 Okay, so we've had a number of discussions today about this series of six questions. And what I'd like to try and do during this session is to spend a little bit of time looking at each of those six questions and what some of the different discussion topics were that came up and trying to look a little bit at if we've one captured all of the important items that came up because I was trying to pull this out of the summaries while we were having the discussions and to which of them do people think are the most important and most critical for the UDN going forward. Just a little bit of background to make sure we're all on the same page as we start thinking about this. The Common Fund Phase 1 support for the Undiagnosed Diseases Network runs through fiscal year 2017. We're now in the process of going through our continuation renewal phase 2 proposal process. And that would be for the next five years starting in fiscal year 2018. The Common Fund does not support programs for more than ten years, but that does not mean that NIH funding would necessarily end at that point. It just means that there has to be a plan for transition and sustainability of the program past the point in time that the Common Fund would be supporting it. So when we talk about sustainability we're really looking at are there ways that we can leverage the way that the program would be funded in the next five years to be able to try and help us get the answers that we need to be able to make it more sustainable when we get to that end of ten years of Common Fund funding to be able to help move it into either another part of the NIH or potentially out into other parts of clinical care and research. So these were the questions that we had in the agenda. We're looking at what are the best opportunities and justifications for continuing the UDM? What should we be emphasizing? What can we think of deleting or adding? And then how are we going to be able to prioritize these different topics? And we really want your feedback. So what I've tried to do is summarize the discussion so far, but if there's something that I have missed, please let us know so that we can capture that and make sure that it goes in at when we start preparing recommendations from this meeting. So under the intensive clinical evaluation, question one, we had a lot of talk about how should we be genotyping first or phenotyping first and could we potentially develop a best practice by looking at these two different options within the UDM and maybe having an answer by the end of another five years of funding? Related to that question, there was some discussion about the need to make sure that all of the data would be captured in order to be able to put together this kind of best practice guideline that we would need to have the phenotype data even if we genotyped first, that it was really critical to make sure we had both halves regardless of which order the evaluation was done in. There was also a call to collect environmental data, more history data, epigenetic data, and really think about the interactions between the different types of data that we are currently collecting as part of the UDM and potentially some of these other avenues as well. There was discussion about if there should be a reasonable minimum core dataset, potentially a set of phenotypes that would be collected on all participants in the UDM or some other type of uniform phenotyping across the network and how this could potentially help in recognizing patterns in the data. And then finally in this question one, we discussed that we could look at having focused expertise potentially at some of these sites or maybe looking at being able to disseminate these practices so that more of the local clinical communities could do some of the work up first before these patients made it to the UDM. So my first question for folks is, is there anything major that we missed? So I think I heard that some of the cases where there was a variant which you wouldn't bring in, there could be some kind of short work up or there could be some expertise applied to them, maybe without their even coming in, but that there be a different, still different kind of either center or work up, short work up without all the other stuff, but interpreting what was there, something like that? So that could potentially build off of what's captured here is this idea of a local work up first, potentially is there a way to either do the outreach to the community or it sounds like you're also suggesting that there might be the smaller way of people being able to have access to resources. I know I have that captured later in some of our discussions. Okay, Rachel? Well, I'm actually stealing one of Darcy's points here and he and I were talking about potentially, you know, as, and as Wendy was bringing up as exome sequencing, etc. becomes more, more universal, potentially having that as a as a first pass screen, whether it's paid for by insurance and is required to apply or that we pay for that we don't necessarily bring in everybody for the full phenotypic work up, if we can make a diagnosis that sufficiently matches their phenotype before they come in and only bring in those people who present deviations from that phenotype and or in whom we don't find a ready answer in the sequencing. And that then led to a discussion of is there the idea of capturing the phenotype in a sufficient way? How much of a work up is required in terms of, you know, a minimal phenotyping? Is there a way to scale that back at all so that we make it make it more generalizable to the general practice? Thanks, Rachel. So to your first point there of doing an exome on everyone first, I see that as being a little bit contradictory to the first point here related to being able to get the phenotype data on everyone. So I'm just curious what the group thinks about this idea of extending an enrollment criteria that would require having the exome first versus the idea of needing to be able to have both the genetic and the phenotypic data and what's the relative importance of those? So I think we shouldn't make a hard and fast rule. It depends upon the patient to patient. I mean, in some cases, you, you it's an obvious that you need to do genotyping first. In other cases, you need to look at the patient first. So I don't think this should at all be a hard and fast