Thank you everybody, we'll go ahead and get started. It's the last day of CHEST and the last session, so I very much admire your commitment and I think you'll be rewarded because we have three outstanding presenters today, faculty members who are gonna talk about diversity and CF and then me too. So I am gonna talk a little bit about limitations of newborn screening, well really diagnostic testing, but in order to keep my talk on time, I'm gonna limit the amount that I talk about. Sweat testing, I'll be here at the end if you wanna have questions about that. So hello everybody, my name is Randy Hunt. I am an Associate Professor at Emory University where I'm the Medical Director of the Adult Cystic Fibrosis Program there. That's in Atlanta, Georgia and I have nothing to disclose for this particular talk, but I do wanna spend a little bit of time talking about newborn screening. It's actually different between states, although there are some similarities and then we'll talk about some limitations as well and again, we have wonderful experts here too, so if I say anything, Dr. McGarry, that is incorrect, please correct me. So for anyone who has heard CF or given your own CF talk, you've probably all talked a little bit about the history and I'm sure most of you have heard about this old nursery rhyme. So CF has been around for tens of thousands, if not hundreds of thousands of years and there's their old Dutch nursery rhyme that loosely is translated to something to the extent that it is, woe is the mother whose child's brow tastes salty for he is bewitched and soon must die. And I guess in many ways that might have been the very first newborn screen, but it wasn't really until 1938 that we had actual modern medical terminology for cystic fibrosis when Dr. Dorothy Anderson published her work and coined the term and over the next several decades, she would really be seminal and developing a lot of the phenotypic understanding that we have of CF and within the first 10 years after coining the term, her and Dr. Hodges had recognized that it was an inheritable disorder of autosomal recessive propagation. A student of hers, Dr. Paul de St. Agnese later would study chloride manifestations in CF and some of his early work would eventually lead to the sweat chloride testing 10 years later that remains one of the gold standards of our diagnostic evaluation for persons with CF. But it would be another 30 years before we actually would find the gene. So here Dr. Choi, Riordan and Collins are pictured after publishing their collective works in August of 1989 where they described the gene that was related to CF and the CFTR-related protein. Since then, mutational analysis has been certainly part of our genetic workup. This is the algorithm by the CF Foundation for CF diagnosis. CF diagnosis can get quite muddy, particularly in individuals when they're being diagnosed a little later so I'm not gonna belabor that point but very briefly and generally speaking, a person for diagnosis needs some clinical signs and symptoms consistent with disease and then some evidence of CFTR dysfunction. That may be sweat chloride elevations or CFTR mutational analyses consistent with genetic mutations that are consistent with CF or even nasal potential difference derangements. But the sweat chloride by far is the most common test and is non-invasive and again, it's not perfect. It has its limitations and I'm gonna skip over those today to focus a little bit more on newborn screening because while the sweat chloride test is important, it still is a diagnostic test. Ideally, if you could capture a person before they have phenotypic manifestations of their disease and intervene early, you could potentially attenuate the disease and so thus that would be really great for any disease but particularly for CF and it became feasible in 1979 when it was discovered that immunoreactive trypsinogen could be measured in dried blood. Trypsinogen is an enzyme. It's typically released by the pancreas into the bowel. In cases where the pancreas is blocked, such as in CF, the enzyme backs up and you can measure it in higher levels in the blood. And it became notable that this was a potential good screen for individuals with CF because of their underlying issues. So after that was discovered within just a couple of short years, a few states instituted newborn screening. Colorado was the first. A couple of other countries started about the same time, UK and New Zealand. But it would take many years before it was adopted universally, at least in the United States and several guidelines to suggest doing so. But finally in 2010, the CF newborn screen was instituted in all 50 states and the District of Columbia and it's been fairly successful, although there is a lot of variability between states as to how they perform newborn screens. So this is retrospective registry data of CF registry here in the United States over about 20 years and this is looking at individuals who were born with CF prior to newborn screening, which is the blue here, or during the time of newborn screening, which is sort of this orange color. You can't see my, anyway, sort of the orange color there. And they controlled for other factors. And what they did find is that if you were born in the era of newborn screening, that those individuals were much more likely to have improved weight to height percentiles, had better lung function at any given age, and they were less likely or had a longer time to acquire Pseudomonas aeruginosa as an infection. And today, still about 2 3rds or 64% of all new cases in the United States that are CF are diagnosed on newborn screening. But as I mentioned, there's a lot of variability between states, so every state starts with an immunoreactive trypsinogen and a positive level is different in each state. Some of them look at 99th percentile of all immunoreactive trypsinogen levels within that day. Some of them look at set values. And beyond that, once they have a positive screen, what happens next is variable. So some states, about approximately 15%, just repeat that IRT test. And if both are positive, they'll reflex and send somebody to a CF clinic for further evaluation. Other states just use one immunoreactive trypsinogen test. And if it's positive, they'll do a mutational analysis of varying lengths. And then some states do a combination. And it's quite variable. So for example, my home state where I grew up in South Carolina, they don't use mutational analyses, at least as far as I know. They just do two IRT tests. And California, they have a little different take. They have an IRT test, and if it's positive, they'll do a narrow mutation panel. And if they have a hit on that with at least one mutation, then they'll do a further sequencing. You can imagine the problem with that is if you have rare mutations that aren't found in that first mutational panel, you may miss people. Likewise, in South Carolina, if you have IRTs that are underneath the threshold because they have a minimal function mutation, they may never be caught until later in life, too. And there's a lot of variability between all the states. So this was work looking at, well, what mutational panels actually are used in the newborn screening? And it was very hard to get this data. So 15% of states actually don't use mutational panels, as I mentioned. I just learned today, Dr. McGarry informed me that there are now just one state that looks at Delta F508 only. That's their only mutational panel that they look at, and that's Wyoming. And until a couple of months ago, it was Wyoming and New Jersey. And then other states use various panels of varying degrees. So in 2004, the American College of Medical Geneticists created a 23 mutation panel that they set forth to be what they felt would be reasonable for large population carrier screening for CF. And again, that was carrier screening. It wasn't meant to be a diagnostic panel. It wasn't meant to be a newborn screen panel. But because it existed, it has been incorporated in all of these mutational panels that are commercially available. The problem is is that not all these mutational panels are equally effective across all races and ethnicities. There's a lot of data here, but