 All right. So Dr. Silver and I are going to do separate presentations. First of all, a shout out to the pro side, absolutely outstanding, outstanding argument. Thank you. And I appreciate every point you made. And I'm now going to take the opportunity to take all of those points and give a counterargument as to why we should not do population based genetic screening for TTR variants. So thank you for all of the points you just made. So I'll get started here. So I'm going to frame our con side, again, with the following four points, why we should not be offering TTR genetic screening. The first point is there are multiple types of genetic testing options, all of which lead to complex results. OK. So I'm going to walk you through all the different testing options. And because we have complex results, Sonia just very beautifully pointed out, we definitely need pre-symptomatic genetic testing, counseling, and post-test genetic counseling. At this time, however, as I'm going to discuss, we currently don't have established protocols in many clinics, including in Phoenix, to meet the need that we actually have for these patients to come through for population screening, which is one reason why I'm a program director at Arizona State University, trying to train new genetic counselors to get out into the community so we can establish these clinics. But I want to kind of talk you through some of those protocols today. Also, I'm going to mention the barriers that everyone here in this room is aware of for black adults to access genetic services. It was just touched on a minute ago. But I want to talk about why that matters when we're talking about population-based screening. And then finally, because of all the complexities I'm going to go over regarding the genetic testing options, the implications of the test, et cetera, it's really important that people fully understand the benefits, risks, and limitations before proceeding with testing. Otherwise, all of the information that we want to provide these individuals is not going to be utilized because they're not going to understand what to do next and how to take that information and actually apply it into real life. It was already mentioned just a minute ago, but there's very limited research about some of the clinical utility of some of the genetic testing that may come back if we order genetic screening for everybody. Because the previous group did such a beautiful job of talking about all of the symptoms, I don't need to spend too much time other than just to mention that there's three different types or classifications of the hereditary form of amylogeosis. And we're going to only focus, of course, on the familial cardiomyopathy. Sonia talked a little bit about the gene, the TTR gene. It's on chromosome 18. And it's autosomal-dominantly inherited, so you only need one copy of a pathogenic variant of this gene to actually have symptoms. However, some of the implications and some of the complications that exist with this disease is that even though we're talking about one specific variant that you already heard about that's very common in people who have black descent, there are over 130 to 150 different types of variants. So if somebody has mixed ethnicity or mixed background, if we just screen for one of these variants, we're going to be missing a potential different variant. And why does that matter when you have it in autosomal-dominant condition, you ask yourself? Well, it matters because some folks that have this disease, the cardiac amylogeosis, the hereditary, actually have two variants. In what's termed homozygous. And if you have two variants, it could change the clinical phenotype. So it could change the expression of the disease. So we don't always want to miss that. In addition, we don't know much about the de novo rate of this mutations in this gene. So this is a little bit of information that has already been discussed and information that all of you know very well in this room. But I really want to highlight what I have put up there bolded in blue. And that is that the penetrance is not 100%. You heard Sonia mention that. And that's important on the con side, because if you test somebody and they have this variant and the penetrance isn't 100%, it's challenging from a counseling standpoint about what medical recommendations you might make because we don't know how they're going to express the disorder and at what age they're going to express it. So it increases the complexity of the medical management discussion once results are back. The different genotypes you see up there highlighted in that box on the right are all the genotypes that are associated with a hereditary cardiomyopathy form. But the one that's in blue, of course, is the one that you've heard about that's most common between we heard today earlier just a minute ago, 4% to 5% of blacks and then also 5% of populations in West Africa. And it's the most common amyloid associated variant worldwide. Underneath that, I have a comparison of the white population and the Hispanic population. So it's definitely not as common less than 5% in the white population and for the Hispanic population about 1%. But I want to include all ethnicities too, because I'm going to touch on that in a minute. So the first question we ask ourselves is if we're going to implement population-based screening for amyloidosis, which test do you order and why? Let's talk about that. So the different forms of testing, we could do a targeted test, which is the specific variant that we're all discussing this evening, which is specific to black Americans. We could do a single gene test where we would look at maybe 130 to 150 different variants within the TTR gene. You could do a panel test. And the reason I bring all this up is because in the clinic, a lot of times labs will come in and