 Well, good afternoon, everyone. It's my pleasure to welcome you to the today's noon lecture. Today's really a very special treat to be able to welcome back a longtime friend and colleague, Dr. Laney Ross, to speak to us. Most people know Laney, but for those who don't, it is important to realize the extent to which she is a leader in the world of ethics in America and worldwide. A couple of things to know. Dr. Ross is the Dean's Professor and inaugural chair of the Department of Health, Humanities, and Bioethics and the director of the Paul M. Shivey MD Center for Bioethics at the University of Rochester School of Medicine and Dentistry. As noted here, she has a secondary appointments in pediatrics and philosophy. Laney has degrees from Princeton as an undergraduate from the University of Pennsylvania for her medical degree and a PhD in philosophy from Yale, and was here at the University of Chicago for 28 years where she was an associate director of the McLean Center. She ran the ethics consult service for many years and was the inaugural Carolyn and Matthew Buxbaum Professor here in the McLean Center. Laney always provides us with really outstanding topics and it's an absolute pleasure to walk you back, Laney. So thank you for being with us. Thank you. It's fun to be back. So I'm going to be talking today. The topic is thinking zebras, not forces embedding ethics into atypical diabetes research. I do want to disclose we own SOC and GE for tomorrow's squibs. I won't be discussing any off-label. I want to acknowledge the two grants that this is based on. And my collaborators, Rachelle Neller, Stay Nui and Manu, an undergraduate here. So is that better? Yep. Okay. Great. And a special thanks to the Phyllis leadership of Lou Phillipson, Lisa Littorno-Freyberg and Jeffrey Krishna who really have been behind a lot of the work on the Radiant Study that I'll be talking about today. So I think this is a great quote. Doctors are taught when you hear hoof beats think horses, not zebras, meaning a doctor should first think about what is a more common and potentially more likely diagnosis. But in genetics, we think of all the zebras. If a clinician isn't as familiar with rare conditions, they may spend too much time looking for quote, the proverbial horse. And I think this is really important because as we talk about rare diseases, we're going to realize that they're often being either misdiagnosed or at least misclassified and the health implications that will have for our patients. And so I'm going to be talking today about atypical diabetes and as you're going to see they're hiding in plain sight. So my outline is a brief description of diabetes. Then I'm going to talk about two different qualitative studies that I had the privilege of participating and I remain working on different parts of these two grants. So let me just begin with a brief description. By general pediatrician, I'm not a specialist in diabetes. So more than 37 million people in the US have diabetes. Most of it, the vast majority is type 2 diabetes, is about 5 to 10 percent that's type 1 diabetes. And then there's this atypical diabetes, also known as monogenic diabetes. And they're two different types, the neonatal diabetes and then the maturity onset diabetes of the young. There is actually a fourth type of diabetes, gestational diabetes. Some of them are actually modi type causes, but some of them are just uniquely to themselves. And I'm going to focus on modi today. So modi classically represents as non-insulin requiring diabetes in lean individuals under 25 years of age. And it often presents to appear to have an autosomal dominant inheritance. And it's important to diagnose when somebody has modi and not type 1 or type 2 diabetes because it can impact the treatment plan. And yet it's thought that about 90 to 95 percent of cases of modi in the U.S. are misdiagnosed, although probably more accurate to say they're misclassified because the individuals are told they have diabetes. They're just told that they have type 1, type 2. Sometimes they'll even be told they have type 1.5. But by missing the accurate classification, they may be being mistreated. Modi prevalence has been well studied in some European populations, but very under studied in those with African and Latino ancestry. So here are the three most common forms of modi. And again, I'm not an endocrinologist. But the most important thing again is that we need to be personalizing the treatment. And it specifically means, for example, avoiding insulin in most cases. So these patients, though, as I say, are getting a diagnosis of diabetes that just not being classified correctly. And so there are four ways to figure out how to diagnose these people correctly. The first would be to screen all adults. And we're coming up with enough different genes that you could actually make a gene trip a chip. But there's 37 million cases of diabetes. That would be incredibly expensive and wouldn't get us very far. I'm sorry, to screen the entire population would be 330 million people. If we only screened those who had diabetes, we'd still be at 37 million. Way too many people to be screening for that. If we just focused, as I said, and the other problem with screening the entire population looking for these modi genes is that they're not fully penetrant, meaning that even if you have the gene, it doesn't mean you're actually going to have any symptoms and doesn't mean you actually need any treatment at all. If you only screened individuals with type 2 diabetes, we're still talking about over 33 million people. We have access issues. And again, we still have the fact that even if you have the gene, it may or may not be actually the cause of your diabetes. So it's getting really complicated. Now, studies done here, Rachelle Neller and Luke Phillips and colleagues, have shown that it may actually be cost beneficial. But that would, again, one of the biggest issues here would be the issue of disparities in that the genes that we've located at this point in time are really those that are found in European populations, which means that we're not going to pick up many of the individuals who may be Hispanic or Asian or African ancestry who may have a modotype diagnosis. The most important method would be about better education of clinicians. So here's the problem. A patient comes in, you think they have type 2 diabetes, you give them a treatment plan and they come in two months later and they're not doing better. And we all sit there and the first thoughts are probably, well, was the patient adhering to the treatment plan, right? And so you try it again and you give them motivational interviewing and they come back in and two months later, they're still not doing well. And so the question is, is it because they're not following the treatment plan? And some of them will say, I'm not following the treatment plan because they feel guilty. And so like, OK, I had a piece of cake. Well, if one piece of cake isn't going to ruin the treatment plan, but for patients to think