 The last report of the day is on the Undiagnosed Disease Network, or UDN. This is a, let me remind you it's a common fund initiative, but NHGRI provides a lot of the management coordination for that program. And Anastasia Wise is going to make the presentation because she spends most of her time on that. Thanks, Rudy. Okay. So I wanted to tell you guys today just a little bit about the Undiagnosed Diseases Network. As Rudy mentioned, the UDN is a common fund initiative, which means that it's really trans NIH and broader than what any one institute would necessarily focus on. The common fund also looks particularly for programs that are going to be catalytic or transformative within their fields and really drive things forward. And so for the Undiagnosed Diseases Network, we have three main objectives for the network. The first of these is to improve the level of diagnosis and care for patients that have undiagnosed diseases. And then our second main objective is to be able to then facilitate research on those conditions that had been previously undiagnosed. And then third, we really want to be able to create and promote this integrated and collaborative community, bringing together both researchers and clinicians, the bioinformaticians, and everyone who's involved in the research and clinical care of these participants in order to be able to try and improve the care of these individuals as well as improve the process to be able to help get them diagnoses. So the Undiagnosed Diseases Network really started with the UDP or the Undiagnosed Diseases Program here at the NIH Clinical Center. And you heard Dan Kassner talk a little bit about this program earlier. This program began in May of 2008, so we just had the 10-year anniversary. And they were started off with a model that was bringing in participants to be able to do thorough one-week evaluations at no cost to the patients. They took anyone, regardless of what their individual symptoms were, so both adult and pediatric, any clinical specialty, as well as taking individuals that were either un- or under-insured. And really, this was the model that was then taken into the Undiagnosed Diseases Network and that we were to be able to try and extend to a series of sites across the country as part of the Common Fund Initiative. So these are now all of the sites that make up the Undiagnosed Diseases Network. We started off with a coordinating center, and that coordinating center provides the infrastructure and our gateway to be able to both get all of the applications in for the UDN, as well as a place for all of the investigators to be able to put their data as part of the Undiagnosed Diseases Network. We then have seven clinical sites across the country, including that site at the NIH. And those seven clinical sites are then the groups that end up seeing the participants for their clinical evaluations as part of the UDN. We then have two sequencing cores that currently make up phase one of the Undiagnosed Diseases Network. One of them is providing exomes, and one is providing genomes to the network. We have a model organism screening center, which provides both Drosophila and zebrafish modeling for following up on variants that are identified in the participants of the UDN. A metabolomics core, which provides untargeted metabolomics analyses. And then a central biorepository for being able to store the samples that are collected as part of the UDN. So how does this process work? So when a patient applies to the Undiagnosed Diseases Network, they come in through our central application portal, or our gateway, that's located on the Coordinating Center's webpage. This provides one single point of entry to the Undiagnosed Diseases Network, because we really do operate as one protocol. Once a participant has applied to the Undiagnosed Diseases Network, that application is then sent out for review at one of the seven clinical sites. Those seven clinical sites review the application, gather medical records, and then make a recommendation to our case review committee to be able to accept an participant into the Undiagnosed Diseases Network. To date, we've had a little over 2,300 applications to the program, and we've accepted over 1,000 participants into the UDN. Once a participant is accepted into the UDN, the individual clinical sites then decide on how they want to be able to handle that particular patient's evaluation. Do they want to be able to do the clinical evaluation first, or do they want to be able to do the sequencing first? This is made as a decision by the individual clinical sites, and oftentimes is very much dependent upon the actual participant themselves. Have they had any sequencing in the past that might be able to be reanalyzed, and what their particular signs and symptoms are? To date, we've had about 700 clinical evaluations and approximately the same number of individuals who have received sequencing as part of the UDN. For the sequencing for the exomes and genomes, we do have enough sequencing capacity within the Undiagnosed Diseases Network to be able to sequence either trios or quads for all of the participants that are accepted into the network. Once an individual has then received their clinical evaluations and sequencing, there are two other core facilities that are also available as part of the Undiagnosed Diseases Network. One of those is our Metabolomics Facility, which can do untargeted metabolomics in order to be able to try and find other hypotheses, link this data with the sequencing information, and try and be able to make diagnoses for the participants. And then our Model Organisms Screening Center can follow up in those fly and fish models to be able to determine if potentially a new variant that hadn't previously been associated with disease has a phenotype in one of these Model Organisms, which would lend additional support to that potentially being associated with the disease phenotype in a participant. And working together, all of these different components of the UDN have so far diagnosed just a little under 200 participants. For the Undiagnosed Diseases Network, we do a lot of work with trying to be able to develop this community. And because of that, there's a lot of work that goes into making sure that the information about the UDN is broadly available. We have a manual of operations, which can be found on the website listed here. It's