they'll offer clinicians the opportunity to do bigger tests with more genes. Because what if there's a differential on the list that you don't want to miss? So why don't you order a panel test just in case your patient clinically looks like it could have cardiac amyloidosis that's hereditary, but there could be something else going on. And you certainly don't want to miss that. So that's why I put that in there. And then of course, we can just do the biggest test available, which has its own ethical concerns, which is full genome sequencing, looking at as many different variants around the genome as possible. The three different interpretations of these test results are the following. You're going to have a pathogenic or likely pathogenic from these results, a variant of uncertain significance, and a benign or likely benign result. So what are the implications of each of these? Obviously, if it's positive, we refer to that as a pathogenic or likely pathogenic. This is something that clinicians can use to make medical management decisions. They can use this to test offspring because you know that it's associated, it's a variant that is associated with the clinical symptoms of the patient. However, remember, we talked a little bit about penetrance. The variant is into 100% penetrant, and there's variable expressivity of the disorder. So that complicates the follow-up a little bit. A negative or likely benign variant, not typically the cause of the patient's disorder. It's not associated with the clinical symptoms. And you can move on. If you've already identified a pathogenic variant in an at-risk relative and your family member test negative, then that's a really reassuring result because they won't exhibit the disorder. And then our favorite as genetic counselors, this is absolutely our favorite result, a variant of uncertain clinical significance is exactly as it says. It's an unknown change within the gene that hasn't been well described in the literature. And the functional studies don't suggest that there's enough data to indicate that it's a pathogenic variant that could cause disease or be harmful. That does complicate the discussion with results when the patient gets his test results or her test results back. So here's a little bit about the interpretation and how that works in the clinic. So it's all gonna vary based on the type of test that's ordered. If you do the targeted, the most basic and straightforward test where you're just looking at the most common variant in the black population, most of the time you're gonna be pretty reassured if it's negative and you're gonna be pretty confirmed if it's positive, but you still have this possibility of false reassurance if the background that individual is mixed and more and more people are coming in with mixed backgrounds. So that could be something to think about. If I do single gene testing and I'm looking at 130 to 150 different possible variants, you're gonna possibly end up with one or two or more variants of uncertain clinical significance. So there's some counseling associated with that. And if I do anything bigger than the single gene test, like a panel test or certainly whole genome sequencing, you're gonna get thousands of different variants of uncertain significance. And that's gonna complicate some of the follow-up. Plus you may identify a variant in a gene you didn't expect. So then there's a whole nother issue to deal with. The sensitivity of course is with any genetic test is gonna vary by lab. So that needs to be thrown into the conversation as well. So how do we make decisions? How do we decide what's best for the patients? It's a critical question to consider in all of this I think when we're considering this possibility of population screening. And first of all, and fundamentally it gets down to two things, the patient's medical history, what are they presenting with? The clinical symptoms obviously are the most important ones. When you think about amyndosis and so much can be based on that. The family history can be important, but as you just learned, the penetrance is into 100% so that can fool you. May look like there's no family history, but there could be a family history that somebody just hasn't exhibited the symptoms. And then I think fundamentally we wanna put the patient in the center of the discussion. And of course as genetic counselors, our goal is to make sure that we are understanding what the patient's preferences are based on their personal history, their values, their cultural values and some practical things. Their financial status, insurance, et cetera, which I'll touch on in just a minute. So we wanna be sure we honor that as well. Sonya did a beautiful job talking about the pre-test pre-symptomatic genetic testing protocol. I have nothing to add to that other than my thoughts and feelings is that it needs to be implemented if something like this is going to be put into clinical practice. I'm gonna end with these couple slides and then hand it off to my partner here. We know that there are barriers. These barriers are real, they exist right now. We have data from hereditary cancer patients about their mistrust of what someone's gonna do with genetic test information because of the history that many black Americans have had with research. And this makes it much less likely that they're gonna even pursue genetic testing even if offered, even if given for free. And I think we really wanna remember that and take key to this. Also, it was already mentioned, but there's very limited data on black populations in general and what other variants may be present in the TTR gene that I think we need to consider when offering screening like this. So we might be surprised with what we find. We have the socioeconomic barriers that we're already looked at that we need to work into our pre-test