All right, so welcome everybody. I'm Andrew Bushar. I'm one of the transplant cardiologists here at St. Joseph, joined by Sonia here. So we'll have the pleasure of arguing for the pro side that all African-American or Black patients should be offered genetic screening for TTR amyloidosis. So as far as when we look at cardiac disease as a whole, when you look at Black Americans, compared to white patients, Black Americans are more likely to develop congestive heart failure and to do so actually at an earlier age compared to their Caucasian counterparts. They've also got a 2.5 increased risk of hospitalization for heart failure. They have higher rates of myocardial infarction and worse outcomes after acute coronary events. And they're 30% more likely to die of such disease than their Caucasian counterparts. So if we just look at cardiology as a whole, we're already looking at a very vulnerable population to start with. When it comes to ATTR cardiomyopathy in and of itself, it's a life-threatening disease. I don't have to speak to this crowd. You guys know that very well. And it disproportionately affects older adults as well as African-American patients. The older adults were sort of addressed in the previous debates. And I'm not sure how many of you guys were at the previous debate. But today we're here to talk about those of African descent. And when you look at the specific mutation involved in these cases, we're specifically talking about the valiant to isoleucine mutation. It's by far more common in black Americans in the USA comprising about 5% of the population. When you look at West African populations on their own, it hits about 5% of West African populations. In a single study, if you look at the UK, we're not talking about a disease process that's isolated to a certain part of the world. We're talking about the disease process that affects everyone on a multinational level. So if you look at a single-center referral process in the UK, when they looked at the valiant to isoleucine mutation, they found that it actually affects about 43% of those with ATTR cardiomyopathy in that single-center in the UK. And when they specifically looked at that population, they found that 50% of that population were of Afro-Caribbean or black descent. So this is a huge number of patients that we're talking about that are affected by this mutation. And finally, when they looked at a Theos multinational registry, that's a transthyretin amyloidosis outcome survey. This looked at both European as well as North American populations. About 2,500 patients, 300 in the USA and a couple thousand elsewhere. In that 300 in the USA, 25% were black Americans. And when you look elsewhere, about 0.5% were black Americans. So this is something that hits at home. This is something that we need to address here in the USA. OK. So just to provide a little bit of background, most of us know that hereditary amyloidosis is caused by pathogenic variants or mutations in the TTR gene. And this gene is located on chromosome 18 and it encodes for the transthyretin protein, which is a Homo-Tetrameric carrier protein that's involved primarily in retinol transport and thyroid hormone transport, as well as may be involved in some other intracellular processes. Pathogenic variants in this gene are associated with amyloid deposition, which is how we get amyloidosis, predominantly affecting the peripheral nerves and the heart, although we know that it can build up in other parts of the body causing complications like carpal tunnel syndrome, kidney disease, and digestive issues. TTR variants are inherited in an autosomal dominant pattern. So any individual who's affected with this condition, their children have a 50% chance to inherit that disease causing variant and also be at risk for the condition. We expect that the variant was inherited from a parent, so we think that the expected risk to parents or other siblings of the affected individual is also 50%. And about 150 or so disease causing variants have been identified. This condition is also characterized by incomplete penetrance and variable expressivity. So not all individuals who have a disease causing variant will develop disease. And for those that do develop disease, symptoms may present at different ages or different severity levels depending on the individual, even within the same family. So just to talk a little bit more about that V142i variant that Dr. Boshara introduced, also sometimes called the V122i variant depending on the naming system that is being used, it's disproportionately more prevalent in individuals of African descent. Like you mentioned, approximately three to 4% of African Americans carry this variant and that's even higher prevalence in some areas of West Africa. And this compares to a prevalence of up to about 1.6% in the general population worldwide. The paper that this graphic is from also notes that this is the most commonly identified TTR variant and accounts for up to about 79% of hereditary cardiac amylidosis cases. And for individuals who carry this particular variant, it's estimated that at least 75 are of African descent based off this paper. Age of symptom onset is around 63 years old, but diagnosis is not typically until several years later. So this really demonstrates the concern for later diagnosis and later implementation of appropriate treatment. And while the true penetrance of this variant is really not well defined, it's thought that there's significantly higher risk for incident heart failure in carriers compared to non-carriers, as well as lower reported survival compared to other types of cardiac amylidosis. So when we look at the racial disparities in cardiac amylidosis with African Americans specifically with hereditary ATTR, they present with more advanced disease compared to their Caucasian counterparts and those with wild type TTR. And that's despite them having a non-invasive method for early detection, namely genetic testing as well as echocardiography. They have a median survival of about 25.6 months versus the 43 months that's associated with the wild type. They have twice the risk, like Sonia was mentioning, they have twice the risk of incident heart failure compared to non-carriers. And they're disproportionately underrepresented in the clinical trials. And that's a huge point here. Despite the high burden of ATTR cardiomyopathy among black individuals, most clinical data is actually from non-black individuals and individuals from Europe, which as we mentioned earlier, underrepresented black Americans, several studies. In addition to racial differences, there are huge socioeconomic disparities when it comes to affordability as well as accessibility to disease modifying medication. So that's something that we need to keep in mind with this population. So when it comes to what are the pros of testing all black adults for ATTR cardiomyopathy, we're talking about early education. This is to raise awareness of the signs, symptoms, and resources in those who are identified to have the mutation so that they can plan accordingly. This is to notify at-risk relatives and to allow for cascade testing. When we talk about education specifically, Dr. Dev Sandesh presented a slide earlier showing that even within the USA itself, there are huge geographic variations as far as both the diagnosis as well as the management of amyloidosis. The highest mortality rates that you can see were actually centered around amyloid referral centers and amyloid referral states. But when you look at the South, the South has the highest