I just want you to focus in on the lines that are within the red boxes. So if you look at the one state now that just uses Delta F508, the very top rows there, then you're gonna miss about 10% of individuals who have white ancestry. And it's really, really low for other ethnicities or ancestries with black and Asian Americans having 40% of individuals who have no Delta F508 at all. As you move down the rows there and you get to the very bottom where the Luminex, which has 39 mutations, it does improve your catchment area. So 3% of individuals who are white will still have no mutation variants detected on that. But there's still a very heavy number of African American and Asian Americans, upwards of a quarter, who will not have any mutations on that panel. So this was a retrospective study looking at individuals within the CF registry over the 20, about 20 years, since newborn screening was instituted in all states, where they looked at individuals who are white and basically other individuals. They grouped them in those two cohorts. And what they found is that despite having newborn screening in place, individuals who are white were more likely to be diagnosed earlier and also have earlier times to first events, which included things like either sweat chloride testing or even being seen in clinic. And interestingly, those same individuals in that group had higher levels, or higher weights in the next one to two years. So this is just tablature data showing that if you were white compared to non-white, you were much more likely to be diagnosed earlier, have earlier events to first events. You're less likely to carry other unknown mutations, and you're more likely to be picked up on newborn screening. And this is looking at, well, what are the mutations within at least a defined population? So this is U.S. data, again, looking at basically everyone in the registry and breaking them down between white and non-white. And it's pretty notable that Hispanic, black, and Asian ancestry are much less likely to have two identifiable CFTR mutations. And they're much more likely to carry no mutations that are found on that ACMG23 mutation carrier screen. And this is true, well, this is also true in other parts of the world as well. So this was UK registry data, along with CFTR2 data, which is a large database of CFTR mutations, specifically looking at Asian heritage versus non-Asians. And they found in this population that if you had Asian descent for your individuals living with CF, that every sort of diagnostic criteria we think about, so phenotype, CFTR mutation, CFTR function, were all different in individuals with Asian. So for example, they were much more likely to be pancreatic sufficient, and thus for potentially have lower trypsinogen levels. They were much less likely to carry a delta F508 mutation. And they were much more likely to have sweat chloride levels that were under the typical diagnostic threshold of 30, 60 millimoles per liter. And this is data from that same group. I just wanna draw your attention to the E, or the dark section of the pie graph there, which just represents that for Asian descents, more than 50% of them had a mutation that was not found on the typical mutational panel that they used. And Sontag, and a lot of, so Marcia Sontag, Susanna Macaulay, Clement Wren, that group has looked at newborn screening within the United States extensively. And this is a qualitative study that they had performed, looking, asking newborn screenings, both centers, as well as CF centers, and divided them into groups that had early referrals and later referrals, and basically asked them a number of questions. And some themes that came up, one of them I wanted to highlight was one theme that was very prevalent amongst many of the centers, both early referrals and late referrals, was this concern that there's a misconception in the community that CF is still a white person's disease. And so here's some of the quotes that came out of the theme from that particular topic. I won't read them all to you, but essentially it's the very concern that individuals with other ethnicities, individuals of other races, may not be deemed as being at risk for cystic fibrosis, either through the community, or have later referrals for those reasons. So what can we do to improve newborn screening? Well, one thing would be to, for any positive tests that come from newborns with known non-white ancestry, they could get fully sequenced. There's some problems with that, though. Not everyone knows their ancestral history. How do you record that data? How does that get incorporated into the analysis? Other thing you could do is look at genetic panels that are reflective of the regional spectrum of ethnical and racial diversity. Some difficulties with that is, first, you have to define what that spectrum is for your region. And even if you're able to do that, which takes time and money, you still may have inherent inequities within that panel because people are not stagnant. They come in and out of regions. You could sequence all positive samples, and that would be great, but it would be super costly, both in time and money, and you're gonna find a lot of mutations that have variable significance, or are unknown, and then you're gonna flood, potentially, your CF centers, and create distress in individuals' parents who, you know, their child may or may not have CF, and it's hard to say with these other mutations. Next-gen sequencing may be an interesting aspect to add on to this, and it could fit into any of these potential aspects. Next-gen sequencing is a parallel, high-throughput system of sequencing that is perhaps more cost-effective, but it has not been, at least in a wide spectrum, been introduced into newborn screening just yet, at least not for CF. So the foundation's very interested in making newborn screening more timely and equitable. A couple of years ago, they came out with a call for applications where individual states could apply with their own applications to see how they could improve their newborn screening process. I think they're two years into this now, so hopefully in the next year or two, we'll start to hear some data from some of the work they're doing, and hopefully, some things will be applicable to the larger community, not just regionally specific, and Dr. McGarry just informed me that she and others are working on guidelines specific about newborn screening that can hopefully be applicable to the entire community and not just one region or one state. So in summary, newborn screening, super important. Early diagnosis is important to capture individuals before phenotypic manifestations, and especially with modulators being so prevalent now and being now approved to younger and younger ages, you want to start those earlier. But there's still significant variability between states, mutational panels probably don't accurately reflect heterogeneous populations, especially like we have here in the United States, and a lot of further refinement is needed, and then communication is really important. Probably not amongst this group, I think we all recognize that CF is not racially unique, but there may still be some individuals out there within the community that need some education about that. So with that, I will finish up. I think I'm right on time, so this is my email. I'm not gonna take questions until the end just out of respect for my other presenters, but we'll switch over. Next up, oh yeah, thank you. Next up is Dr. Sanjay Devarajan. He is an assistant professor at Baylor University. Hey, everyone, aloha. Thanks to Dr. Hunt and Dr. Cohen for putting this session together. It means a lot that you asked me to do it. So as Dr. Hunt had mentioned, I'm an assistant professor of pulmonary and critical care at Baylor College of Medicine in Houston, and I've been in the CF space since I joined faculty in 2019. I do have a CF Foundation PACE grant, which is my only disclosure, and I am a self-loathing Twitter or X user, but if you do follow along on that platform, you can hear some stuff about CF and bronchiectasis there from me. So I'm actually just gonna ask a question to the audience. If you guys could scan this QR code. Let me know, is