about a 200-page long document that actually outlines the entire network-wide protocol for the UDN, all of the different components that go into the Undiagnosed Disease Network's evaluations, as well as some of the more logistical factors that are involved in how participants are seen and evaluated as part of the Undiagnosed Diseases Network. That includes some information about our single, or it's typically referred to as a central IRB in our manual of operations, because it actually predates the NIH's single IRB policy. But the UDN does operate with a single IRB. It's located at the NHGRI IRB at the NIH. And we have this one protocol for the entire network, all of the other sites that are part of the UDN. And it is indeed all of the sites, not just the clinical groups, but all sites that are part of the UDN sign reliance agreements to be a part of the single IRB. And then this allows us, as part of our data sharing and use agreement, to be able to share identifiable information within the UDN between investigators, obviously on a need-to-know basis based on an individual investigator's role. But to be able to have them have that access so that the individual who's doing the model organisms work following up on a variant can actually learn more about the clinical phenotype that was seen in an individual participant. And there's a lot of work that happens in those interactions to be able to bring together the different communities as part of the UDN. We also share data through the Matchmaker Exchange, which you heard a little bit about as part of the genome sequencing program in the presentation before this. And we put our data in through Phenome Central because we use phenotypes as a way of being able to collect phenotypic data as part of our UDN evaluations. But this allows us to share both phenotypes, HPO terms, as well as genetic variants and genes with others as part of the Matchmaker Exchange. That feeds into how we are also sharing our information more broadly as part of the Undiagnosed Diseases Network International. There are a number of countries now across the world which are involved in the Undiagnosed Diseases Network International. And all of the members that are part of the UDN are also sharing their data through the Matchmaker Exchange in order to be able to try and make matches of these very rare conditions and hopefully be able to make more diagnoses. Another way that the UDN is sharing and making information available is through our UDN participant pages. These are not required for UDN participation. It's a separate consent form that's offered to the families if they are interested in participating in this project. And these participant pages then allow the participants to decide on how much information they would like to be able to share on a page which is then able to be found by searching through things like Google. This allows for the information to be made available in a way that's more readily accessible to families. We make sure that all of the information about the signs and symptoms is provided both in the more standard terminology, HPO kind of terms as well as in more lay-friendly language so that someone who's just looking up the terminology would be able to find something about shortness of breath rather than necessarily needing to have a clinical description of their condition. That information is also then turned into a list of genes which we are interested in finding additional information on. And that is available on the UDN website as well and actually searchable so you can put in the gene that you're interested in. You can see whether or not there's a participant page that's related to that gene as well. Or if you have a particular, if you want to just go through the list, you can actually see all of the individual genes. So you can search by gene or you can search by the participant pages. We have over 60 of these participant pages that are currently available. And they've been a very important part of our matchmaking strategy to be able to try and find other individuals who have these ultra rare conditions. Just to give you an example of why this matching matters, this is one of our first participant pages that was put online for a male infant who was 20 months old at the point in time that they were seen by the UDN. They had seizures, cataracts, a macrosephaly, and global developmental delay. And on all of our participant pages we have these little boxes that talk about contact us if you think that this sounds like you or a patient that you might be seeing. And that relays you then to the help desk at the coordinating center who can help with linking individuals with the appropriate clinical site and clinicians that have been involved with any of these participants. In this particular case, after our one UDN patient, we were able to identify a second individual using gene matcher, a third individual from the centers of Mendelian genomics, which you just heard about. Another two individuals by looking at Baylor Genetics Clinical Laboratory sequencing that they had been conducting, as well as two participants that had actually found us through that participant pages web project. And this allowed us to then come up with a set of seven individuals that all had the same de novo variant in NACC1, then allowing us to be able to identify a syndrome that was characterized by this epilepsy, cataracts, and developmental delay. And so this is really the kind of community building and matchmaking that the UDN is hoping to be able to help leverage, to be able to make diagnoses for these undiagnosed patients. The UDN does also have data available in some more traditional senses. And the fact that there is 28 publications that have been written up so far, most of these are publications describing individual case studies or new diagnoses within the UDN. Our information on the UDN is available in clinicaltrials.gov. Though the UDN is not a clinical trial, it's an observational study. Our information is available there for participants as another place that they could find that information. There are some participants in the UDN who are sharing their data through MindGene2 as another more patient-facing forum for being able to provide information about their cases. We're providing data into DBGAP as well as we have over 160 variants that have been shared with ClinVar to date. And the UDN is