black American populations and those are under-reporting mortalities when it comes to amyloidosis and that's an issue with education, that's an issue with diagnosis. When we look at patients with ATTR cardiomyopathy that are identified, the median time from onset of cardiac symptoms to the time of diagnosis about three to five years, we're already behind the eight ball when it comes to these patients. So rather than be reactive, we need to start being proactive and we need to start testing these patients ahead of the diagnosis of their phenotype. When we talk about medication accessibility, it was presented in the earlier discussion with the older patients, screening for older patients, that the cost of taffomitis is exorbitantly high. And this is because this is a disease that's been labeled as a very rare disease. And so taffomitis has come across as an orphan drug, okay? If you start testing more patients genetically and identifying more patients, this no longer becomes that rare disease. This no longer becomes a disease where we need to rely on orphan drugs to treat it, okay? This is something that can really, genetic testing is something that can really push the bounds and really allow for higher accessibility for medications going forward for these patients. All right, so in current practice, there are situations in which it is important to discuss genetic testing for hereditary amyloidosis. One of which is when a patient is diagnosed with TTR cardiac amyloidosis. Genetic testing is recommended for all of those patients regardless of age to differentiate between wild type and hereditary amyloidosis. It can help better characterize clinical manifestations, prognosis, guide treatment selection, and really highlights the importance of screening for family members who could be at risk. Another situation kind of segueing from family members being at risk is family members of individuals who have a known TTR pathogenic variant who are interested in predictive testing to better understand what their risk might look like. And one paper by an expert group suggested an approach to pre-symptomatic genetic testing in at-risk relatives as well as screening in asymptomatic carriers. So it's important that asymptomatic individuals undergo appropriate pre-test counseling to discuss the benefits and limitations of genetic testing for them at that point in time. This should include discussion of possible changes in medical management, family dynamics, psychological impact, and insurance or financial implications. And it's important to note that testing in asymptomatic minors is always considered inappropriate but for adults who choose to undergo this type of testing and test positive for a disease-causing variant, it's suggested to begin monitoring for symptoms around 10 years earlier than the predicted onset age, which is impacted by the variant type, family history, and expected age that that variant might present. So with that being said, there's still many affected individuals who are misdiagnosed or diagnosed much later than they should be like we've talked about. And one of the reasons that this genetic diagnosis might be overlooked is due to a seemingly negative family history. We might think that with a dominant condition, we should see a really strong family history of symptoms, but we actually see that inheritance can be masked by multiple factors. Could be that there's failure to recognize that a family member's symptoms are caused by amyloidosis. There could be the early death of a parent before they might develop symptoms or a parent might not develop symptoms until later in life or may never develop symptoms because of that incomplete penetrance and variable expressivity. And another point to consider when it comes to genetic testing for hereditary amyloidosis is that TTR gene analysis is already universally available on direct to consumer or DTC genetic testing. Anyone can purchase this testing in-store or online and submit a saliva sample to get various genetic information which often can include the presence or absence of the three most common variants, including that V142i variant. So for patients who haven't had pre-test counseling by a medical provider, they don't have a known family history. This might be very surprising. They might not be expecting a risk result or really prepared to process the significance of that result. But there are resources out there for healthcare professionals who want to help interested patients access clinical genetic testing to better understand the risk for this condition. There's options for doing testing via saliva sample or blood draw, very simple collection process. Commercial send out labs often have insurance billing assistance to help patients better understand their financial responsibilities. And typically there's an alternative $250 self-pay price for testing. And then for patients who actually have a known family history or who have suspicious symptoms of the condition, there are sponsored testing options out there to help patients get no charged genetic testing. So many providers might not be comfortable or trained to provide this pre-test counseling that we know is important, but that's what genetic counselors are for. And there are resources for providers to access genetic counseling services, whether that's referring to counselors at local hospitals or clinics. Genetic counselors may be on staff at the testing laboratory that testing is ordered through or providers can partner with a telehealth company that provides these services for pre-test counseling. I also always just like to point out the Find a Genetic Counselor resource that's available online where you can find a genetic counselor. So we just like to wrap up with a case example of a patient that I saw in clinic. This gentleman had self-referred to discuss his direct to consumer testing. He was really motivated when he did the testing to find out more information about his genetics. His ancestry results showed Nigerian and other West African ancestry. And his health screening results showed that he carried that V122I variant. So he had never heard of amyloidosis before his results. And naturally he starts Googling things and becomes really concerned about the symptoms that he sees online. And he starts becoming hyper aware and concerned that any changes that in feelings that he's having is onset of symptoms. So I really wanted to be sure that we touched on a couple of things. One that we needed to do clinical confirmation testing because it's different than direct to consumer testing. There is a good chance it would come back positive and it did. But on top of that we wanted to really adjust expectations, you know, kind of ease anxieties of the things we might not expect with this variant while confirming some of those clinical risks that were relevant to him. And it allowed for follow up education for his family members as well to announce that they're at risk too. They can get genetic testing and counseling. It allowed for evaluation of him and referral to our multidisciplinary amyloid team. Shout out to those in the back to help with follow up screening and management. So because he chose to pursue this testing and follow up with counseling, he was able to better understand his own genetic information and access these benefits. And with 4% of our African American population having an expected test result like this patient, we think that these individuals should be offered the opportunity to have those benefits as well. Thank you. Thank you. Thank you.