there a question there that popped up? Can you see it? It's there? Okay, great. All right, we'll come back to that. If you guys wanna jump in, I'll go ahead and get started as you take a look at that. So I'm gonna be discussing outcomes in black people with cystic fibrosis, which is a research interest of mine, and what we're gonna be doing today is giving you a little bit of background on the impact of CFTR genotype in black people with CF, specifically in the United States, but we'll talk about people that may have been involved in the African diaspora as well, and then I wanna give you a little bit of the data that we have that should be coming to a journal near you soon, which is a retrospective registry-based data set looking at outcomes in this population. So what do we know about black people with CF? So as Dr. Hunt had mentioned, this was always sort of deemed to be a disease that was found in Western and Northern European circles, and in particular, classically, the Ashkenazi Jewish population, but as we have learned over the years, particularly in the last 20 years, it's certainly not limited to that population. As a matter of fact, it's interesting that the first sweat test was done in 1959. I didn't know that, but that was actually the year that the first black person in the United States was described with fibrocystic disease of the pancreas, which is what Dr. Anderson had described in the 30s, and was sort of our opening salvo into what CF was as a disease state, and really, when you look at the black population, specifically in the United States, but this extends to other countries in Northern America and North America as well as Brazil, it's really hard to describe the situation with regard to genotype and cystic fibrosis in the black population without talking about the transatlantic slave trade, and I'll tell you why, but this was a very harrowing but unique moment in history where there was a huge amount of genetic admixture that happened. In fact, much of what happened with regard to the black population was when you had slave owner and slave rapes and pregnancies that occurred, that there was this abnormal genetic admixture that happened, and there are vestiges of that still. We're gonna stop for a second. I wanted to take this poll. So what is the incidence of CF in the black population? I think... Is it one in 5,000, 10,015, or is it less frequent, one in 50? We've got 11, 12. All right, we'll go with that. So, very good. So most of you got that right. So yeah, it does, it certainly, the incidence does vary based on race and ethnicity, which, of course, are sort of imperfect labels, as we know, but in the non-Hispanic white population, the incidence is one in 3,000 live births. In the Hispanic population, it's one in 10,000, and in the non-Hispanic black population, it's one in 15,000, and what I have listed under those incidences are the most common genetic mutations seen in these populations. So you can see, F508 deletion is gonna be the most common, as we learned in medical school. Something about 85 to 90% of people with CF will have at least one of these mutations in their genotype. And then it actually, there is some variability, but I wanted to focus specifically on this 3120G to A mutation. This is a splice mutation that we currently don't have modulators directed against, and it basically, this is paired with another so-called severe mutation, then you will end up with a severe phenotype. And if you look on the right side, actually, this is an interesting study that was done about 10 years ago now, I think, which was actually kind of a pooled analysis of genetic data. It's actually carrier status testing in Sub-Saharan Africa, and what you find there is actually, in Sub-Saharan Africa, the most common genetic mutation that you're gonna see is this splice mutation. It's actually not the F508 deletion. So the tie-in to the transatlantic slave trade is that this is a mutation that is circulating in the African population, not 508 as much, unless you have more European descent, but this was an opportunity for F508 and this splice mutation to come together and create a severe phenotype of CF. And the ones I have highlighted in red here, these are either class one or class two mutations that don't have a so-called CFTR modulator directed to improve quality of life. So within sort of underrepresented minority communities, what do we know so far? So Dr. Jane is in the audience. She published a great paper that looked at sort of national trends based on CF Foundation registry data, and what we see is that there is a higher mortality in the Hispanic population with CF. In California, Dr. Mimibu did a really interesting study in chest about 10 years ago that looked, that actually had a much higher hazard ratio of 2.8 for Hispanic people with CF. And as we have learned about and what we will learn about even more in depth is that CFTR mutation detection is less frequent in newborn screens from people from minoritized groups. There's a lot of data on that now. And there's older data, kind of smaller data sets, which have showed kind of poor nutritional status, pulmonary function in black people at CF, compared to non-Hispanic white people at CF. And as we know, these are sort of two sort of cardinal risk factors that can sort of alter a patient's outcome. And as Dr. McCauley and Dr. McGarry have published a couple of years ago, what you see is that in minority groups in general, but particularly in the black population, you see less eligibility for kind of the higher efficacy CFTR modulator therapies that we have now. So while we have some very excellent drugs out there that can really change a person's trajectory, this is going to be sort of sorely impacting people from minority groups in terms of eligibility. So with that, let me pivot real quick. I wanted to talk to you about the project we've been working on, which is a survival analysis in black people at CF using registry data. We were looking at the years 2012 to 2019. So it kind of reflects the just before highly effective modulator therapy area, timeframe I should say. And we're basically stratifying outcomes by race and ethnicity. The primary endpoint is actually age at death or lung transplant, using that as sort of a composite marker of sort of on, you know, development of severe disease with a look at FEV1 change over time, or decline rather, as a secondary endpoint. The hypothesis was that based on our experience with Hispanic people with CF is that black people with CF would similarly have worse outcomes. So this is sort of your classic figure one. Essentially we censored at age 54 just because the mortality data that we get back in the registry is a little less reliable once people are beyond the age of 55 and above. But we ended up with just over 30,000 patients in the cohort, about 3.7% of which were classified as non-Hispanic black. And, right, race and ethnicity designation is sort of found within and is reported by the CF registries, which is where we get this data. As I mentioned, this is unpublished, but this is sort of unadjusted Kaplan-Meier curve data for these different racial and ethnic groups. And as you can see, there is a sort of a distinction between two groups here. As it turns out, in the unadjusted data, actually the distinction that we see is in the non-Hispanic white population and the Hispanic population with a median life expectancy difference of 34 years in the Hispanic population and 39 in the white population. And I'm not going to show this to you, but when we did some covariate adjustment, actually that signal goes away. And what were our covariates? Well, we kind of looked at sort of the body of CF literature, which is pretty robust these days. Dr. Jane is going to talk to you about the impact of sex on outcomes. But we looked at nutritional status, insurance status based on ever public health insurance use, genotype, pancreatic insufficiency, which is tied to worse outcomes, as well as a host of sort of what we think about as kind of standard treatments within this community, as well as the sort of bacterial or microbiome of these patients, as well as lung function. Importantly, I just wanted to point out a couple