 So, my name is Darcy Krueger, I'm from Cincinnati Children's Hospital, and I come from a perspective of non-genetics. I'm a neurologist, and I deal a lot with tuberous grosses, which is not hard to diagnose unless you're on the fringes, and so I deal less with establishing a diagnosis, but I deal a lot with what do you do when you have a diagnosis, and so I would like to start the questioning with starting with the idea that we are called an undiagnosed diseases network, but are we only a diagnostic network, and I would posit that we're not. And so the question is, where do you see, if we look at the perspective of how to make this a translatable or a usable tool five years from now for the average clinician who is proposed with a patient with a hard to establish diagnosis, you know, how do we deliver, or what is it that we want to deliver to clinicians and patients at that time point and make that transition smoothly? I mean, we've heard a lot of things, a lot of different issues that come up along those lines, but so let's start with the simple, is how long should we follow these patients if we want to know what comes out of that, and knowing that these patients are coming from different directions and they're going different directions, and we are just a node in a lot of different trajectories. Thoughts? Well, I'd say some patients you want to follow for a long time, and some you don't want to see again, and I think, yeah, I know, but you have to. So the point is that there's some incredibly good cases that you want to know what's going to happen, and you want to invest a lot in your own research and in follow-up, but it's probably not true for all the individuals because if you follow up cases that aren't so good or have mainly subjective findings, you're really wasting time that could be spent on those other cases, because everything really is triage in this. In some of these patients, you are going to be the first person that actually listened to them and actually gave them something that was tangible to them, and so despite all the best efforts to have a referring physician, some of these patients are going to identify you as the person who figured them out, and they're not going to want to move on as well, and that creates problems on two ends. One is what you say, Bill, exactly from a resource standpoint is that's not our purpose, and the second becomes problematic because clinicians become alienated, and so your referral population also dries up. So over here, Susan. Also the degree to which you can partner with your referring physician, the better you have a mechanism by which you can facilitate that engaged relationship with the patient. If they're your partner in making this happen well and exchanging information with the patients, then when they come back, they're part of your team in an indirect way. That helps with some of the nobody ever listened to them piece, and it also helps with the if interesting information comes back eventually you get it back to. I was just going to say that standard subspecialty practice is co-management with a referring physician, and so I don't think there's anything unique about this. It's just the subset of cases is unique. I mean, I think 50 or 60 percent of my practice comes from outside the state, and I'm not involved in their long-term management, and they almost all have rare inherited diseases that are then managed, co-managed with local referring physicians who maybe don't have the expertise, but nevertheless are able to manage the family on a local basis with our help and intermittent involvement. So I think it's pretty, you know, this is going to be, as Bill said, based largely on standard clinical assessment. Yeah. I would just also add that, I mean, if you were to follow folks prospectively, whether you want to or not, and had some kind of a registry where you were gathering patient-centered outcomes, health care utilization, just general health outcomes, then you might be in a better position to help prove the value of this diagnostic service, and so that it does have sustainability beyond the next phase of the UDN. Jonathan. I have two questions for the network sites here. First of all, is genetic counseling incorporated in part of the visit to the center, and second of all, once a diagnosis is made, is there any effort to identify sites in the U.S. or North America that have expertise in that particular disease? So it may be that they go to a UDN site, a diagnosis is made, and there is a program or there's a clinic or a practitioner, say in Chicago, who has a particular focus on that disease. Is there an effort to not just say, oh, by the way, you can look up these things, but to make a specific recommendation? Well, I can talk for our site at UCLA, but I think it's similar in many other sites, is genetic counselors are really integral parts of the evaluation of really being in the front line of communicating with the patient weeks prior to their visit. So they know exactly what to expect pre and post. I think they play the role of Bill has nurse practitioners, ours are genetic counselors, but even our coordinator is a genetic counselor, and we have another one and stuff. So they do a tremendous job in even sort of putting together important formation from the medical records and so forth. And the second part, we're trying to, but that's it really to get the resources and so forth nationwide. Sometimes it's so new that there is no such resources. So that's something that could be a goal of the UDN to actually just find the resources to help create them. Wendy, you had a comment. Sue is along similar lines with the modest numbers that are coming through the UDN with these rare disorders. It's very likely that many other patients are being identified around the world, but a handful in terms of those. And so is the idea that you're going beyond the diagnosis and we'll start then doing deep phenotyping, but perhaps bring those patients. There might be half a dozen of them into the UDN to establish what that phenotype is, start the research programs, the parent support community. I'm on this wavelength because I think it's really