relating to the fact that ultimately precision medicine will take advantage of any and all information that bears on the problem. There is never a situation, in my opinion, where you would sequence the phenylalanine hydroxylase gene and impute the phenylalanine level based on the sequence. You will measure the phenylalanine level. And so we have to understand the fact that there, while we're focused on genomic medicine, there's a whole range of other things that are going to be important in terms of improving care. And in some cases, it's going to be the combination of these other things with the genomic information that is gonna give us the best results. And so I think it's really important for us to have a focus on genomic medicine, but to understand that it's not the be all and end all. Thanks Mark. I think that's actually a very important point and that is something that we tried to make sure we were cognizant of when we were laying out these questions and that we were talking about sequencing as augmenting or adding information to what's currently learned when you do these types of newborn screening programs rather than necessarily replacing the existing tests. Clarifying question. So in the projects that are currently funded are the traditional newborn screening data being combined with the sequencing data or I mean across the board? So all of the newborns will receive traditional standard newborn screening testing. And then the way that the different studies are looking at it, some of them are then doing sequencing on a subset of those individuals. Some of them are looking at a NICU neonatal intensive care unit setting. Some of them are looking at healthy infants. Some of them are specifically looking at infants that tested positive on some of those newborn screening tests. They're looking at a variety of different populations from there. What exactly is the FDA concerned about with respect to data being associated with a record? So the FDA was concerned that it posed potentially a significant risk which would necessitate an investigational device exemption if we were doing sequencing as part of a research project and then putting that information into a medical record where it could be queried later for other conditions that might come up during the child's lifetime. They were particularly concerned with if any of that information went into a medical record that had come off of a sequencer that was not yet FDA approved, that you needed some sort of investigational device exemption that would then look at the risk of that particular situation and address those concerns with the device itself. So they're banning you storing the information? No, they weren't saying that they were banning us storing the information. They were just saying that because these devices are not approved for clinical use that if you were doing the sequencing on a research machine, even if you were doing it in a CLIA setting that you needed an investigational device exemption in order to be able to put that data other places. This is one of the first cases where they've come to us and just to discuss this. This looks like a breach. You don't ask me. So I, you know, we have one of the grants and I think that the challenge they're concerned with is if we were to take a whole genome sequence or a whole exome and deposit all of the raw data or even the variant call file into the medical record in anticipation of using it later without doing what we normally do in a clinical lab which is Sanger confirming or making sure those results are up to the reporting standards. They're okay if we put our clinically interpreted report with the variants we have identified and interpreted and validated into the medical record and we are going to be doing that as part of the study but they don't want us to put the whole variant call file in there so that later on, you know, it will be queried. We need to... Yeah, I mean, I think it's important to recognize that the FDA should respond to these concerns and we can't speak for them. So can we set this aside that's not the major aspect of this program? The major aspect of this program is how do we go about using sequencing in the newborn period? The question is to understand why they object, really what the rationale for the objection is and understand that they are much more powerful than all of us could mind. Well, not only that, but I don't think we can speak to that. So I honestly don't think we can speak to it. So let's move past that and get into other scientific issues. Last question, please. I'm here from Belgium. My question is the least scientific you can get. It's good to hear that you breathe the press and then apparently whatever you get in the press then makes sense. Now the thing is our local press took up whatever was published here on this one and all of a sudden it says like, Americans are ready to sequence neonates. And then we had to reply and say to the questions are, are you ready as well? So it sounds like you can breathe the press but on secondary thing, we get in trouble. So maybe this is another point to do on how do we communicate globally on these things? It's just something that pops up as you mentioned it. Well, it's good to know. When we surveyed all of you, the response on newborn sequencing was two thirds, not at all, and one third of you were already doing it in specialized center. I'd be just curious, could you raise your hands? Who is actually doing newborn or neonatal sequencing? Or do we have exomes? Okay, so there are a few hands. I didn't want to raise them very high, for some reason. And we also decided to drop this topic as one of the breakout sessions for this afternoon based on some of the responses and prioritization we got from you. But it seems just from hearing the dynamics of this discussion, it should be a topic for some future discussion or the few people that have already gone down this path a little bit to link up with Anastasia and the team and think about what could be done as a collective group. So, thanks a lot.