and post-test protocols and then the health disadvantages. So we need to make sure everyone has access to care before we implement a program like this. So I think it's on the horizon. I think it's gonna happen. Maybe we're just not there yet. And I think the reason we need to take some more time is to develop more research to look at the significance of these variants. Establish these pre-symptomatic testing protocols. I can't say that enough. It's so important patients really understand what they're doing and then the post-test referral with a genetic counselor when possible. Continue to find ways to build trust with this community and other communities so that we can help each other. They can help the research, but we more importantly can help them. And then of course ensure the access to proper follow-up. So I'm gonna hand it off to Dr. Silver to finish this off for us. Hello everybody. Thank you all for being here and I wanna thank San Dev and April for putting us all together. And Sonia and Andrew, great job. And I'm particularly grateful that Catherine chose me to be her partner on this debate. And if I was smart, I would just say ditto, drop the mic and sit down. But what I'd like to do is share with you some personal filters. We all see disease and patients and all these abnormalities through a personal filter, what we've learned, what we have seen, what we have not seen. And so I wanted to share that with you. My very first filter was here. This is me, believe it or not. Sometime in the 1980s, I was a fellow in the pathology branch of the National Heart Lung and Blood Institute and hearts from around the world would come in. Those yellow buckets are me carrying hearts around. And what I learned was amyloid through that lens was a end stage disease. Patients presented very late, often detected late in life with a lot of the symptomatology that Catherine pointed out or not detected at all. And that's what I thought amyloid was. And there was no genetic testing back then. So I didn't have those insights. But let me fast forward. I'm gonna skip that slide. To 2016, when I was allowed to be a member of the Tau's Registry and there was some very important learning that came out of that registry, the high level was that it's an overwhelming disease of older adults with a dominant cardiac phenotype and the valine to isoleucine defect was the common condition. And the phenotypic expression differed between wild type and from the genetic abnormality. But what I learned probably most importantly was these variances in location. And I think Andrew actually talked about this. I don't know if you can see this. I went back, I didn't mean to. But you can see that if you look at United States about half of the patients are wild type. And as he pointed out, in certain areas outside the U.S., particularly Europe and Asia, they are more commonly a genetic disorder. But we're here, we're in this community and I don't know the Phoenix-specific allocation, but it's dependent on where you live. And the other part is from the Powell's registry, 48% is wild type, so they're not going to have a genetic marker. And the other half is a genetic marker. But in certain geographies, and this is South Florida, so they're warm, we're warm, I don't know what that has to do with anything. But you can see that the wild type is pretty dominant, about 64%. And then if you even look at Taos in the general registry and then in South Florida, even the mutations that are prevalent in those populations are very different. So I really feel that we should not. And I had a question that I asked our genetic provider, which is Ambry. I said, here's the question. Of all self-identified black patients sampled, how many have a pathogenic result? And as Catherine explained, you can be negative of VUS or pathogenic or likely pathogenic. And here's what they told me. 32% are negative, 54% have a VUS and that still doesn't tell us what to do, and only 15% are pathogenic or likely pathogenic. And then they said of the pathogenic or likely pathogenic, 20% have a TTR mutation. So if you look at 20% of the 15%, if you screened 100 patients, perhaps three out of 100 would give you a TTR variant that was actionable in terms of finding a therapeutic agent that could potentially help them. So I think really the important issue is it's not never, but it's if not now, when, why we don't need to do it on a wholesale application right now. One is that the diagnostic test does not lead automatically to genetic counseling. The other is that genetic counseling does not lead to treatment in terms of affordability or compliance. So it is probably not ready for prime time. And this is a slide that my colleague Amber Andrade showed at the last debate that you had here, is the cost of care is tremendous. The cost for in the United States is predicted to have almost a million-dollar cost for quality of life-year adjustment, gain and improvement in care. And really a 93% reduction in the drug price to get down to a hundred-thousand-dollar cost for quality life-adjusted improvement in care. And that threshold is still too high. So I don't think that it's something that we're going to be doing in the near term. So let me just summarize. I think we should not do it now in a wholesale fashion as a very limited proportion of patients. Testing does not translate into diagnosis, counseling or treatment. The cost of therapy exists for existing and emerging therapies. Really relegate treatment right now to more of a tease than a realistic treatment opportunity. And so does the delayed presentation of many of these patients. And the cost of testing resource would be better directed to improvement at awareness of the common signs and symptoms and really access to care. So I'm going to stop there. And I think we're ready for rebuttal. So thank you.