about what it requires for patient to understand whether they've been relatively adherent and then think about the role of the physician. At what point do we stop thinking maybe there are being adherent or as well adherent that people are in real life. And maybe our problem is that I'm treating them for the wrong type of diabetes. So we really so educational clinicians is really important. And again, the group here has been doing a lot of work for outreach to try to educate clinicians both to make sure that the patients are getting the right treatment, but also to make the clinicians aware to be able to refer them for atypical diabetes. And finally, the last is educating the public about what this is. And what you're going to see is that for many of our studies, the individuals who are in the studies are of high health literacy, of high educational status because in order to question your doctor, you sure you're treating me for the right type of diabetes? And the answer is you have type two diabetes and I had to do that. I do that in my sleep. The answer is, but maybe I'm not. Maybe I'm an atypical case. Again, so empowering as well as educating the public really going to be tricky. So that's what I want to show you is some of the data we're coming at because I think in the end it's going to be about the better education of clinicians and the patients. So let me begin by talking about the first study that I want to talk about, which is participant challenges in a monogenic diabetes registry. This paper was published this past year. They knew he was a postdoc working with us. Manu is an undergraduate here. And of course, everyone should know Rochelle Naylor in the Department of Peeds and Endocrinology. So the University of Chicago has a large monogenic diabetes registry. And at the time we were starting the study, which was in August of 2022, there were about 4,400 individuals enrolled in the registry. And about a quarter had a known cause of diabetes. And for those with Modi, we had about 499 programs and 333 relatives from 209 unique families. And this is an important point that we'll come back to because what it says is that only 42% of all programs had at least one family member enrolled in the study. When you think about it, if you have an autosomal dominant cause of diabetes, the best way to find out other people who also have atypical diabetes would be to do cascade testing. If you have autosomal dominant, that means your siblings have a 50% chance of having atypical diabetes. It means one of your parents has it and it means that 50% of your children may have it. So the fact that we only have, we have less than half of our programs enrolling anybody else in it means that we're really, it's a missed opportunity. And we'll talk about why that missed opportunity is such a big problem. And in fact, the aim of the R01 that Lou had put in focused on ethical issues in enrollment. And so what were the obstacles faced by an individual to enroll in the registry? And what were the obstacles to enroll family members in the registry? So we did semi-structured interviews looking at participants' experiences in navigating the healthcare system before and after receiving a confirmed genetic diagnosis. Participants' experience in deciding whether to share or not and with whom to share their modi genetic test results. And finally, participants' perceptions, expectations and suggestions towards the registry's framework to support cascade genetic testing. So that was our three foci. And our methods, we used qualitative interviews and we did a thematic analysis using Atlas TI after developing a coding trick. The details, the most important one to look at is basically that you'll see that their ages range from everywhere from the 30s to the 60s and 70s that many of them prescribed medication before receiving their diagnosis and after. So there was a change in management so it really is very important to have been able to diagnose these individuals. And we found six primary themes as we reviewed these qualitative, very rich interviews. And I just want to focus on two for the purpose of this talk today. One is the medical odyssey and the second is the whole issue of disclosure. So medical odyssey, so most as I said would have been misclassified. And so here's a typical quote. So it kind of got me thinking, so this is the participant, the patient, right? So that kind of got me thinking about it. And then later I had some routine lab work on and my fasting blood sugar was a little bit elevated, not extremely high, but a little bit elevated. And then I went to see a doctor a few months after that to get checked out. And she was the one that kind of said, you don't really fit the profile of type two. You're not really type one. So you're somewhere in between, I'm going to call you 1.5. And here's another example of a patient. They claimed I'm type one. I usually fall into the typical type one and they started with insulin after a couple of years. But my antibody was always negative which is atypical for type one diabetes. So I'm feeling just very atypical. So I just kind of read more about diabetes in general and I read of this form of Modi. The more I read, the more I'm like, hey, that sounds like me. So an incredibly educated participant. Here's another one. I started with Google, but then it went deeper. I went and found some of the different medical articles that were listing the different types, what the gene modifications were like, what the medication recommendations were and what the long-term consequences or whatever long-term outcomes were. Some of them had higher rates of eye disease and some of them had rates similar to the general population. So these individuals are really doing their own type of snooping and they will eventually come across the fact that we have a registry and we have a big website and we're trying to encourage them to enroll. The physician was sometimes an obstacle for some of these individuals. So rather than necessarily coming to us directly, they might go back to their primary care or their endocrinologist. And here's what one said. First of all, going to your general practitioner, convincing them that you deserve a referral to the endocrinologist who's going to book you out based on your hemoglobin A1C, which as these individuals were telling us, sometimes were only slightly elevated. So you're not going to get an appointment for about a year from when you get your appointment, which is what happened to me. So even though this individual realized that he was probably being mistreated because he was being misclassified, took him over a year to be able to get into an endocrinologist who might be able to help. And another said, I'm not going to go pay out of pocket for a specialist who doesn't really seem to be interested in figuring this out. And again, at that point, my hemoglobin A1C was 5.2. So it was like, you're fine. I don't know why you're here. That's what they're being told by the general endocrinologist, which meant then if the physician was