important to actually have an idea of the spectrum of the phenotype. At the last case review committee, there was this question of when there is already a diagnosis or at least a variant that seems to be the right diagnosis, is it the goal, is it part of the purview of the UDN to still bring the patient to expand the phenotype? I still don't have a clear idea of what the answer to this is because I think that would be important. So let me offer a perspective and some experience, for example. When we saw a patient who had basal ganglia calcifications and symptoms and called this Fars disease, we acquired an interest in that enough that when other patients came along with the similar neurological problems, we accepted them more readily. Let's put it that way. We have that purview to do that. And now we have 15 patients who have Fars disease within our cohort and a couple of them actually do have a diagnosis, but most of them do not have a molecular diagnosis. When we saw a patient with facial onset sensory motor neuropathy, which is really a type of ALS that begins with sensory problems in the mid-face, et cetera, this is a poorly described disorder. There are only five cases or 10 cases or something. We've now seen six or eight ourselves. And some of them have, let's say, a molecular basis, CSF1R, mutations, et cetera. But we're able to do that because they truly are not diagnosed. And we can do deep phenotyping of them just as you suggested, Wendy. And we also saw patients who had hereditary leukodystrophy with spheroids, et cetera. So we're able to do that. And I think the other sites are able to do that and establish some expertise. And out of this might come a clinical protocol for a natural history study and then perhaps even a treatment study. That would be a goal. On the other hand, we can't use the, let's say, the plan for the Mendelian Sequencing Course, which is to say, oh, we're going to see 30 patients or five families or 10 families with such and such a particular disease. I think that's really not the point of this. We want to see patients who apply by themselves and have gone undiagnosed for a long time. That's the essence of this program as I see it. But it's also true that we're all around the room to decide if it should be that way or if you want to morph it into something else in the future. I would almost wonder, coming back to the question we had on the first question, which was, do we want to have subspecialty expertise? That it creates certain efficiencies, but it comes at a cost of you break up these closer collaborations between working physicians and then you also make it harder for patients to have access. And so that will be a fundamental question that will have to be decided because there's pros and cons on each side of that that relate to what you're saying. And I almost wonder if, you know, we think of protocols or algorithms of whether there needs to be probably a two-treat approach, you know, that those diagnoses for which there are other resources available either through regional centers of expertise to that patient specifically or at least within networks or within a specific institute or things like the Rare Diseases Clinical Research Network that has the clinical arm that would pair with many, but obviously not all of the diseases that we deal with. And then there's those that still have further discovery or such rare that there is no expectation for such a network to exist or such expertise exist where they're kept in-house. I think it might be very appropriate that we think along parallel lines because these really are distinct populations. I'm very sympathetic to Bill's response that they should use their money most effectively and to do what you described really makes sense. But at the same time, it seems as this whole program is setting up a protocol or a standard of practice for 10 years from now. And so it's kind of like you're keeping two things in mind at the same time. And I see the new sites as opportunities to experiment. I mean, maybe one of those new sites should just take results that need re-looking. And maybe another site should just take things that are adult neurologic or where they have expertise. So it seems like as the network has expanded, there's an opportunity to be running several different experiments, so to speak, consciously so that you get to the point in five to 10 years that you actually do have a protocol that can be then incorporated into standard practice. Particularly like having a site that reevaluates information. I think also, I mean, not only if you have a standardized way that you're looking at this, you can define superiority when you have competing models, but also you have different models that may be more suitable for different centers that can get to the same endpoint. I must say I'm really in favor of having some kind of follow up, but I think it could be done by questionnaire and then pick out the cool questionnaires for comeback. Yeah, and I would say from my TSC experience, I'll get to you Susan in just a second, but I would say from my TSC experience, one of the things is that once you release them to a different center or a different expertise, when you hand them back to the people, realize that the care delivery is gonna be very diverse and some are gonna be up to date and what you would consider forward thinking and some are still gonna be living in a pre-diagnostic era where you handed them back but really they were unprepared or the family just didn't follow through. And so you're gonna wanna capture that in some standardized way as you look at these trajectories of saying that this program had impact and this is the way it had impact. I thought some of the framing questions were very good. We'll go to Susan and then we'll come over to Susan first. So two questions are one of the things that said a large center network that's available in terms of potential resources for recontact and follow up is the CTSIs in the various academic centers. Is there some way to leverage those, that network of centers or investigations that might could be added on particular for follow up and in the same token, is