rule. I think there would also be some difficulties with access to the program if we were to require an exome first because of insurance payment being an obstacle. Although I would say in the scheme that kind of we were discussing, it was that not that you'd have to have it before you'd come in, it could be provided to you at a step before actually bringing you in for for the intensive clinical evaluation, which is I think by every account much more, much more costly than the than the sequence analysis. It's also a geographic consideration. We're already getting patients a thousand miles away. So we'd like to have some data before dragging them down. I want to do things in an orderly way. So I don't think we want to be hemmed in either. We need that option. And I think another point to remember here is that when exome or genome is done clinically, that is kind of different than what is done in in the UDN. We are we are doing quads and we are doing trios, where most commercial sequencing, which many of these patients come are just end of one. So when we look at the data, we kind of analyze it kind of differently because we have the benefit of having other family members. Great. So are there any other points to add? Yes. Yeah, do you then repeat when you do a quad? Do you then repeat the patient on whom somebody else had just done an exome sending spending a thousand dollars? Yes, there are some individuals who had pro band only exome and with a non diagnosis they may add additional family members. But I think the field really is moving more towards trios and to a lesser extent quads. So I think that's really going to become the standard, especially as sequencing costs go down. Okay. So Susan, give another point. Just we were just having a little sidebar here, which is making sure if you did try to get commercial sequencing data, getting it released is sometimes tricky. Not if you're in a center that can release it to itself. But if you have to get it from somewhere else, it can be hard. So I think most of the commercial laboratories, if not all of them do have a mechanism for release of raw data. There are some hoops that you might have to jump through. But that's really just to protect the data. But but I think most labs are considering that the patient does own their own data, and they will release it with some assurances. Yes, Cindy. I'm not trying to get free exomes on my patients, but you know, 50% of our patients have Medicaid and in our state Medicaid just started covering a small amount for microarrays. So you know, whole genomes are way in the future for them. But I think in trying to make sure there's more diversity among the patient population to, you know, facilitate maybe pre exome analysis, you know, in order to maybe be seen in the major UDN center, but to, you know, allow other patients to to get in. Okay, so if we've covered the general topics that were discussed during question one, are there any of these topics that folks would give higher priority to when we're thinking about how to design a phase two the next five years of the UDN? Yes. Well, this is perhaps a little biased. It being that I represent the metabolomics core, but I guess point three, should there be a minimum core data set? And I guess this gets to the question of how do you define a diagnosis to a degree? I mean, sometimes you get a diagnosis, you find a gene and that makes everything clear. Sometimes you get a gene and you're waiting for you go to tell you what it means. So, you know, is there a minimum data set should we couldn't do it with current budget? But should all patients, for instance, get a metabolomic profile on top of everything else? So you've got a larger data set, maybe addressing pathophysiology, etc. There was a lot of discussion about the importance of that kind of thing. So just something to throw out. Thanks, David. And I think that we can touch on that a little bit more. There'd been in some of the other questions, a lot of discussion about potentially needing to increase the funding to the core. So I think we can get back to that point there. Does anyone have any other items that they would really call out as being higher priority than the others? Or do you see these as being pretty equivalent kinds of recommendations? So what about lower priority? You can say that you think one of them is lower priority to that is helpful. So I think I'm going back to us. Steve Prescott was talking about earlier, is that we need to think about, for example, environmental history and epigenetics, because that I think again is mission creep. We're not going to have enough ends to really make any sense of that data and that all that hard work. So I'm not saying we shouldn't do it, but I'm saying that I think that point needs to be, again, rethought of. Yes, Howard. I would like to recommend that we be careful on prioritizing this area. We have about 170 people that have gone through this so far. The clinical workups are still going on. We're still trying to figure out where we are. I just would think we have a little bit of time on this before we get too far in this because I think by August, we're going to have more information to know what to think about. So I just urge caution on prioritizing too much here. I think that's a very good comment. Right now, what we're really trying to get is a general sense of are there certain items that people think are really critical to what makes the UDN the UDN? And are there certain things that have been discussed where people think that yes, that's something that we might need to keep in mind. But after the discussion, people think that that might be a little bit of a lower priority given what has come out as being where people see the UDN as potentially going for a phase two. Yes, please. I'll ask a historical question. In the UDP, has there ever been a finding that depended on the environmental history or the survey of the patients? And again, my part of my criticism is we start talking about objective data and this is not. Now we had a case of chromium and selenium toxicity where the Chinese nutritional people had put in 1000 times the amount that they intended to. So but that was pretty obvious. We didn't need a survey for that as it turns out. So I think this is ancillary information. Okay, any other comments on question one? We just had our first five day