an obstacle that the odyssey did not always end when patients received a new diagnosis. Because after some of them would come and they would get a diagnosis, they would go back and here's what one participant said. My doctor never thought about it, never heard about it. And she received the results. She was like, okay, you have Modi. She looked me right in the eye and she goes, so tell me why I should care. And I looked at her like, because you've been trying to help me take a drug for years that I don't need to take. Or another one said, the last endocrinologist I went to were just like, oh, well, that's nice. This is how we treat diabetes here and really just blew it off and didn't have any interest in thinking outside the box. So again, just think about it from the perspective. We gotta educate the clinicians. We gotta educate the patients, participants and just how isolated and how much empowerment and to actually fight the system to get the proper diagnosis. And then wanna look at then, so hard enough to tell your doctor that they're mistreating you, then we have to disclose to relatives and try to convince them to get a testing. How it works in this country, HIPAA privacy laws, the doctors can't go and call your relatives. They have to inform you and give you enough information to encourage you now to go tell your parents, your siblings and your own adult children. And so here's what they said. So actually I'm feeling frustrated when I do tell them this and they don't know what to do with it and they don't. They're not researching or even taking it serious. We have it pretty much narrowed down to my dad's side but their relationship with me with all of them is a little strained. I do plan to and they were so good about giving me info when I was collecting it to get into the study that I do feel like with them it's just so hard for me. So here was a participant whose family really was giving pushback and so she really didn't feel comfortable disclosing to further than just some immediate relatives. And then another said, he my brother didn't want to hear it. He didn't want to hear from his little sister who he calls me the geek egghead. He didn't want to hear from me. I couldn't possibly know more than his doctor did and that was his attitude. And the third said there's diabetes in my family. So when I called a male relative to say I found this diagnosis and I think most likely we probably all have this Modi and he was like, no, my doctor already told me what I have and just resistant, right? So their family members are sort of, I trust my doctor, my doctor's treating me for diabetes, we're done, stop bothering me. So even though these individuals were told they could get testing through our registry free of charge, they weren't willing to come. So what are the similarities and differences of the experience of people with Modi versus all other rare diseases? When you read the rare disease literature you hear everyone talks of the experience of a diagnostic odyssey. For many it's about misdiagnosis where here it's misclassification, but very, very common. And it's problematic particularly if it leads to unnecessary treatment or the wrong treatment. And then it led to of course problems with getting cascade treatment because we're sort of putting the onus or the burden on the participant to go tell their family. Now there is some pushback and in at least some European countries, the clinicians are allowed to bypass the pro-band and actually go directly to family members. Some family members might like that, others may feel, wow, if I'm not gonna have privacy from my own family, maybe I don't even wanna get treated myself. And so that's a very controversial and currently not accepted here in the U.S. And if I look at Millie Malikar telling her that that's what we were gonna do from an IRB protocol, she might not be very happy. So, but it is an interesting question though on the flip side, leaving the concerns to making it the burden of the participant. And so what can we do? Well, we can do things, we can give them pieces of paper explaining it, we can offer it if they would come in to talk to them about why this is so important and things of that sort. But it really is, we have this bottleneck of the fact that it's the pro-band who's responsibility it is to inform their family members. Second lesson is that the obstacles are both patient and physician-centered. The fact that these patients as research participants, so going back to their own physicians and not having their physicians believe them or even willing to look up what this atypical diabetes was and how it should be treated. So we have the obstacles that the physicians aren't helping, we have the family not fully embracing it. And you can imagine how difficult because of the high literacy and the empowerment that these patients have to really experience. And so we're gonna have real challenges when we get to individuals of lower health literacy, we're also gonna get to real problems in communities that don't necessarily trust clinicians as much so those who self-identify as racial and ethnic minorities. Problem was our study, it was self-selected, it wasn't a random sample from the registry. And of course anybody who has the diagnosis of Modi might not be representative of the larger US population living with Modi, given that, as I mentioned earlier that about 90 to 95% of people with Modi have not been classified out of this time. So what about the person who we think has atypical diabetes because they're not acting like somebody typically would with type one or type two but they don't have a known monogenic variant. So for that, Lou Phillipson and a group of us here at University of Chicago as well as at collaborating institutions started the rare and atypical diabetes network known as Radiant which is a network of academic health centers across the United States that aims to discover and define rare and atypical forms of diabetes by conducting both genotyping and non-genetic deep phenotyping. And so Radiant was the name of a large U-grant that were in the process of trying to get a renewal. And here was the incredibly complicated protocol that we followed in order to be able to identify people who didn't seem to have type one or type two, didn't have a Modi genetic diagnosis but we still thought they were probably atypical. They could probably be explained by some Mendelian genes if we could only locate it. And this was all described as you can see in an article not written by me explaining the whole protocol. And so they're three stages. It goes through adjudication. There are a lot of people trying to figure out what these new genetic variants might be. Radiant also has policies about what information it's going to return to participants. And that's become much more popular since probably in the last 20 years we used to just get research results and we'd publish it and we'd never actually say anything back to our participants or informants. And there's been a big shift, a lot of it pushed by patient