things, which is in this cohort, 41% of black people with CF did have CF related diabetes, which is related to worse outcomes. And while we don't, and it's also tied to worse survival in cystic fibrosis adults. And while we don't have real good mortality data yet on the impact of CFTR modulators, just take note that the black population is the least likely of these groups to have been taking CFTR modulators during this time. And so what did our data show? Well, this is the adjusted data looking at age to transplant or death. And essentially, we're using the black population as the reference population. And as you can see here, based on these P values across these ethnic groups, there were no significant differences here. And so basically, you cannot basically use, based on this data, race or ethnicity as sort of a factor in terms of worse outcomes when you adjust for these factors that are known to increase your mortality. But what if you were to kind of break this down further, like this was our initial hypothesis, but we were kind of interested in figuring out how many of these patients actually go on to actually die of complications from CF, and how many of them go on to get lung transplants. Because if you think about it, those are two very different outcomes, even though they do tell you something about the severity of disease at the time of the end point. And so this was what's called a competing risk analysis, where we used the same covariates we used to adjust for the previous model, but this time we looked at a hazard ratio in terms of getting a transplant. And what you see here is a little bit of a different story. What you see is that when you use the black population as the reference population, these other groups, particularly the white non-Hispanic population, the Asian CF population, and the other slash multiracial population, are actually at higher sort of hazard for achieving lung transplantation, which would conclude that they would actually be more likely to go on to get lung transplantation during their life. The corollary to that is what about death? Well, the overall model didn't achieve statistical significance, but when you look at direct comparisons using the black population as your reference point, that there actually is a lower hazard of death in the white non-Hispanic population compared to the black population. And the other findings are insignificant. So what that would kind of tell you is that you might have a situation where despite this primary endpoint being negative, when you sort of break up the outcomes, that the black population is more likely or less likely to go on to receive lung transplantation and potentially, potentially more likely to die of disease than their white non-Hispanic counterparts. This is the graph for our second year outcome, which is looking at decline in FEV1 over this timeframe. And actually, it's more or less a wash. You do see that the black population does have a slightly faster rate of FEV1 decline in these years than the Asian population, but it really comes out to less than 1% per year grossly, which we didn't find to be a clinically meaningful outcome, or difference, I should say. So the conclusions here from this study is that there's, from a primary composite outcome of age at transplant or death, there's no differences based on race and ethnicity, but using competing risk models that black people at CF are at a lower hazard for lung transplantation, and there's potentially a trend towards higher mortality in this population. So several limitations we could discuss. Happy to discuss more detail during the question and answer session, but with regard to the designation of race and ethnicity, there's potentially a lot of bias here because this is really based on conveyed data, either by parents of children who are in the registry or adults. And so as Dr. Aaron Bond has sort of tour de force this morning in the spirometry lectures, it might be sort of an unreliable sort of designation in these registry studies. And then to go back to Dr. Bond, some of the work he's done, what's the effect of the GLI reference equations, the race-based equations that we're using, or that ATS has recommended we use up until 2023, is that if you're basically, if you're somebody who's black who has a higher percent predicted than you otherwise would if this was sort of race-neutral equations, you might actually be referred less to transplant, and you might be at higher risk of death. Now this is editorializing to be sure. There's definitely more data that needs to come out of this, but I think there is an opportunity to do that now that ATS is suggesting that we switch to race-neutral equations. And of course, this study doesn't tell you about the impact of ETI, highly effective modulator therapy, which has the potential to totally change the survival in the long run, but more to come. I want to thank Kristen Staggers, my biostatistician, the CF Foundation, and Dr. Jane, who's here, who mentored me through this, in this research project. Happy to take questions after. Thanks. Thank you. for closing out the conference. That is big props to come here. And we just thank you so much. So I'm going to talk about the need for equity and safe tier modulators. And we're going to discuss some of the things that have already been discussed. So we're going to talk about modulators, racial and ethnic disparities in it, overall disparities in clinical trials, and then how really the way that we have created a lot of barriers since they've been approved as well. So CFTR modulators, if you don't do cystic fibrosis, is a game changer and totally should go and read about it because it is amazing. So personalized medicine for gene mutations was really only in oncology until cystic fibrosis came around. And it is potentially going to move to other diseases and other drugs. So what this is is really a big investment in basic science and then translation to pharmacology. So a lot of work was done into really understanding what are these different gene mutations do and how did that translate into the protein. And so the basic day fact in cystic fibrosis is that the CFTR channel is either there and not opening or it's not even in the membrane at all. And because of that, you don't have chloride movement or water movement, and then you have thick, sticky mucus. And the unique thing is what they did originally with just one mutation, and there was one drug, is they said for this mutation, we're really going to understand what's going on. And they developed the drug specifically to bind onto the protein and open the channel. And that is when we really changed cystic fibrosis to begin with. And since then, there's been a lot of work. So now we have this triple therapy drug where two drugs go, they bind on, they help stabilize the protein, they help transport it over to the membrane, and they help it form. And then we have the third drug come and sit there and open up the channel. And it's just amazing. And then now we're going into the problems of this. We have this amazing drug that took cystic fibrosis through so much pain and so much research just to get kids to live to their teenage years. And the hospitals were full of teenagers, and CFTR Modulars has changed it. So now we promise hope. So now when I have a baby coming in newborn screening, I can tell them, you have a drug, and there is hope. So we now say, save for college, that your child's going to have a career, that they're going to be able to go to school, and they're going to have a life. And what we've seen is, through work from our next speaker, is that this also means having children, having families, and the hope of growing to be elderly and live a full life. And this promise is so amazing. The problem is that we don't offer this promise for everybody. And so what I'm going to talk about is how racial ethnic minoritized people with CF are less likely to qualify for these modulators. So we did this work because it was highly touted as, like, 90% of people these drugs work for. And what we looked at is actually that that's not true. So looking at people who are other races, so this is Hawaiian, Asian, or people who are multiracial, it's actually only 