inpatient admit so it's not been abandoned. We're just being conscious about where we use it where we don't. Okay, any other comments for question one? So this may not be the right time, but I thought there was some suggestion that different units might do different things and that that was a plus because there would be multiple experiments or contrast between the units. Yes, you could have some variability. Part of that is this idea of, you know, potentially focused expertise, but it is also captured under one of the other questions, the idea of being able to have data from the various different types of potential ways that the sites are doing things. Okay, so for question two, the transitions of care, some of the things that we heard in the discussion were that the primary mission of the UDN is diagnosis, but we need to think beyond that and how you can change the life of a particular patient that right now the UDN is isolated from clinical care and practice, that we need to think about how to translate what the UDN is doing into a clinical care setting, that we need to think about how to make the research components more accessible and potentially leveraging other collaborative networks and research opportunities, that there was a need for a standard plan for what would happen next to these patients, that once their UDN evaluation was done, that it would be useful to have some sort of standard process for how the patients were handled in their transition back to their referring physician. And here's the point that we're just talking about there with Judy, that there's a need to capture, evaluate, and refine the diversity that is present in the clinical sites and that we need to really make sure that we're capturing this information so that it can inform future versions of the UDN. And then finally, once again, going back to this idea of leveraging existing resources and thinking about what already is out there in the community and what needs to be developed. Are there any major points that we missed from question two? Yes, Brendan. I think when you talk about leveraging existing resources, a lot of times we think about NIH supported, but there's enormous infrastructure out there that's industry sponsored, that's, you know, institutionally leveraged, and that's both at UDN sites and not at UDN sites. So I think it should be interpreted very broadly because I'm sure, you know, you find a variant in some phenotype. There is somebody in, you know, broadly speaking who will have resources beyond just obviously an R21. So I guess it should be broadly interpreted. I think that's a great clarification. Does anyone have anything else to add to the question two? Yes, Christine. I think we should have a definition for recontactive patients, especially for new gene diagnoses. So how far out are we going to be doing this? Is it five years, 10 years, forever? I think that's a great point. We can add that in probably as a clarification to the idea of a standard plan for what happens next with each of these patients. And Kalim, did you have a comment? I was just going to say I'm not sure. I agree that it's that isolated from the practice of clinical medicine. I think, you know, as Bill has said, it's really a return to the way that clinical medicine used to be practiced. It's this is by virtue of the diagnosis, you're bringing them back into traditional clinical care. And I think I'm just saying from the standpoint of portraying this to a council or whatever, just trying to make sure that it doesn't seem that the UDN is completely isolated from standard practice. It's an extreme of that spectrum. So perhaps focus on how to translate this back into clinical care and practice versus that the isolation aspect. OK, Sue, did you have another comment? I was going to second that motion because I think you will be enlisting the primary providers, whatever only are on the spectrum, that aren't part of your investigation team in continuing to facilitate that exchange information with the subject. So it's something about communication probably belongs in here and not again, not to emphasize the isolation, but building collaborative care. And I think this was brought up and I'm sure you're going to talk about it later in the training component. Yes, Bill. And in terms of leverage, I think Bruce has already demonstrated how he can leverage his own university's resources for this. And I'd point out that Mayo and Emory and Utah are establishing programs as well by leveraging their own resources. Are there any additional comments for question two? OK, then same question. Are there any of these points that people would give higher priority or lower priority than others? OK, it sounds like from the just the discussions here that a lot of these are very integrated with one another. Yeah, OK, so we seem to be in agreement there. So for question three, we talked about patient and family partnership. Some of the things that came up in the discussion were that we could potentially study patients and family psychological perspectives and look at how we could better classify them in order to be able to provide them with better support and care in the long run. That there is a need to be clear about the expectations of what is going to happen as part of a UDN evaluation and what is going to happen when these patients transition back to their primary care and referring physicians. That there is a need to create a patient advisory group for the UDN. We had a little bit of discussion about a group that's in formation, but there was a call that this should really be something that happens for the UDN going forward. And there was also a call to partner with Nord and other support groups to be able to start establishing more of a mentorship model where patients who went through the UDN we could help to provide them with links to different patient advocacy groups who might be able to provide them with support going forward. So this kind of links back into that transition of care idea. Are there any points here that we've missed? Yes, Callum. So one thing that I did notice in some of the admissions to the program that we've seen and comparing with our own patients is that because they were coming from centers that are unlike those in the network where there's an intense genetic effort that often there were family members who probably