advocacy groups. Some of it even being pushed by the fact that NIH is paying for a lot of it. And if it's our federal dollars why aren't we sharing it more widely? And so Radiant decided that it was going to return results. It's in stage one it returns auto antibody results which is very important because you usually have positive auto antibodies in type one. Stage two is for genomic information and we're going to return all identified genes associated with diabetes. We're going to exclude variants of unknown significance which becomes very important from a disparities perspective that we don't have large samples of individuals of African and Asian ancestry then we may not actually date these may be variants of unknown significance which if we got enough samples we might actually realize were highly significant or not. So we have that information. We are not sharing it back. They also in stage three which is the deep phenotyping we did laboratory and cognitive test results. And how we wrote the protocol was that participants cannot opt out of receiving critical abnormal lab results in stage three. So stage three may include things like a calcium so you can have a calcium of 12.5 which many in the audience might be nervous that it was something other than diabetes and things of that sort. So though we developed a list of what we would consider critical results it had to be consensus and those even if you say I don't want any results those are going to be reported back and that was made quite clear in the consent forms. So radiant actually is a fusion of two different networks that are seeking to identify new diabetes variants. Dr. Phillips incorporated an ethics component and so that's why when they merge these two we retain the ethics component. And so I've been working with the rating group but then last year NIH announced bioethic supplements and we applied in 2021 and were funded for this project from September 2021 to September 2022. And our supplement actually decided to focus on the return of non-genetic results. It's a huge literature on the returning of genetic results what to do with variants of unknown significance not that I'm saying that anything's been finalized but there's been a lot written about it but we were interested about what happens when you do deep phenotyping and you get details of patient reported outcomes physical exams and what does it mean to promise reporting back all of these results? And so that was what the project we wrote and that was what got funded. So now I'm going to talk about that study the non-genetic data in a monogenic diabetes study and this paper was just published a month and a half ago and it's called investigator and participant expectations for returning non-genetic results insights from the radiant study. And again, the same four of us collaborated on this study and it was a mixed method study to explore both participant and investigator perspectives. So the participants, so again, these are people who have diabetes. We think it's atypical, they don't have a modi variant and we wanted to ask them about their decisions regarding the return of results sharing the information with their healthcare professionals who should explain tests and test results for the participants and who should order and pay for additional evaluation arising from abnormal research results. So if you're going to do these tests and return it and you tell them it's abnormal or needs repeat follow-up who's responsible. For the radiant investigator, we wanted to ask about their perceived roles and responsibilities regarding the return of clinical and lab findings to individuals with atypical diabetes and also ask whether participants should be allowed to abstain from receiving abnormal but not critical results. We even wanted to know whether they thought they could abstain from receiving critical results but given that there was too much pushback my colleagues, my clinician colleagues and I don't blame them, we're like, no, if it's a really critical lab, we're returning it no matter what. So we acknowledge that in the consent form, we acknowledge that in this study we weren't going to go there. So the mixed method, so that we were going to do qualitative interviews we were also going to do some surveys. So for the radiant participants, we did the brief and realm, which are just looking for adult literacy issues. And we also asked them some questions to state their agreement from one to 10 with some statements about returning results. For the radiant investigators, again, we audiotaped and then we asked them a survey about their own experience with some of these phenotypic studies that they might be doing and be asked to return and explain to the participants. We had originally thought we were going to include the PHQ-8 and the GAD-7, which are tests for anxiety and depression, and then realized that if you did that, one of the questions, for example, on the PHQ-9, the ninth question is, are you currently suicidal? And then if they said yes, how are you going to deal with it? So we instead dropped that question, there is a validated PHQ-8 and just asked about history of suicidality because we realized that we're dealing with this blurring of the lines about being a clinician and being an investigator. And for another talk, I can talk about a study that we're doing, which is looking exactly at the struggle that many clinician scientists face because they're enrolling people who they're actually also taking care of. And what does it mean? How do you wear those two hats? When do the lines blur? When do you have to really distinguish between them? Anyway, so the decision, as we talked about, what it would mean if we actually return these results and if we got very hard results about sending individuals even to an emergency room and things like that. And since these studies will only be done in several sites so people are flying in from all over the country and then hospitalizing them outside of their own medical network and all of that, the decision was to exclude those questions and just ask history of anxiety, history of depression and things of that sort. We got IRB approval for our project because we're only looking at their attitudes and perspectives, we got verbal consent from participants. So at the time we were doing this, so this was an early part of the radiant study, only 21 participants had completed all three stages and remember it's in stage three where we're doing the deep phenotyping. So 21 participants had completed all and all had agreed to be recontacted but we only had 21 participants. They were all invited to participate and were interviewed on a first come basis. Although after seven interviews we sent targeted reminders to male participants so that we could get five males and five female participants often hard and genetic studies to get men. We did 10 participant interviews were conducted and they lasted about 60 to 100 minutes and all though had agreed that they had wanted to receive all results. So there wasn't a lot of