80% qualify for these. And you can see this last column, the ETI, it's only 72% qualify. Now, when we go into people who are Hispanic, you can see that one quarter of people do not qualify for these drugs. And look in the far other column for, it's only two-thirds actually qualify for ETI. And then it gets even worse for people who are black or African-American, that it's only 63% qualify for these drugs. And so that means that you have huge proportions of certain races and ethnicities that don't qualify these drugs, while the majority, almost everybody who's non-Hispanic white are qualifying. And what we did then is when we said, well, does it really matter, those people who aren't eligible? Maybe they just have very mild mutations and their lung function is really good and they would have survived no matter what. And what we found is that's not at all true. So you look at, in each group, you can see that their lung function is not high, they're all abnormal, and that they are much lower than people who are eligible non-modulators. So there is this need for these drugs. And this is really what we've been talking about here, is that based on your ancestry, your gene variants are going to be different. And when looking at this, so this is class one to three are what we consider classic mutations, typically quote-unquote severe, meaning that there usually isn't any protein in the channel that's working. And you can see that there's a huge variation on this. When we look at mutations that are class four to five, which are quote-unquote mild mutations, although we know that's truly false, we'll just call it pancreatic sufficient, that you can see there's a big difference here. But the worst is, these are the mutations that we know what the name is, and we have no clue what's going on with them. And these are called unclassified mutations. And this is really where we see disparities created from basic science, that we don't have the basic science understanding for what even these mutations do. These are mutations where I tell the family, this is like the alphabet number of your mutation, and I don't know. And that's not helpful in this era where mutations determine whether you're getting diagnosed and whether you're getting treated and whether you live. And even worse, look at this. Look at black and African Americans. 9.1% are not fully genotyped. We have not even found two gene mutations in these patients. People who are multiracial or other races, look, it's 9.8%. Even in kids who are Hispanic, it's 8.5%, versus 3% in non-Hispanic white. This is a disparity of sending people for sequencing. This is a disparity for understanding all the gene mutations that really cause CF. So this is a really unique paper that I have sort of fallen in love with. So somebody went through and they looked at what are the top 50 variants in each race or ethnicity? And they said, what is unique to just that race or ethnicity in the top 50? So you can see only four of the 50 mutations in non-Hispanic whites were unique to that race. But look at, it's 40% of mutations were unique for Hispanic people. It's about 30% of mutations are unique for people who are black. And about 40% of people who are Asian, their mutations are unique. And those are the ones in red that in the top 10, that that mutation only occurs in the top 50 in that race or ethnicity. So you can see that even though that these mutations are quote unquote uncommon in CF, those uncommon mutations are common in certain races and ethnicities. So this is looking at what mutations qualify for CFTR modulators. So you can see that in the top 10 mutations, each race and ethnicity, including people who are non-Hispanic white, have a big number of those top 10 that do not qualify for modulators. But the biggest difference really is, is if you look at the DELF508, there's a huge difference in the percentage of people who have that. So you can see it's about three quarters of people who are white versus about half or below half of people who are Hispanic, black, or Asian. And when you think about overall, how do we get into all these disparities? And what we have found is that throughout the history of cystic fibrosis and including all the clinical trials, there's been a lack of inclusion of minoritized people with CF in these drug trials. And that makes a difference when these drugs are based off the drug trials. So I had gone through and looked at like a decade of clinical trials, and this was before modulators, and only 18% of CF clinical trials reported race and ethnicity. So 80% of studies had no race and ethnicity in their table one or anywhere in their paper. Of those who reported race and ethnicity, only three quarters included even one person who was a race and ethnicity other than non-Hispanic white. So when you look at all of it, only 13.5 of all clinical trials in CF reported race and ethnicity and included even one person who was a race and ethnicity other than non-Hispanic white. Most papers just said 100% Caucasian, even though Caucasian is not a thing. So this is really troublesome because they're testing these drugs and developing drugs for a proportion of the population that does not represent the whole. So I had presented this and I met with drug companies and I met with the CF Foundation. I did a lot of advocacy on this, and then modulators came out, and then now this is the follow-up from the modulators. So of modulator studies, only 40% of Ivacaftor studies even described race and ethnicity. 20% of Lumacaftor-Ivacaftor, only 10% of Tezacaftor-Ivacaftor, and a whopping 14% of ETI papers even described race and ethnicity. And I can tell you when the landmark papers came out for New England Journal and Lancet, there was no race and ethnicity described in either one of them. And the journal wrote back when I complained about it an hour after they published, and they told me, quote, there was not enough room in the paper to describe race and ethnicity. And I can tell you that that has been the sentiment across the CF community is that it's not important because it needs to be important. And we all know that you can make lines in table one or at least even in the supplement about race and ethnicity of the population. Now on top of this, so not only do people that there's huge disparities in who qualifies, there's huge financial barriers. So these drugs not only broke barriers and made the news because they were so amazing, but they also made many news articles and broke barriers about the amount that they were charging for these drugs. So when Ivacaftor first came out, it was $293,000 per year. When the next sets of drugs came up, they went up and up and up. And so now the drug company, which we named Vertex, it makes record-breaking profits. They made just off of the CF drugs, 8.9 billion billion in profit last year, including they decided to take 3 billion in stock buybacks. And what this is really translated to is that people cannot afford these drugs. And this last year, I don't know if any of you have dealt with this, but you definitely will, is they really changed the copay assistance program because they didn't want the insurance companies and the drug companies both want more money and they didn't like that the other one was profiting. So they both changed their guidelines to compete with this and it left patients with CF in the lurch. So after five months of having your copay be zero or like $5, it went to U.S. $5,000, U.S. $3,000 for this month and patients had to come off their drugs. I'm not lying and telling you because we had this at UCSF and the majority of states allowed this to happen. And as you can see now, we did a lot of advocacy to show that Vertex would make more money if they actually covered this so people wouldn't come off their drugs, but yet this is the way it is. So they also battled with many countries. So CF occurs many places other than the United States and these drugs should be given across the world because they really do transform care. So you can see that across the news and across the country, there's been much advocacy with little results about getting drugs covered. And this is really out of the norm of pharmaceutical companies since the age of HIV and AIDS