had related conditions that were only found very late in our assessment despite the fact that we were taking I think fairly advanced family history. So finding a way not only to engage the patients that I agree with all of those elements in the psychology and in the expectations and in thinking about the long whole, but actually also finding ways to engage more of the families up front in as much as it's feasible with HEPA compliance and everything else to be sure that you're not missing an obvious but low penetrance familial condition. So being able to engage more with the families at an earlier point in time to be able to collect better family histories and information to provide that feedback to the plans for the clinical evaluation. OK. Yes, Paul. I think the other thing we're seeing sort of explicit this way, but there's a difference between the pediatric patient and the adult patient. The adult patient we can facilitate going back to their internist, getting them to go back to a pediatrician is next to impossible. So if they've come to us from a subspecialist, that's an easier handoff back to Seattle, Portland, whatever. But sending back to a general pediatrician there is not really tenable. They usually freak out. They usually wanted to be handed off and not returned. So we need to think a little bit about I guess I kind of falls under the expectations of how much of this care really becomes the responsibility of the UDN when you're bringing a patient in. How much are they expecting that this then becomes their home care team versus the physician that had referred them to the UDN and managing those expectations? Yes. Yeah. And that's the reason why I really brought up the clear expectations about teaching families what research is. And then offer them the ability or an avenue by which to empower themselves to be able to help with the transition and try to get them so user friendly that the pediatrician will then take them back. So you can train people to be user friendly families so that they can help bridge their own way, get back. But the one thing that I wanted to mention is that if we're talking about what happens after the Common Fund doesn't fund this and then we have to find different funding to keep this alive because obviously in the patient arena we would be devastated if this program ever went anywhere. And discussing the fact that you can't ask for it yourself, the alumni from this organization could be very beneficial to help try to push the envelope to get funding from somewhere else. So it would be good to just keep the alumni together in some way so that we could help fight for whatever needs to be fought for in five years. Thanks, Simon. I think those are some great ideas potentially as topics for a patient advisory group for the UDN to start thinking about the idea of what the expectations are. How can we manage those as well as potentially building networks of patients who have become a part of the UDN? I would say that they're also a primary source for your advertising out about what services the UDN is able to do. In our TSC networks and consortium that we have, there are financial and academic disincentives for referrals to occur. So a lot of that is overcome by directly patient to patient communications. Thanks, Darcy. So are there any other topics that we need to add to these? OK, so same question once again. Are there any of these topics that people feel are higher or lower priority within the question? Yes, Susan. I think creating the patient advisory group should be your highest order of these. All of the rest of them will fall from that. Because they're going to be the people who are going to be best able to help you make things clear about expectations, facilitate those partnerships and create other models. So the sooner the better. I'm seeing heads nodding. Well, I also don't really think there's much of a difference between number three and four. That we would help in the establishment of a patient advisory group and that that would be one thing that would be part of partnerships with other support groups as well as a mentorship model. So that can just kind of be combined into one, I would think. Thanks, Paul. I think a patient advisory group always has to come from its own people. You know, you can't suggest it, but it takes one person to do it. So you can suggest it to all your patients in a given disease. But they are not going to do it unless they're really motivated and takes a special character to do that. And then they're very successful. And then the system works. But, you know, you have to may have to tell it to 10 or 20 people. Before one person takes it on. And you would think they would, you know, want to know. Yes, and this is something that has come up as we start thinking about this. We've been calling the patient engagement group within the UDN and trying to come up with the best way to create a group that would both be able to be beneficial to the patients, not overburdening them and making it so that it's really a group that's driven by the patients themselves. And Rachel, do you want to say anything else to that? Well, just that we are still struggling with with how to accomplish and I think part of what we struggle with is the need to form this group quickly ASAP, but also then getting to the point of finding the right people who are able to participate fully in this patient engagement group is something that may take time. So how do we balance those two those two priorities? So can I can not help us with that? Because they would know exactly the sort of people we would need. Sure. Yeah, absolutely. You can outsource a bit of that to us. Thank you. OK, any other questions or comments on our question three? OK, then we'll move on to question number four, which was training, sharing and collaboration. And some of the topics we discussed was that there was more training needed overall. There seemed to be general enthusiasm for the idea of doing more training and outreach with the UDN. There was comments on expanding outside the UDN, being able to use the UDN as a blueprint for how this type of training could be done, that you could have more folks coming in and learning from the individual UDN sites. That there was a need potentially for some curriculum development and being able to create new expertise in the community by educating