Ok everyone welcome back um in the most recent lecture I explained to you how the human eye works and we looked at the entire visual pathway from photoreceptors where the light hits going through the cells that are in front of the retina up to the ganglion cells and then communicating that information through the optic nerve and back into the visual cortex and we emphasized hierarchical processing that goes on. And then once we understand that we like to start to talk about perception which is when the brain makes some kind of conclusion about what it is seeing or or sensing if it is another sense beyond seeing and we gave examples of depth perception. So I gave you a number of examples of that um we also talked about eye movements in the last lecture which um are very important for doing things like keeping the image stabilized on the retina for a moving target or if you are moving your head or some combination of the two. So one thing to think about to continue from last time is um when we have various depth cues that I gave think about the combination of cues and I talked about many different kinds of cues like for example um one object is in front of another or you look at the overall size of the object um on the retina right the size of the image of the object on the retina. So we looked at these things and the brain is taking all of these into account in order to make a judgment about depth. We also had what you would expect a binocular disparity right coming from two different eyes but I just want to emphasize last time through I think I gave um many examples almost a dozen examples of monocular cues which just use a single um eye in order to make conclusions about depth. So in order to combine the cues one way to think about how this happens it is very much like statistical decision theory which also shows up in machine learning. So if you wanted to construct some kind of model of how the brain might be doing this um perceptual psychology is very often like to consider it to be a um a kind of example of a Bayesian model Bayesian or probabilistic model and as such um the brain is considering how useful is each one of these cues in the particular context where it is being observed what are the priors right the brain is using um a lot of information about priors right given the context um if I have been out on the forest many many times in my life and then I go out on the forest again there are a lot of expectations of what to see around there right you will not see um um a bunch of cars you know driving right through the middle of the forest or something let us say or um um you know something completely absurd suddenly appearing in front of you on the forest or certain expectations about the context your brain is filling in the um this information in some ways trying to reconstruct a a a full picture without having um a requiring additional information or additional sort of reasoning power. So, it is falling back on priors very often so um so these are some things that are very important for Bayesian modeling and analysis and this seems to happen as well in the human vision system. So, there is prior bias right you are biased by the expectations of what you see and um in the process of putting together information from multiple cues the brain is trying to decide whether that information is consistent in which case it will increase your confidence in what you are seeing or is it contradictory right it is contradictory it will lower your confidence. And when we see some of these optical illusions they may contain contradictory cues and this causes some significant amount of confusion. So, how useful how useful or how discriminatory let us say is each cue in the context context could be in combination with all of your other senses and your memory of what places like whatever you are seeing I have appeared like before right um um such as one extra thing I wanted to add to the ah depth perception and this generally applies to all aspects of perception these kinds of ideas here and not only combining multiple cues from the same sense, but also combining information from multiple senses to make some kind of coherent view of the world with a very high amount of confidence um. Another related topic which I will not cover very much, but you could also talk about scale perception and compare that to depth perception right so how large is the object that I see um if you make a virtual world and you start putting furniture in there does this correspond to furniture that you have seen before does it just look kind of vaguely similar like maybe there is some kind of sofa chairs appearing well based on the way the chairs look you might be able to estimate how large it should be, but also the depth perception is coming into play again how far away is this object right is it that the objects very far away and enormous or is it up closer and smaller. So, you can see that depth and scale are very closely intertwined these are very important ah aspects or concepts for virtual reality because maybe you would like to reach and grab something if you are tracking your hands for example, even if you are not tracking your hands you may still have a simple some kind of simple controller interface, but you want to with your virtual arms reach and grab something. So, how perception of depth and scale come together will be very important in a context like that right and as well your perception of scale and depth are going to be affected by your interpupillary distance in the virtual world and so another interesting thing right we talked about that right. So, if I put your eyes very very close together in the virtual world you what you may perceive yourself as smaller or perceive the outside world as larger you can think about that very very philosophically if you want they are more or less the same thing geometrically right. So, how does your brain choose to interpret that when you are in some kind of virtual world it is very difficult to say it probably depends on the amount of realism if the virtual world looks very much like some familiar physical place then if you make the IPD very small you will most likely feel small in that world right. If you make the IPD very large you will most likely feel large in that world if it is a completely synthetic cartoon like world it is very difficult to say what will happen what your what your how your brain will interpret that right questions about this.