diversity in that. And again, these are very educated, health literate individuals were not surprised by that but at the time that our study only one had actually received an abnormal result. Here's what our participants look like as you can see their age range from the 30s to the 70s. You can see that all of them had at least some college with I think it was 70% having at least a graduate degree and the brief out of 20 the lowest score was a 17 showing again high literacy and the realm with a high of 66 the lowest is 65. So an incredibly highly educated group. And here when we asked them about their attitude about return of results and what the investigator responsibilities are what you can see is that the statement results from this study that pertain to medical conditions other than diabetes are helpful. And of course they are highly, highly saying yes. If you look at the bottom what they don't agree with research results about medical conditions other than diabetes should not be shared because I did not sign up for things unrelated to diabetes. Basically they wanted everything. They wanted to know not just about their diabetes but if you found something else, please tell me. Our investigators we collected very little demographics because there were only 13 clinicians involved in the whole radiant doing the part three physical and we felt that getting any information other than that they were an investigator would identify them because there were very few females for example very few who were non-European ancestry. We were able to get up to the 13 one was excluded because a team member. So it left us with 12 and six women and four men agreed to participate. And what you can see in the laboratory tests and clinical practice many of the conditions were things that they frequently ordered so that they had a high comfort level and in the deep phenotyping when asked about specific parts of the physical exam again most of them had performed those although only half continually performed the fundoscopic exam and very few had actually been performing cognitive testing or using the PHQ or GAD7 in their clinical practice. And their confidence not surprisingly correlated with how often they're actually still using those type of phenotyping studies that they did. We asked them about their attitude about the return of the results. And here what you can see is that strongly agree over 90% said it is the responsibility of the participant and the healthcare professional to act or not act on research results even if I disagree. So here they were really saying as a researcher I got it if they don't wanna do something I tell them I can try to encourage them to do it but in the end it's their decision, right? But then you can look at the bottom again you could see that 0% agreed with the statement research results should not be shared if the participant does not have access to a healthcare participant. And what we were getting at here is so you return these results and you're not gonna do anything cause you're in a research study but they don't have health insurance so how are they gonna pay for the followup care? They were all adamant these individuals need to have that information they get to figure out how they're gonna deal with it. And they also were 100% in agreement all research participants should be required to have health insurance in case of an abnormal results they said no 100% disagreed. They don't have health insurance there's still other ways that they can seek out healthcare even if it went beyond the study. So very much wanting to give autonomy to the participants. And then we did so that was what they wrote on these scales and then we had we had interviews with them and really pushed them on some of those themes as well. And for the purpose of this talk these are the sub themes that I'm going to talk about since I'm gonna go through each of them not gonna read them out loud. So again, hearing about the experience of being diagnosed with atypical diabetes it's gonna sound very similar. You know, my doctor expressed surprise because my body type is not what they typically think for diabetes. So there wasn't much more than how do we manage it? And once it just before I turned 60 my A1C turns up 6.1 and at that point the doctor diagnosed me as type two. And so another few years down the road was when I had DKA at 64 which made the doctor say it doesn't sound like type two anymore. And so that's how they got their diagnosis of being an atypical diabetes. Their motivation for participating one of them was clearly it was going for improving their own diagnosis. Yeah, I wanna get to the bottom of my diabetes and see what I have because it doesn't fall into any category. So that's what I wanted was just to get some answers on what I have. And another said for me it's to hopefully understand better the cause for my glucose intolerance my diabetes if there are better methods to treat it and how common it is. So one of the motivations is clearly this is about me I wanna improve my own diagnosis but they also were clear that they wanted to advance science. One of my endocrinologists actually they couldn't explain how this had developed so rapidly. They just said, would you be interested and they explained that it might not explain mine or that it's just background research information. I said, sure, why not? So sounding very altruistic there. And in other words, well this study the objective I hope to gain wouldn't benefit myself. It's really just a kind of the information that can be gathered and utilized for future and for anyone else that might have the same type of symptoms that I might have. So understanding I might not get a diagnosis but this may help people down the road. Some of them talked about those people maybe even being their own children or grandchildren. So one of them saying, you know a better understanding of why people like me get diabetes. I don't know that I'll have the understanding but the medical community hopefully will help my son or my grandkids get it. So it'll be more proactive. Or another said, oh it's just I have a personal wish. I'd love to figure out what's going on. I'd like to know if I'm gonna pass this along and what signs to look for but I also look at the grade of good. You know, if you can learn something from me that would benefit the population at large or even people that are future diabetic hopefully that comes in handy. And finally another one said, as time went on I realized that I was feeling very positive about something good coming out of something so bewildering and kind of scary. And that would be to help someone else down the line someone I'll probably never know or meet. So there was a real strain of just pure altruism about receiving genetic results. They all agreed that they wanted all results that were being offered. In fact, all participants had also selected to send it not only to themselves but to their primary care doc except for one who was concerned about privacy issues and said, I wanted the results to come to me and