drugs being available to across the world to low-income and middle-income countries. And even recently with COVID, many drugs being available has not been the normal. So besides all of that, Latino people, including Latino people with CF, had the highest rates of being uninsured. Now if you're uninsured, there's no way you're gonna get these drugs. And low-income and uninsured patients often deal with competing social and financial demands. If you're living paycheck to paycheck, a little blip or a little confusion in filling out all this very complex paperwork or a minor change or a large change in somebody's co-pays, you're gonna have to make decisions and often those decisions are taking this drug, which I hear repeatedly by people with CF, that they are taking half dose on some of these drugs to make them last or they are missing their mortgage payments. So and this also, all these financial demands really make a decision whether you're gonna participate in research or not. If you're gonna get $50 for a study, which means you have to take the day off of work and I have to pay $30 in parking plus bridge toll plus gas, that's not as making any financial sense. So we need to change the way we're doing things. If we really wanna prioritize inclusion in cystic fibrosis and really this financial toll of out-of-pocket expenses is devastating and really has a long-term effect. There's a lot of really interesting research about wealth and outcomes and you're not thinking about just month to month or day to day, but like, can you own a house? Can you save for college? Can you be financially stable? And we really need to be helping families and not creating these amazing drugs that they did all the fundraising for to develop, and then not making them available or making it really financially devastate them. So, and then also, financial toxicity and the stress from it really has a direct impact on the quality of life and CF outcomes. And I think that there's probably, we're gonna see in the next 10 years, is more research in this area of families and the stress they're going through and how that really affects their lung function and their outcomes. And then, like we've mentioned already, it's like, so why does it even matter that they're less qualified? Because CF is becoming more and more diverse. And this is a combination of the United States becoming more diverse. CF newborn screening has really contributed to this. And what you can see, this is like a five-year mapping of where people moved to North America from around the world, that it's gonna continue to change to continue to be more diverse. And so the CF community really needs to lead with that, that our community is becoming more and more diverse. There's lots of research showing that, as we talked about, Hispanic and black patients have an increased risk of mortality. This was pre-modulators, that they die younger age. And that, like we talked about, that they're less likely to survive. And I'll just say that after the last talk, I know that for my patients, it's very difficult to get them to even get evaluated for a transplant. And we have definitely had patients rejected because their families even just speak Spanish. So I think there's a lot of bias and racism in who even qualifies, and that I'm not at all surprised that you guys found those differences. And it's really sobering and needs to be worked on. This is work I did a while ago looking at lung function differences. So even with controlling for everything that affects, that we know to affect lung function in CF, that there's a huge difference in kids who are Hispanic. And there's older work looking at people who are black, that it's lower. And then since we're in Hawaii on the West Coast, that the disparity in lung function is twice as wide in the West Coast versus the rest of the country in people who are Hispanic, and we don't know why. So that with these changes in the disparity in modulars, this really is going to worsen our pre-existing health disparities. And we need to be vigilant and put a lot of energy and a lot of time to really mitigate this. And it really is an emergency that we need to be working on. I do have to say that in France, they're very equitable. And every person with CF gets a trial of drug for the modulators. And if they respond to it, they get drug. And that might be a thing that we need to pursue. Because if people, there's no way that we can be able to do drug trials for people who have like de novo mutations, where there's only a handful of people in the world with that mutation. And all people with CF deserve to experience health equity. And that means experiencing good health, living longer, having a full life. And we need to be working towards that goal a little way. So thank you. All right, thank you all for sticking it out for the last of the meeting and the last talk. So appreciate it. All right, so I'm gonna switch gears a little bit on some of what we've been talking about and move into sex and gender disparities in cystic fibrosis. These are my disclosures related to this. I do receive funding from the Cystic Fibrosis to study both sex and gender differences in the CF population. So I think we've heard a little bit about some of these new therapies that have come about for people with CF. And this is a really nice graph that I took from the CF Foundation patient registry that just really tells you where we've come with this population. Where if you can see on the bottom x-axis, that's time in years. And the y-axis is number of individuals with CF. And the green here represents children with CF, which has stayed relatively stable over time. But you look at the blue, and this is the population of adults. And this has been growing tremendously. And as a result, this is partly due to some of the medicines we've heard, amongst other reasons. But I think it's really lend itself to us having the opportunity to look at a variety of aspects of people with CF and think about what are we missing here? Who are the populations that we've really overlooked all this time while we're trying to work on people just living past childhood? And of course, there are still unfortunate scenarios where people don't. But I think there's a lot of opportunity to look beyond that. So just to start out more on the sex disparities work, there has been a number of studies, really across registries from the United States to Canada to Italy, et cetera, which have shown that there is a male-female sex disparity in CF. And it's important to understand that incidence and prevalence of CF is equal in males and females. This is an autosomal recessive disease. But the survival and exacerbation rate is different. And this was first published by Margaret Rosenfeld, who's in Seattle, who used the CF Foundation Registry back in the late 1980s and early 1990s, showing that the median survival in males was about 28 and females, 25. And this was subsequently repeated in other registries. And looking at a little bit of a later time point, myself and others, once the survival had improved up into the mid to late 30s, we took a look at this in the CF Foundation Registry in a population that included over 30,000 people and still found that there was an increased risk by hazard ratio of death in females, meaning females' sex assigned at birth. We also controlled for a number of variables that have been thought to be important in survival of someone with CF and continue to see this difference. There was a number of other factors that came in, including earlier bacterial acquisition in females, but we really couldn't understand the exact reason from this type of study alone. And I think this is important to put in the context of the general US population, where when you look at some of the CDC publications on life expectancy, it's about 79 in females and 73 in males. It's been changing over time, but still, in general, females live longer than males. And you look at that relative difference in the CF population and really this equates to about an eight to nine year disadvantage in CF females for reasons that I don't think we fully understand yet. A couple of these include, as I mentioned earlier, bacterial acquisition that's being seen