there a way to identify or make an encyclopedia of or whatever experts that you could, I mean right now it's I know this guy in Chicago that does a good job with this but is there a way to better codify that so that you can provide appropriate follow up resources for identified patients. I was just gonna say I think a lot of the questions that we're talking about come back to the same fundamental truth that's what Walter brought up at the start which is a lot of this is dependent on how you get into the system and who you see. There's so much subjectivity. Something that looks like it's an undiagnosed disease to one person might be a very obvious case to the next person over. Something that's phenotype expansion in one setting may be actually completely interesting and de novo molecular insight to another person. So I think finding some way of having a minimal shared reality is important both as Wendy said for the, not just for the present but also for extending it outside the network. I think that's one of the things I consistently feel is that if we don't have some sort of minimal shared reality we end up finding it very difficult to even relate perfectly between sites but particularly to relate between the network and the rest of the visible universe. All right go ahead and then we'll come back to it. It looks from the map that there's nothing really in the heartland of America in terms of a UDN site. So I just think if someone brought up before the potential for telemedicine utilizing experts who have been identified around the country who can weigh in on some of these cases because that's also gonna improve diversity in the patient population. I mean a lot of my patients they can barely make it into our clinic let alone travel to DC or maybe up to Duke for an evaluation but I think that there's opportunities for diversification with that. Two more comments we'll go here and then Christine. So I have three brief comments. One is on follow up we do have a phone call with everybody after a couple of months after their evaluation and then we follow up with them yearly via questionnaires and those will be things that we will refine over time I'm sure. Second is on identification of experts. So the Coordinating Center is based at the Department of Biomedical Informatics and we're relying upon some CTSI developed technology that uses PubMed to identify sub-sub experts and so we're developing search strategies to leverage that technology to be able to refer people to experts or drop on those experts during the evaluation. And then the final point is when Susan spoke I understood there could be several definitions of the transition of care and for us it does have a couple of meanings. One is if they have a diagnosis and are transitioned back to their clinical team but many of our patients then also something we need to facilitate is a transition to research. So finding expert researchers who are interested in following up on cases like that. Let's have some points. Christine final comment. Just one last point. We are instituting a grand round series but I think the first one is in a couple of months I believe and I think we are going to be mainly highlighting our successes in terms of diagnosis but I think we could also use it as a forum for truly the undiagnosed patient and to use that as a way of building this network of experts from the outside. Who's the audience for that? It's mainly network right now but I think that it can be an outreach. It be planned to open it up. Yeah. All right, you look desperate. We'll let you have one comment and then I'll summarize. Okay. I just wanted to respond to Cindy's comment about patients not having access to travel. One of the mandates of the UDN is to provide transportation and lodging to everybody free of cost to the patient. There's also mercy medical angels that will provide transportation outside of our own grant funds. So access should be available to everybody even if there's nobody in the heartland that's a center for the UDN. Yeah, so that's a good point. So to summarize, when we talk about transition to care our primary focus, our primary mission is diagnosis. But I think the general consensus is that that's just one kind of key piece of what we're doing and that has certain obligations that if we talk about this program having impact beyond its initial mission, it's how do you change the life of the patient? It's dependent on several things. It's dependent on effective utilization of resources and within the network, those resources are insulated to some point to the current medical delivery systems but not real life limitations of distance and patient access and referrals. But when we look at what the models of how this would be translatable into a clinical setting that's gonna have impact on both resource utilization, resource access and then also those collaborative networks that were identified that are kind of key both in continuing clinical care as also advancing research in these disease areas both amongst ourselves as well as with collaborators. And then also we need to have a standardized plan on how we evaluate what happens after we've made the diagnosis or when we've left the patient without a diagnosis and to realize that within the network there is diversity and we should capture that and evaluate that and refine that through the course of the network's longevity but also that that's going to also be important on how the future versions of this exist beyond what is specifically funded at the moment. And we have some efforts to go ahead and do that now but as mentioned I think we should continue to look to refine that and ask ourselves how that can be best implemented and recognize that there will be differences once we release patients on what they've had access to and what the outcomes have been both regards to research as well as clinical outcome and there may be existing resources and other funded opportunities that we can already leverage to follow those patients or to continue investigation and or treatment but we may also need to look to develop new resources that make that easier and more effective. I think I'll stop there.