these folks through training programs put together by the UDN. There was also discussion of wanting to increase collaborations. One idea that came up was bringing in health care providers to be able to get their perspective. And there was also an interest in international collaborations that we heard. And then finally, we had some discussions about exploring opportunities to be able to connect the data and really wanting to take all of the different data sets that were in the UDN and making sure that we were leveraging resources to be able to bring them together. Are there any topics that we missed from question four? Yes, Rachel. Well, I think this cuts across some of the other questions. So it may have been addressed there, but but I think the sub question there was how much support do do the outside collaborations require, like collaborations with outside researchers and how much support do do graduates of the UDN need and being connected to those resources? And I don't see that representative fully here. Do people have some thoughts on that? I know that we had some discussions about there potentially being a need to provide funding for the cores and that making them accessible to other sites potentially being able to have it so that more sites could be collaborative with the UDN and sharing data back and forth. And we'll be talking a little bit about that in some of the other questions. But what are folks thoughts about funding and support for these types of increased collaborations? Yes, and I just want to clarify kind of what I meant by that, because it might be different than what you're saying, which is that, you know, you have a patient who goes through, you have an interesting, potentially interesting finding and you want to do something more than ad hoc connect them to researchers you might know in the network. So then, you know, you have to do a search for who's the expert. And then you have to contact that expert and you have to facilitate what that collaboration might be. And so that was more what I was talking rather than core services. It's kind of the bespoke follow up that's required to get as much scientific knowledge and also benefit the patients as much as we can. And I think we'll touch on that a little bit more when we start talking about the virtuous cycle. But does anyone have any thoughts on that and support for being able to build resources for being able to find and connect to collaborators in the research community? It sounds like that's more of what you're trying to capture. Yes. So I think the biggest hurdle in that sort of outreach is that until unless the collaborators all and I think somebody alluded to that earlier, is unless the collaborators already working on that particular gene or that model, they just don't have the manpower most people given the tight funding that even if it looks like a great thing, they know that they're talking about allocating their own resources, somebody in the lab, a graduate student on a project that may be high impact, but high risk. So until as there is any money behind it, I don't think that is going to happen. No matter how I mean how hard we try. So in some ways, what Rachel was referring to earlier maybe was knowing if you find a gene that investigator XYZ at Stanford actually actually studies that gene and that particular pathway and that is an easier cell. But otherwise, I don't think, I mean, it's very difficult to do this. Yeah, the Canadian system uses that, you know, they post individual genes and the PIs can kind of look at the list and say, well, that's a gene I found in my network. I'd be interested then they can apply for a small grand of 50 K. You may want to think about that as a strategy because those people are experts. They know what the genes are. They have preliminary data that they can bring it into a network. And so I think that's another avenue. It's not truly an R 21. It's more like, you know, I want supplemental funding to put one person on this gene in the context of the research of the lab. Yeah, they're actually even smaller than R 21. They're like, like you said, like they're like 25, 50 thousand. They're small awards. Yes. No, they're actually 25,000. Yeah. So I thought like they're run by Phil Heeter and Janet Rassant and 25 K might be on the low side. But that's what it is 50 K would probably be. And I agree with you. Yeah. And actually we're trying to be part of that. So not officially, but we're trying to do it sort of on the lamb. Maybe I didn't tell you guys that. Did I? Sorry. So we'll and I should be interested in some doing that something like that. And I, uh, okay, you tell us, Anastasia. So we have had some discussions about this type of a model part of the issue with the way that they're doing it is that they're having the clinicians do the review and doing a very rapid turnaround where there's only a couple of months between the time that someone puts in an application and they are making the awards. And that just doesn't match up very well with any of the existing NIH tapes of mechanisms where if we could do something that rapidly with an administrative supplement, but then someone would have to already have an award that was studying that gene to be able to supplement. So we have to look and see how this could mechanistically work within the NIH system. So just for clarity, they can't divulge their list of variants because this organization has promised privacy to the people who are working on those lists on those variants. So what one has to do is describe a phenotype or tell what the variant is, that is the clinicians have to do that. And then it goes and the organization in Canada decides if there's a match with an organism or someone who's studying that variant in an organism. So I have no access and I never will have access to the list of 5,000 variants that are associated with model organisms in that group. But if I want to give a list of 20 variants and ask them to find one of their investigators who's studying that particular gene, then they can get back to me and put us together. That's the way it works. It's a little bit like gene matter in a way, in the modified version. A little bit, but there's little money associated with it too, as I say, 25K. And Rachel? I understand what you're talking about the need for rapid turnaround and that not linking up to NIH