then I could choose on my own outside of the study to give results to my physicians. The study is potentially collecting my genome information and you could be denied insurance, health insurance or life insurance or something like that. So I wanted to know what the protections were. So here was somebody who wanted to have total control and decide who he was gonna share this information with. And this is a theme that comes up in many of the research that they do. I think that surprises some of us as clinicians how much our patients and our research participants don't wanna necessarily tell us everything. They go to different hospitals so they have privacy about one health condition that they might have. They pay out of pocket because they don't want somebody to know that they're seeing a certain type of clinician, et cetera, et cetera. So about receiving abnormal results, remember we only had one case so far of somebody receiving an abnormal result and that turned out to be a spurious result. So we really don't have a lot of good qualitative details on it. And so the only one we had was, so one of my results came back sky high through the roof. I received a call from the doctor letting me know like asking if I was okay and just letting me know of the high results and asking if I could go ahead and get my labs done again just to make sure everything was okay. And that was just an error. I have to tell you that was not paid for by the radiant study. It was done by the privacy of its own doctor. So what is this difference in responsibility in the clinical and research settings? So there is some patient understanding of this blurry line of when they, between research and clinical practice and including some who actually the researcher was actually their primary endocrinologist as well. But here is how one understood this blurry line. I think there's an obligation to make sure that the person has the opportunity to know that information and to provide ways of giving clinical care. You know, I don't think it's really the study's responsibility to follow up and make sure that they actually are doing it, but I think it's the responsibility of notifying providing some guidance and helping to coordinate some of that. So clearly someone of high health literacy but also empowered to figure out, give me the information tell me what I need to know and I will get it done. But you can imagine that if we had had participants who are of lower health literacy, that might not be enough. And so we need to think about that blurring of the lines. And so here was the second one who said, well, in my case, it's the same person doing both. The radiant investigator is my physician. He's supposed to be looking out for my best interests and trying to think about how to manage my diabetes. In his role in radiant, it's a researcher. He's trying to think more broadly and try to understand or just help discover what causes various atypical causes of atypical diabetes. And you know, if those findings don't have a direct relevance to my healthcare, I don't think he's obligated to share them with me. So here was someone who clearly distinguished that her endocrinologist was when he was playing the role as researcher. The investigators felt this conflict as well. And here was one investigator, but I think we do have an obligation. Again, I mean as physicians, but even I would say as a researcher, if there's something that has a potential like real health implications that we do, we need to do our best to inform them and let them know. So this was in response to what are you gonna do if people don't wanna get their results and really feeling a lot of discomfort about not sharing that information. Oh, I think my responsibility is the same as a researcher and as a clinician because I owe that information to the patient. So the responsibility is definitely the same. And if there was an abnormal lab, I would try to communicate the same way I would do as a clinic patient. And that was despite the fact that we kept saying, but what if they said they didn't want this information? And there was just like this medical information, they have to get it back. I mean, I think that the responsibilities convey the information and advise them. So on the flip side, some investigators really wanted that bright line, right? I think the responsibilities convey the information and advise them to follow up with their provider regarding it. I don't think I need to call the person the following week and make sure they did it. So distinguishing as his, if he were the endocrinologist, he would call and follow up, but as a researcher, he wouldn't. And another one said, no, I wouldn't follow up because like I said, that's now the patient's responsibility. My responsibility was to inform them that they need to see their specialist for their primary care, but then they have to take ownership of their health. So you really heard some of this tension that some were feeling, I can't distinguish those two roles and others felt they could. Then we tried to understand how they would distinguish if they got actionable results. And here was, you know, in a clinical environment, you get the results back often within hours. And so you have the opportunity to intervene very quickly. Whereas in the research environment, you set up a test result that it may not come back for days. And so the impact can be different. The results ought to be communicated, but you know, it's a different level of concern. So pointing out just the way we structure research where we'll batch things makes it harder to actually be a clinician in those circumstances. And another investigator said, I mean, in practice, I think there's a lot of clinical judgment that goes into what's an actionable result. For the most of the research protocols I've been involved with, we define what's actionable as part of the protocol. So basically saying when I'm on protocol, if it says it's actionable, then I do what the protocol tells me to. And if it says it's not actionable, then I just leave the results as they are. We've questioned a lot about financial challenges because some people, as we know, do participate in research because they can't necessarily afford access to specialists or even primary healthcare. And here were some of the comments by the investigators. I mean, the possibility of secondary findings is not a reason to exclude them, them being people who don't have health insurance. In fact, it's a reason to it. It's a good reason to bring them in because frankly we have a lot of patients who only get their primary care through participating in one of our studies. And another said, I think to make a requirement for health insurance would be more of a hindrance and a benefit because I think you'd be self selecting a certain group of people. And if one of our goals is to actually recruit undisturbed populations or racial minorities, we would be missing a lot. No, I think it does open a can of worms in saying no, follow up with a medical provider. So even though acknowledging