in the females, and this is a little bit older data, but really showed that for children that acquire Pseudomonas aeruginosa, that the females have a much earlier mortality, and even when they acquire it late, you see that separation where females die earlier. When you look at, there's, I think I forgot to reference this, but this is work from Ted Liu and others in the CF community that have done a lot of work looking at survival and some of the main predictors of survival in CF. And you can see some of these here, but sex has remained on the list of some of the main factors that impact survival in someone with cystic fibrosis. So why is this? And I really think it's likely multifactorial. There's a number of hypotheses out there. Some of those include the size of the lungs, or particularly the size of the airways, or the diameter of the airways. You can imagine in an illness where mucociliary clearance is key, that if your airway lumen diameter is different, that could lend itself to a difference in outcomes. No one has proven that or been able to look at that in a thoughtful way, but I think that exists as one of the hypotheses. There's also behavioral aspects, whether it be adherence to therapies, mental health differences. This is slowly getting studied now, but I don't think we quite know the answer to whether or how much this is driving the difference. There's also physical activity level. We, I think, in many patients, but in CF in particular, the more physically active one is, the better people clear their airways out. It's thought that male patients are potentially more physically active. That's obviously not universal and has, again, not been well studied, but on the list of hypotheses. Along with other comorbidities, such as nutrition, diabetes, there's also thought to be differential response to therapies, genetic and epigenetic phenomenon, and finally, sex hormones. And I'm just gonna spend a minute or two talking about sex hormone influences and then move a little bit into a slightly different area. But you look at, this is a study that myself and others did using the CF Foundation Registry, again, to try to understand where and when are we seeing this sex disparity come about. And this was a population that was included over 5,000 people who had data spanning their time of puberty. And time of puberty is very hard to define in registries. We don't have anything such as age of manarchy, we don't have Tanner staging, we don't have that kind of information. But what we do have in the registry is peak height velocity, and we use this as a point of marking of puberty and found, actually, that the age of puberty in a male versus a female with CF was actually fairly similar to the general population. Now, this was in a time where people with CF were much better nourished than many decades ago, and I think that's why we were seeing this. But you look over here on the left-hand side, this is just representing the point of puberty in males versus that point of puberty in females. And then you take that point, and we actually looked 10 years prior to that in each individual person, and 10 years post-puberty in each individual person, and broke that down by males and females, again, assigned at birth, and found that really the separation when it came to pulmonary exacerbations was occurring about four to five years post-puberty, where females started to have more exacerbations detected in the registry at that point and beyond. And this increase in exacerbations has been studied by several other people, including Christina Montemayor at Johns Hopkins and a group in Ireland that published this really nice New England Journal paper back in 2012, trying to understand this a little bit, and it's kind of complex, and I'm just gonna summarize it very quickly, where they looked at actually the characteristics of pseudomonas in males versus females, and also in females on hormone contraception versus non-hormone contraception, and found that pseudomonas aeruginosa, which is one of the most common and virulent bacteria we see in people with CF, actually changed its morphology in different settings, in particular when estrogen levels were high in females, meaning the point of ovulation, they found a lot more mucoid pseudomonas than at other times. They also found that that time, meaning not on hormone contraception, correlated with higher exacerbations. And you'd say, why is that? That's because when you're not on hormone contraception, the female hormones are actually cycling, where you do have those peaks in estrogens, et cetera, whereas when you're on hormone contraception, it suppresses the endogenous hormones, and it's a different type of estrogen. So a lot of this was thought to be due to the surge in 17-beta estradiol that occurs when one's not on hormone contraception in a female. So this set off a slew of work really understanding, in particular, estrogen and its impact on the pathophysiology of CF. And there's been studies looking at the estrogen impact on CFTR function, on other ion channels, on mucocellular clearance when it comes to the air surface liquid, when it comes to infection, and when it comes to inflammation. And I'll just tell you, this work is ongoing, and unfortunately, most of it is focused on estrogen. There's not a lot of work yet on progesterone or testosterone, and I think that will be coming in the next several years. But I think what I really wanted to spend a couple last few minutes on is talking more about how does these observations in males and females, and these differences that we see, impact what we might think about when it comes to sex hormones, and the impact that could have on people as they're undergoing gender transition or gender-affirming hormone therapy. So just a reminder, and I think there's been a couple of really nice talks I've seen at this meeting focused on this area, but sex assigned at birth is a biologic construct, whereas gender is a social construct. And both important in different ways, but I think really it's some of these gender-diverse individuals that I would put in the minoritized population that we don't know a lot about them, we don't design studies well to try to help these people, and they have a lot of challenges that I think we're really missing, whether it be within CF or within other areas of respiratory and non-respiratory disease. So when you think about that, in general, the prevalence of the LGBTQIA plus population is actually very large, and that population is a very large encompassing group of people that does not just include transgender individuals. It includes a variety of different gender-diverse populations, and that population is also growing, and so that's very important to understand that it's extrapolated to be that up to 7% of people in the U.S., and that's adults, kids, et cetera, and it's more in certain populations, identify as LGBTQIA. And when you look at a Gallup survey that was done in the last couple years, you can see that just looking at the transgender non-binary population, that made up about 5% of individuals between 18 and 29. That's a huge number of our CF population group right now, so this is an area that we can't just overlook because it is going to impact people that we take care of. And how really to optimally care for these people and what issues to consider are really quite unexplored. And I'll show you, I don't have a lot of data, but I want to just mention a couple of case reports and studies that are ongoing and hopefully going to help us understand this population. So these were a couple of case reports published in the last few years, literally individual case reports. One of these on the top, and I'm sorry it's a little bit small, was a previously stable trans woman. So someone who is transitioning from a man to a woman with CF who had been doing very well, as you can see by a stable lung function on that y-axis. Then this person gets first hormone, which is a testosterone suppressing hormone, which most of these people who choose to undergo hormone transition will get, followed by estrogen. And you could see subsequent to that, that as the, I don't know if you can see that line coming up from the bottom is the estrogen