cycles. Would it be possible potentially to build this into either a coordinating center award or clinical sites award such that they could have funds in their pool to say rapidly issue out either a contract or a subcontract? There are ways that things could be done through contracting mechanisms, but that is a different model once again from what the Canadian group is doing because like Bill said, they're doing the matching. There is a clinical review board that's been set up and it's still being done within the group that's doing the funding. So it would be a different model if we awarded it to a core that was then running that process and putting out the awards. But it is an idea that we can pursue. Yes, Donna? And to make it a little more complicated, but to make it up to 50,000, a lot of times very, very small groups don't have enough money to impact research whatsoever, but they can get their money doubled. Like if they bring money to the table, will somebody then double it? So I work very closely like with the American Anthracic Society and my 30,000 has turned to 60 every year for the last eight years. So is this a possibility that it could be a small amount of money in a coordinating center that then could be matched by the families and then let the mentorship program teach them how to raise their 25,000 to get it matched, then make the 50,000 to start their research. Yeah, look for some kind of partnership model. It's also kind of put skin in the game for the it teaches them it's a small way to teach them how to start to do this right. The problem is it has to go fast because human geneticists I've learned like to publish fast. And so every collaboration I've had with human geneticists, you have to throw all your resources at once to it to, you know, bring it to bear in a three or six months period. This won't work for any other model organism. And then there's offline won't work for zebra fish or mice. And so it's a bit of a problem because, you know, the pressure very often they have one case and within six months there is another case. And so they're not willing to wait six months. So it's not that easy. I was going to say that this actually when we're thinking about points where healthcare pairs or public private partnerships might begin to impact. This is one point. So if you've got somebody who's cost a particular pair, a substantial amount of money and now you have a variant that might actually help them help not only that individual but their family, it's conceivable that might be a point where for a small amount of money, the the pairs might actually be interested in contributing. You can imagine some of we heard about Regeneron there are their entire projects in Geisinger, for example, that are completely funded off that model. So it might be somewhere where through Innocentive or some other online crowdsourcing strategy to get funding, you might be able to build a public private partnership. We would have to be managed quite carefully. I think as Bill says, there's a lot of sensitivity and Hugo pointed out a lot of sensitivity in this area. But managing that sensitivity is probably worthwhile to get the number of variants that you need push through the system, push through. Thanks, Cindy. And while I certainly agree that the basic science component is critical, but not to overlook the translational part and reaching out and collaborating with translational researchers who can help with the therapeutic side of things. Thanks, I think we'll get to that in some of our later questions as well. Are there any other things that need to be added to question for? OK, so then are there any of these topics that folks think should be of higher or lower priority? Well, I like international collaborations because that speaks into the sharing and we are one world. There are all sorts of patients out there that we're not even have don't have access to that we would if we had international collaborations that were more extensive. And once you start, you know, you get it. And I just yesterday got an email to get involved in Africa somewhere. Yeah, you know, and I get people who ask me knowing me three, four times a year in foreign countries. So it's right out there. It's available to everybody. Yeah, we need the ethnic specific variants in those first. But yeah, my my experiences, I'm collaborating with Australia now to for you the end in Australia is that like in Canada, people are competitive and they feel like this is really, you know, they should be doing this on their own turf. I'm sure you've sensed that yourself. So it's easy to say that you're going to have international collaborations, but they come mostly out of non develop underdeveloped countries, not from Canada, Australia, Japan, and now not even from China anymore either. We have collaborations with Australia and Gareth Bainham. We have collaborations with Kosaki in Japan and with Austria and Italy. Of course, and we have, especially in Japan, there's actually a case where we found a second case of a particular gene disorder because of that. I think part of it starts with our willingness to send them our list of variants and that's the start. So we've done that. I agree. It's not hugely successful and it's on a relatively small scale right now with individuals. But I think somewhat the whole milieu and philosophy is changing a little bit towards sharing because people are actually getting scooped when they go out their own anyway. OK. Any other comments on priorities for question four? Yes. Just to say that since this is a three part one, it's hard to prioritize because each one probably deserves its own focus there. Training is not something you bounce off against international collaboration. They're they're of equal priority and importance in many ways. I think that's a very good point. OK. So then we'll move on to question five, the virtuous cycle and integrating data. And here we heard a couple of things come up in the conversation. One was that we should think about treatment, not just diagnosis, that there are a number of challenges for funding and that if we are going to focus more on mechanism, that there would need to be more funding also for cores to be able to do more of that type of mechanistic study. There was an interest in the UDN model having synergies not just within each of the individual sites, but between