the difficulty of giving this information to people who may not have access to healthcare, all wanted to enroll these individuals in the study. So what did we get from that? Again, I think there's been very little attention to the non-genetic. There's a very rich literature on the return of results of genetics. I think our participants, and that includes both the researchers and the patients with atypical diabetes, pointed out the importance of returning results, not limiting it to genetics, but also the non-genetics. And I do think that it showed us the tension, really shouldn't be the distinction, the tension between patient versus researcher, clinician versus investigator and how they interact on those two different relationships. And that's actually part of a different grant that happy to talk about in the Q&A. So the return of results, everybody in this study at that point had wanted to receive all results. All the investigators supported returning the genetic results, excluded those that had been excluded by the protocol and putting many of the variants of unknown significance. They also supported the return of results of non-genetic. And again, I think if you look historically, before the year 2000, you would see very few studies ever returned to any results and very few investigators who wanted to return results. So I think we've really seen an attitudinal shift in the last 20 years. Some investigators wanted to return clinically-action results, even if the participants didn't want to receive them. You could hear their clinician side of them. No, they need this information. And I'm saying, but they're in research. So it's voluntary and they were really a lot of pushback. They also supported returning results, even if the participants lacked, as they said, access to other providers. And that this whole blurring becomes very difficult. And so you hear it from both sides and then you wonder, so everyone likes to talk about the therapeutic misconception that our patients are misunderstanding the difference. I think there's also the therapeutic misconception even within the clinician investigator as well. And so, and that to me is a really important issue because it's one of those questions. I don't know that we're really training our clinician scientists about. So this other project actually is trying to understand what type of ethics training clinician scientists would like in order to be more effective as both clinicians and researchers and when they wear both hats. So the limitations of this study, the radiant just like the R01 that I described was, well, this one we did it very early. So we didn't have a lot of participants and all of the ones who had participated were very high literacy. And at that point we had only had one result returned. We are planning to return abnormal cognitive results which may create even greater challenges, but none of them had been abnormal at the time. So we don't have any sort of qualitative or quantitative data to look at for that. Again, many individuals with atypical diabetes are either not identified or misclassified, but I'm trying to emphasize just how much health literacy requires on the participant patient side that I really think that's gonna be a severe limitation unless we figure out ways of really engaging with clinicians who take care of people of lower health literacy and really convincing them to enroll their participants or their patients in this studies. So the barriers to inclusion is the need to understand that their diabetes was not typical, the ability to invest time into advancing science, even though they might not get a diagnosis themselves and the time and flexibility to participate. As I said, there were three stages, one of them required them to come to one of the sites so even though we're recruiting across the United States there were only a limited number of places where they could come to get their phenotypic. And even though we would pay for their affair, pay for their hotel, it's still being able to take off a day or two from work and things of that sort. So what is the radiant supplement highlight that when clinicians and researchers were historically hesitant to return the research results that has been the shift? And although the difference between clinical care and research is acknowledged by both, there's a lot of blurring and sometimes even though they say in their survey, I definitely wouldn't do this, definitely wouldn't do that as we talked and pushed them with case examples all of a sudden they really wanted to get those results back to the participants. So again, I wanna end where I began by acknowledging the funding organizations, the NIH and these two different grants and all of my atypical diabetes collaborators. And at this point I'll take questions, thank you. So the question is for those who might not have heard. So could we use the public health system as a way of making in a sense like a modi diagnosis or reportable disease? First of all, our public health infrastructure we've decimated in the past 10 or 15 years. So until we get a real influx of money, I think there are a lot more important things to be doing. So that's point 1.2 is one of the stresses is some studies are starting to come out, for example, of the UK has done a 500,000 person and they're showing that some of these genetic variants are actually more common than we had anticipated so that their penetrance and expressivity is not as high as we might have thought when you're working in high risk families. So that gets me nervous as well having the public health department come in when we don't really know what their penetrance and expressivity. So at this time, no, but it's a interesting novel way of trying to get that information. Of course, that does get again to questions of privacy because if we told people, so if we get a genetic diagnosis, we're sharing it through the public health, it may also be a detractor for people who might want health privacy because of relationships with their family, estrangements and things of that sort. So thanks, that's a great question. Julian. So the question is, did you, when you were looking at the return of results, did you also look to see whether there are any demographics that might explain it, whether it's their political party, their worldview and things of that sort? No, we didn't. We didn't. It's an interesting question. I think though that in all fairness, the shift has been almost complete. I mean, you really go in 2000, nobody's returning results. And in 2024, we're returning results in the research realm. And let's look in the clinical realm. We went in 2000, where if you wanted to get your medical records, you had to either pay for them, or you could send it to another doctor, but you couldn't get access to your results. And today we have open charts and sometimes our patients are getting their lab results before we do. So I think that whole shift of patient owning their own access to their own data is sort of like a fade out, a complete. I would be surprised. I