now in the process of starting phase two of the undiagnosed cases network. We've been renewed for another five years of common fund support. This will include a coordinating center, clinical sites, a metabolomics core, model organism screening center, and sequencing core. And we put out five new FOAs to be able to compete for all of these different components of the UDN. All of these components are currently going to Council review in May of 2018. And you guys will be hearing about some more of them later today. And we are anticipating making awards in fall of 2018. And with that, I would like to thank all of the UDN patients and their families that have participated in the UDN. As well as all of the UDN investigators and the common fund UDN working group. In particular, my co-coordinator, Bill Gaul, who works with the Undiagnosed Diseases Program and our common fund program, Lee Mary Perry. And with that, I'd be happy to take any questions. Thanks. Any questions for Anastasia? Yeah, thank you for that presentation. Two questions. I understand substantial value in making a diagnosis for these patients and kids. Do you have any estimates of how many have clinical utility to the identification of the diagnosis? Yeah, so the UDN is really focused on being able to make diagnoses and trying to improve that diagnostic process, versus on the actual therapeutics piece of it. There have been some success stories, even with just more clinical information from the Undiagnosed Diseases Program and being able to provide some sort of change in care or management over the course of the 10 years that they've been seeing participants. And we've seen a couple of cases similar to that that have come out of the UDN. But it is a little bit early to be able to see that kind of change in care because right now we are tracking it. But our information goes back to the referring physician who had referred that participant into the UDN. And then we follow up with them every year to be able to learn more about if there have been any changes to their care or management. And we've only been taking applications for about a little over two years at this point. Are there general things, lessons that you've learned in terms of strategies that are working to make the diagnosis? How much either genome sequencing is giving you that exome wasn't, or transcriptomics, or metabolomics? Are there general things that can be more broadly shared with the community? Yeah, so that's one of the things that we're really hoping to focus on more of in phase two is trying to be able to delineate. Are there particular components of this model that seem to be lending itself more to being able to make these diagnoses for these rare participants? Or is it really being able to just provide what the latest cutting-edge technology is that might not be available in clinical care? And so that's one of the things that we're really hoping to be able to build on more. I would say that so far from phase one one of the things that we've really gotten out of it is the importance of being able to have all of the individuals have open discussion with one another, whether that be having multiple different clinical specialties discussing the case at the clinical site, as well as having the clinical teams having very thorough discussions with the individuals in the model organism screening center. Just the importance of having that information shared more broadly. We've found to be of extreme importance. We've also had a lot of success to date with being able to integrate RNA sequencing data with some of the genomic information in order to be able to find additional information about second variants, as well as looking at cases where we might have multiple diagnoses or mosaicism. So this is a terrific program. I'm just learning about it. So in phase two, I read somewhere that part of the objectives will be to think about sustainability for these centers. And in order to do that, I think it comes to Wendy's point also, which is what is the most useful thing that comes out of this and how is it used for treatment? So what are your thoughts on that right now? And is it necessary? Do you think that 2022 will come up pretty fast? Is that a target date for self-sustainability of this program? Or what are your thoughts on that? Yeah, so as a Common Fund initiative, the Common Fund will only provide support to programs for a maximum of 10 years. So the next five years is basically when we would end up being at the end of our Common Fund support. So for the phase two, we very much are focused on this idea of sustainability and trying to be able to determine what components of the Undiagnosed Diseases Network are sustainable within the community? Are there pieces of this that have become standard of practice and clinical care? Are there pieces that can be billed more to insurance? Are there pieces that can be picked up more by institutional philanthropic funds? And what pieces of this might still need to have NIH support more long term in order for this type of model to be viable? So that's really what the focus of phase two for the network is, is trying to determine what are the critical components to make the UDN sustainable long term and to be able to try and figure out what those key pieces are for being able to make the diagnosis. So Steve, if you didn't know, the model for the Common Fund has always been five or 10 years of funding, and then the idea was sufficient progress would be made that it would be picked up by whatever other institutes of NIH were most closely tied to it. Well, that was part of my question is, does sustainability here mean that one of the other institutes will pick it up? Or does it mean that it actually moves into the clinical business world of clinical centers? I would say we don't know the answer yet at this point in time. That's part of what we're trying to be able to determine. We do have plans for a 2020 workshop to be able to kind of look at what's come out of the data so far because at that point we'll have more like five years worth of data from the UDN to be able to look at and evaluate and then try and determine what the right course is. Is this something that would continue to need some form of NIH support long term or does this really become something that can be pushed towards broader clinical care? Other questions for Anastasia? Okay, thank you very much.