levels, and the pulmonary function starts to decline. And this team was very aggressive in their description of all the care they did, nothing else came about, but this person started to destabilize when it came to their FEV1 for reasons that were unclear. And there's lots of details, but this person also started to have more pulmonary exacerbations, et cetera. In another case of an 18-year-old trans woman who was undergoing feminizing hormonal therapy, this person, and that x-axis, I'm sorry, it's hard to see there, is months on hormone therapy, and that y is pre-hormone therapy, I'm sorry, the middle line is pre-hormone therapy versus post-hormone therapy, that the cultures on this person had been quite stable with actually just MRSA for many years. The person had been doing well from a lung function standpoint, gets on estrogen therapy, and then very shortly after, grows pseudomonas aeruginosa for the first time. We can't say that these things are causal in a few case reports, but I think it just brings attention with some of the other data about the impact of estrogen, of could there be something that we need to watch for. And I think myself and others have sent out a survey to the CF community just trying to understand this population, and I'm not gonna go in, I'm trying to make sure I don't keep you over too long here, but I just wanna show you a little bit about that, that we actually only sent the survey out twice, and it was in January and February of 2020, right before the pandemic hit. But in two short, quick surveys, we actually got about 30 surveys back from care centers just describing some of the people they take care of who identify as either transgender or non-binary and the therapies they take. And certainly we found that people are choosing to take gender-affirming hormone therapy, there's some using chest binders, there's some using testosterone, and then there's some choosing surgical options. So I think it's important for us to understand this a little bit better. I'm gonna skip over that. And think about some of the unique aspects. And that's not just hormones. You also wanna think about stuff like chest binders. This is a garment that someone who is choosing a more masculine shape may choose to use, and there's been little to no studies about this in the lung literature in general. There was one small study I found in a healthy population of trans men that found that when they wore this chest binder, there was a reduction in their forced vital capacity. That's probably not surprising, but how that may impact somebody with an actual lung disease, and particularly someone who has to clear their airways, we have no clue yet. And I certainly, by presenting this data, not only on estrogen on chest binders, am in no way advocating that you tell your patients not to do this. I'm more advocating that we understand it so that we can support our patients' choices, and the literature is really scant on this. So I think we as a community can do better. There's also been, I know there was earlier today a great talk on lung function also, and I just wanted to point out that this is an area also really that we need to think about, because we've just gone through this thinking about how to deal with race within the reference equations, but we really haven't done much to think about how to deal with sex or gender. And in a population such as CF, where we focus on FEV1 as the center of their care, and follow them over a lifetime, you can imagine that it's really hard to know what to do with this. The ATS guidelines currently favor that we stick with sex assigned at birth as part of our percent predicted equations on PFTs, but for those who are on hormone therapy, whose chest wall may change in different ways, it's not clear that we should do that. And the other piece is, is anyone really asking their respiratory therapist what sex or gender they are putting into their PFT? And when we did that survey, we found out most didn't know. So we ended up going and asking people for absolute FEV1s, because they had no clue what had been entered into their percent predicted equations when it was done for their patients. So I think there's many unknowns, as I mentioned, and I think importantly, the other thing to think about is really the impact of the mental health challenge on this. People who have chronic illnesses such as CF already have a higher rate of anxiety and depression. We also know that people who are gender diverse have a much higher rate of anxiety and depression, as well as suicide rate. And so we have to think about, how do we support these people? What can we do to overcome some of this and make it so that they feel more comfortable talking about this, so that we as a community feel more comfortable? And a group of us are actually thrilled that we were recently funded by the CF Foundation to study this topic. We're calling it the PRIDE CF Study. And basically, this project is a fourfold project where we're going to collaborate with the main PRIDE Study investigators in California. They have over 20,000 people in their PRIDE registry, and our goal is actually to recruit people with CF into their PRIDE registry, combine that data by mixing it with CF Foundation registry data to really understand the historical nature of what some of these different gender-affirming therapies are doing, what are the mental health stresses, what's the overlap between having a chronic illness and identifying as gender-diverse in some way, and how can we help these people? And on top of that, I think we're gonna take some scientific sides of this and understand a little bit more about PFTs, understand a little bit more about the gender-affirming hormone therapies. So we're hoping in the next couple years we'll have some of that information to provide. But I think for now, I think as a community, things we can think about are how to train our team members to be a little bit more sensitive to appropriate pronouns. I will say that I am from the state of Texas, and it's not acceptable, really, to be having these conversations, but I think it's unacceptable for us to not. So I think we just have to think about the most thoughtful and sensitive way to do that. We have social workers and mental health coordinators in our clinics, but I don't think we're all universally training them to identify gender dysphoria. I think we have to have shared decision-making when it comes to the PFTs in particular, and what sex do we wanna put on there, what is the patient comfortable with, explaining to them what that means and why there may be good and bad to changing that. We have to capture things like what their gender is. Our current registry, while it's a wonderful resource that the CF Foundation has, it currently only captures sex assigned at birth, and so you can't do these types of studies in that platform. And then I think another key point is, and I'm actually sitting on a panel with the National Academy of Sciences that's trying to understand what's the impact on disability for people who identify as not their sex assigned at birth. When something like your PFT, which dictates whether you're gonna qualify for disability, could be different, how is that something that we're factoring in? The same goes for transplant. The same goes for eligibility for clinical trials. So a lot of issues that we haven't broached on, and one may say, well, this is a tiny population with a tiny population, but I think we have to understand that we really should not leave anybody behind. We're in an era of personalized medicine, and every person matters. So with that, I'm just gonna say thank you to my clinic and research team at UT Southwestern, to the sharing group that's spearheaded a lot of this and is funded by the CF Foundation, and to my collaborators in our PRIDE study, Greg Sawicki, Casey Kidd, Tracy Kaczmarski, Vintang Pritchett, and John Palla. So thank you very much, and I'm sorry if I were a couple minutes over. Thank you.

equity

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treatment

outcomes

cystic fibrosis

disparities

access

CFTR modulator therapy

gender diverse individuals

addressing disparities

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