them. And also this idea that finding the right researcher was really key. And this gets back to the point that Rachel was just bringing up about once you have a variant, how do you find the right researcher to follow up on that if you're moving more towards these types of mechanistic studies? So is there anything that we missed for question five? OK. So then are there any of these topics that people feel are higher or lower priority overall? So what do folks think about that? OK, so we wanted to talk about treatment and management as well as diagnosis. Or just management as opposed to just diagnosis. OK, so it sounds like we're hearing management. Yeah, people are saying management in place of treatment, treatment being a component of management is what I'm hearing from the muttering. But isn't care in the original aims? I mean, yes, in the language in the objectives talks more about management, optimal patient management, but nothing is really finished under your treatment. So I should just put treatment out there. And that's it. Whether you reach it now in 10 or 15 years, and it's just a goal and not care and not whatever management. It's also vague. So treatment is what you want. So I do have a question about this, because this did come up in the discussion. There was really some points of contention here about should the goal really be this diagnosis and we might be able to move towards management of some of these patients? Or is our goal really to drive towards treatment? And so are we really looking at, you know, management and maybe some mechanistic studies to better understand as part of the research? Or should one of the goals of a new phase of the UDN be to drive towards treatment? Yes, Paul. I'm all for treatment. I do a lot of oncology and but it's going to, it's a whole different ball of wax. We're going to start having compounds and toxicities that's going to be a lot more complicated on an IRB. Right now with diagnostics, a little bit easier on an umbrella IRB. Treatments are not going to fall on an umbrella IRB. Thanks Howard. Yeah, I agree. I think we mean I like treatment, but I think we have to be careful of really expanding the mission when we are already just trying to get our head around where this is going. So I like the idea of management. It could include treatment. It could include a lot of other things. But if we say treatment, it also carries a very specific meaning to people in the lay audience. And I just think we got to be careful when we say treatment. And David. Well, I'm not sure if these came out of the discussion or not. I think in my part of that, I was trying to make the point that there's a distinction in the approach of the UDN, which is diagnosis versus the approach to treatment, not to imply that we need to do both. The point was that we would need to think about how to translate our approach, which is diagnostic into the treatment realm. I would agree with the other comments, though, that treatment is not where we should be. Perhaps it's defining path of physiology, which sets a path to treatment. But I think treatment is, yeah, mission creep with the capital M. So I hear overall a lot of enthusiasm for the idea of potentially delving more into mechanistic studies and potentially some things in the realm of management for some of these patients that might come out of having better understanding from the mechanistic studies or the clinical evaluation of the patients, but not making a new goal to move towards treatment within the UDN. Yes. And so Donna and then Callum. Just like because of mission creep, I worried about that too. And it should be transition, not just diagnosis. So, you know, the diagnosis and then how do you transition that to the next step? I think that captures what we've been discussing really well. And Callum. I was just going to say, I think mechanism is an intrinsic part of making the diagnosis. I don't see how we're going to establish causality with N of one without having some sense of what mechanism is. Great. Are there any other comments on relative priorities within question five? Okay, then for question six, moving the UDN forward, we had a number of topics that came up. One that we seem to keep circling around to was how is this going to be funded? Are we looking at providing more money to cores and potentially leaving clinical sites to find their own money? Should we still be putting money into clinical sites? Should this be moving more towards CTSA's or potentially something similar to the comprehensive cancer centers? So I think there was a lot of uncertainty and question about how this should be funded long term for sustainability, though I also don't think that this is necessarily a question that we need to solve before the next five years, but something that we need to think about. How do we ask questions in a phase two of the UDN that will help us get to a point of being able to know what might be sustainable at the end of the 10 years of common fund support? We also had some discussion about what happens to the patients after they receive a diagnosis. We've talked a little bit more about that in the transitions of care question. And we also discussed the value of having access to the UDN cores and that opening them up to a broader audience could potentially have value to the larger community that's seeing these undiagnosed cases and that having ways for other clinical sites outside of the UDN to be able to access UDN resources may have benefit to the community. And then finally there was a lot of discussion about should we be broadening the UDN to be able to include mechanistic studies in the goals. And I think we just had some further discussion about that on question five. So are there any other topics that we missed in this general summary discussion? OK, and are there any of these topics that people would like to further clarify or state that they see as being either a higher or lower priority? Yes, Briswan? I would say the mechanistic would be higher priority. OK, and Sue? I think you're going to want to keep your eyes on the prize, which is making the diagnoses for the patients. All these other things fall from that. So how do people feel about Callum's comment that mechanistic studies are a part of making the diagnosis? Do those two things agree with one another? Seeing lots of heads shaking and nodding, so