mean, we might see some slight differences, but there's just, it's a very high consensus at this point. Mike. Standing press base. I think that it is, are several things. Not only that we want the city to decide who's going to vote, not elect, who will be the section. I think the critical thing to do is to be aware of these theories. What I really want to turn is Jeff Roscoe, a trauma child, is out here today, all children who is part of the culture needs to receive the best of, you know, medical medicine. That creates another level of pressing thing. And what would you suggest? So that as we use the power of the moment to advance their death manner and our participation in medical partnership, what we do about the inequities and the craziness is just going to be happening. All right. So for those on Zoom, two questions. The first is the inequities that are really created by our current insurance and that there are many parts of treatment, particularly for individuals with rare diseases that may not be covered or we need to go and get pre-approvals and things of that sort in all the complexities of that, which is unique to the United States given that we don't have a national health insurance. And the second question was the maternal child health bureau wanting to really have genomic testing of all individuals with special needs to try to figure out what the underlying basis is. So hopefully that we can advance the therapies and the inequities that leads to because we're putting all of our in a sense all of our eggs in one basket that we're gonna understand it through genetics. Sort of what Mike is really saying and ignoring the fact that so much of even in a rare disease is the environment and all of the psychosocial factors that come into a disease. So the answer is, Mike, as you know I totally agree with you that the inequities are a huge one and that we're sort of downstream trying to deal with people at this point and what we really need is a public health infrastructure and a better primary care system so that we're not always going for the subspecialists and things of that sort. So I'm on your side on everything you said. So thank you, thank you for that comment. Is that there isn't a mechanism to follow up. It's like maybe not for me, you have to say you can't do surgery of the data network. We don't know what surgeons are needed. Got it, got it, got it. But I think the whole aspect of the ethics of not screening a form of public information or which patients have permanent glory is brought with us, brought with them. So Mike then went on to talk about that you shouldn't get test results unless you have a whole systems in place that we don't talk about newborn screening as a test but we talk about it as a system. And I agree with everything you said but that's actually a little bit more in the clinical setting and this is the research setting. So I'm gonna refrain from going too much further on that comment. So Mike asked the important question, returning the results if we're not even sure what is noise and what is clinically significant and that was why, for example, in the radium we spent so much time agreeing on what we were going to call the critical results while we're gonna be considered within normal limits and in the genetic part of radium the decision was only to be required to return diabetes genetic information that was relevant to their cause of diabetes but to ignore the variance of unknown significance because of the concern of noise and that people may act and not necessarily act in a good way because we really are clinically unsure. Now, some people might push back and say why not let the participant be involved in that ambiguity, that uncertainty and just engage them in that. And again, it gets down to is there a difference in what you would do clinically and what would you do in the research realm? So it's a tough line, correct, right? So the point that Mike is bringing up is that the tension between the roles of clinician investigator, participant, patient, each of them may have different thresholds for uncertainty, for ambiguity and how they interact and sometimes you'll get congruity in that they both have similar attitudes and sometimes you don't and how do you deal with that? And that's why the whole notion of what we call translational bioethics, that notion of thinking about these issues and how do we approach it? And again, that's just from the clinician side. We then also have to figure out how are we gonna educate our patients who will be in a sense participants and as Julian would like every patient to be a research participant and every research participant to be a patient but to really do that right requires a lot of education and helping people understand what that really means and I don't think we've come close to that, Peter. So thanks, this is great. I've really struck the several quotes from patients or family members who said, I go to my doctor and say, I have no need in their life so long. And so it does seem to me that sort of, it seems as though it's almost more than the disclosure of results, patients. It's disclosure of results and I can handbook for their doctors about what to do with the results. So it's a great point. So Peter brings up, these patients, they go to the docs, they say, I have Modi at the docs is so what and what are they supposed to do? Some of them literally bring in reams of paper but sometimes patients bring in reams of paper that aren't necessarily clinically relevant and doctors have to sift through it. So the real question is, how are we educating? And my biggest fear is that because we think that, I mean, I remember being trained in medical school, common things happen commonly and it's drilled into you. And so when a patient isn't responding well to a medicine, the first nine thoughts are they're not because they're not doing what we told them to do, they're not being adherent. So how do we get us to switch faster or to at least have in the back of our mind, I'd be not adherent, but there might be something else. And maybe there's something I can do that before I have to get to a whole genome that I can at least start thinking that there's something that they're doing right and I'm missing something. And that I think is really a lot about education. So, you know, I'm a big fan, I'm doing my MoCA Reboard Certification and now it's in the continuous. It's no longer every 10 years should take an exam. And I think that's part of the way and you know, including some of these atypical and yet again, on the flip side, imagining 40 patients in a day and saying to yourself, I treat type two diabetes like this works for 19 of them. Why isn't it working for this person? So how do you really get the physician to remain curious? I don't know that answer, but we need to be thinking about that. So it's after one o'clock, I wanna say thank you to all of you and it's nice to be home. Thank you to all of us and really anyone who wants to come and sit for three rows and spend a few more minutes with us.