that's good. OK. Are there any other comments on question six? OK. I think we're going to have to talk with the CTSAs and NCATs about whether it's even viable to have that group support this in the future. And there was one thing that was suggested in one of the intermissions. And that is that it might be reasonable to figure or to hypothesize what might be the sustainable model for this in, let's say, six years from now and try that out over the next five years. So if people feel that that's appropriate, then we would have to maybe change reasonably drastically now and just see how things go so that six years from now or so things can be moved into a different model for funding. So I think build the problem with that is going to be that we are just starting. So you're not going to know. I mean, you guys have a lot more experience. So I digress. I mean, you have issues of experience, but most sites are just barely getting their hands around even the course. So I think we don't really know what's going to work and what's not going to work. And I think as somebody had mentioned earlier during the day is that our goal should be for the next five years to see what works and what doesn't work. So I think that is very important before we start making decisions about changing this or that. No, I agree with you. And I think that our personal our experience is a little bit irrelevant because it's it's not sustainable in the intramural program. It's just not the way the nation is going to handle this, et cetera. So you're absolutely right. I bring it up as a proposal. It's not necessarily a good proposal. Yes, and I can let folks know as far as a timeline here, if we do receive a continuation from the Common Fund and receive another five years of support, the next batch of funding announcements would be coming out about a year from now. So that's kind of the time frame that we're looking at to be able to gather more information. We're going to be putting together all of this information to be able to present it to the Common Fund around the end of the year. OK. John, so how do folks think about additional core needs? Is that something people feel is really important within a phase two? Yes, I think basically all patients who have who are being evaluated and certainly most of all those who have a neurologic disease or to have an eye exam and they shouldn't be skipped, you know, you just can't, you may see so much more in the eye than you see in the rest of the body and I think it should just be done. And I'm not sure it's always done. For the EM core, the key is accessibility to tissue and from most of the UDN, it's neurological and I'm not so sure how you're going to solve that problem. Can you just poke in the brain and get a piece of tissue for EM microscopy? So, you know, there is muscle sometimes in the muscular, neuromuscular sorrows. Sometimes you can get a, you know, a sensory nerve but it's also true that some of the genetic defects that affect clinically only the brain will have manifestations in the organ L seen in fibroblasts. Okay, any further comments on question six? Yes, first one? Not a comment, but since this is going to be put together later this year in the fall, so maybe one of the things to consider would be for the next in-person steering committee meeting. Some of these questions, this could be on the agenda for that meeting and some of these questions could be revisited at some level because we will have certainly more data. We will have actually real data about some model organisms. We will have patients, people who would have actually evaluated an N number of patients. So, we should probably clarify at least a small portion of this. Yes, I think it's great to be able to continue updating the data. Okay, any other comments? Okay, then our last task here is to really look a little bit across these different six questions that we had and are there any of these particular topic areas that people felt we really need to concentrate and focus on or do people feel that these are really things that are very synergistic and complementary to one another? I hear some mumbling down at the end. Mumble, mumble. I don't see how you separate these. I'm seeing some heads nodding around the table. That is true, but I think data integration is going to be very important. How do other folks feel about that? Do people feel that the data integration is going to be one of the real critical components of the UDN moving forward? Yes, Rachel? Well, this is something we kind of struggle with at the coordinating center because while we're gathering quite a bit of information in our centralized gateway, so much is left on the table, right? I mean, you have the local studies. You have the functional studies that may be supported through supplements or they may be just, as we said, ad hoc because somebody knows someone. And so those data are not currently systematically being collected in part just because of the resources and manpower needed to track all of those data down. But I think they would be unquestionable value in building a data set that's unrivaled in terms of its breadth and depth. Yes, Colin? I was just going to say, as I said this morning, even understanding the process and the decisions and how they're made across each case, whether they enter the network or not. And then as they progress through the network, we'll give some valuable information and it's probably more cost effective than funding everything for everybody. I think that's the tension that's obviously at play here. And it's just trying to get the sweet spot. How do you test some hypotheses in the context of what could be an astronomically expensive undertaking? Thanks. So does anyone have any final comments on prioritizing between the different questions? OK, then I would like to thank everyone for coming today. You will likely be hearing from the framers of your different sections as we put together the notes from this meeting to make sure that we have appropriately captured your recommendations. We want to make sure that we have all of the great information and ideas that we've heard from everyone today. But I think today's meeting has been very successful. We had a lot of really great discussion and you've been very helpful in helping us to think about our phase two for the UDN as we move forward. So thanks, everyone.