 Well, good afternoon, everyone, and I have to say it's certainly I want to thank everyone who's organized to get all this large group together. And for someone who has spent about 30 years trying to educate the cardiologists on electrobiology and genetics, it's terrific to see such a wonderful group of people. I think my first lecture said genetics for a clinician was the American Heart Association in 1986 with the Bureau Foundation, and I've probably been doing it a dozen times a year, at least since that time. So it's very wonderful to see so many wonderful organizations here today, and I hope that we will develop something from it to go forward. The other thing that is sort of a vindication for me today, not for what you think, but seeing Gene Passamani, who certainly was instrumental in organizing this, he was my fellow at WashU, and then when he got fed up with me, went off to Washington and told me what to do for the next 25 years and writing grants and everything. I went to Baylor, and one of my favorite fellows was Bill Zogby, who became a cardiologist and he learned to get away from genetics because he used these big machines we all use like echoes. But of course, every night he would go home, and his wife, who you know is one of the world-renowned geneticists, Huda, would tell him about genetics. He'd come to work, I'd try to tell him, but he went off. Finally, both of them have seen the light in the hair today. Thank you. So if nothing else, I might have achieved something. Well, Bill wanted me to say something about the diseases per se in cardiology to illustrate because I think all of us know. Cardiology is a field where you deal with big things and big machines and you do things in a big way, sometimes in a crude way like angioplasty, but that's what it's all about. It's very visual. So to bring in something like a pipette in 1986 was a tough issue. It's still tough, but genetics has moved along, and so I'm just going to say something about few of the diseases that clearly many people in cardiology have made possible, but I will speak about the single gene disorders, the medelian disorders that all of you know, and also say something about the polygenic disorders, although I want to emphasize there's not really a big difference except in the knowledge we have to apply them at this moment, as I think that Dr. Arnett pointed out. Clearly there are estimated about 7,200 Mendelian single gene disorders, and about 3,500 of them today have at least one gene, at least one mutation. And of those, about 252 involve the heart or the blood vessels. So you have a lot to choose from, and as you've heard many times today, where can you find all of that together? The chances are you won't, but it's certainly organizations and meetings like this that could make that possible. Here's a few of them, as you can see, that are associated with sudden cardiac death, and hypertrophic cardiomyopathy is still the most common cause of sudden cardiac death. Now I just want to illustrate here, right now our guidelines would say in cardiology, if you've got a year of medicine and you read the guidelines, you can be a pretty good cardiologist, and you have to stick with those guidelines. But there is more to it than that, and that's the utilization, and that's the problem we come up against. You speak about randomized clinical trials. If we did a randomized clinical trial today, or 20 years ago, nitroglycerin would be wiped off the mat. It will never get through. Never. We did that with dejoxin about 10 years ago. After 100 years, we threw dejoxin out. We don't use it much anymore. So we have lots of things we do that would never satisfy an RCT and never will. So keep that in mind as we go through. But here's a story, depending on how you tweak this, but if you're 12 years old and you've got a history of hypertrophic cardiomyopathy or family, we'll say to the echo guys, echo them every two or three years, at least the next 20 years. You knew you'd do a lot of other tests, not just echoes. Now remind, most of these disorders are out of some dominant. Only half of that family needs to be echoed. So it's not only the anxiety of not knowing if you did the mutation. Certainly, as pointed out by Dr. Nitt, that not all of those mutations, even though they're pathological, will develop a disease. But you can certainly be very cost effective. Every time you do an echo, it isn't just an echo you do. You always do a few blood tests and a few other things with it. So there is both the cost effective as well as improved management for doing mutations in hypertrophic cardiomyopathy. Now it isn't that simple. As I know that Heidi would be the first one to tell you that if you order up a test for HCM, I think it's fair to say somewhere around 60% to 70% will give you a known proven mutation today. What do you do with the other 30%? Now my cardiologist said, oh my god, it's only 70% effective. I just want to remind you that in the emergency room, if you do an ECG, only 7% of ECGs in people with chest pain will change their management. If on the wards ordering chest x-rays or cardiologists, I checked this one out. We did 138,000 in-house chest x-rays on our cardiac patient, the Heart Institute. It changed management in about 7%. So just because it's only 70% effective doesn't mean you shouldn't use it. And so that too is something we have to get rid of. The other point that's come up a lot is, gee, this genetic revolution is complicated. Believe me, I had a choice in the 70s to choose electrophysiology or genetics. I chose genetics. I have only four little things to deal with. It's a hell of a lot easier than reading ECGs or doing electrophysiology. So I would like to make clear today, genetics is very easy compared to most other choices. Particularly echoes one. Now we also look at this, that screening for sudden death in young is a common cause. Arportrophic cardiomyopathy, certainly in North America, is the most common cause of sudden cardiac death below the age of 36 years. After that, of course, coronary artery disease comes in. Look at how good we are at 1% for physical examination. The ECG will show abnormalities. Most of which, of course, is non-specific. You are obligated to look at the story and say, what are we going to improve this? This is the 21st century that tests are available. Now, there are other times when it's diagnostic. For example, the synachronon of hypertrophic cardiomyopathy is hypertrophy, a thickened ventricular wall, either in the septum or in the apex or caseically concentric in about a third of them. But there's another disease called Fabry's disease, which does have a treatment. You can give them an enzyme and treat the disease. Sometimes it's not easy to tell the difference between these two, in which case genetic testing becomes a diagnostic, and sometimes even in other metabolic disorders. Pointing out here that it isn't just from the point of view of genetic counseling or advice, but also for making a diagnosis. A long QT syndrome, which takes up a lot of time in the cardiovascular world in electrophysiology. And here, I just want to illustrate that about 70% to 80% of that syndrome is due to these three channelopathies. But if you have, in terms of the long QT syndrome, due to one of these potassium channels, beta blocker is our preferred therapy. Never proven on the basis of our CTs, but it looks like it works, because people don't die. And that's good enough for most of us. Now, on the other hand, if you have long QT two or three, which is due to a sodium, a potassium channel that's different than the treatment is different. And by a gain, just by experience, beta blockers don't work as well, and mix halitine, flecanide, or ranilocene are the preferred drugs. So here you select a drug on the basis of genetic testing. So from my point of view, looking at single gene disorders, it's clear that there is great value in genetic counseling because it is the most common cause of sudden cardiac death up until age 36. It clearly is diagnostic in some cases, and it has therapeutic implications in diseases such as long QT syndrome. As I indicated to you, it can be very cost effective in a disorder such as HCM. Now, there's no doubt about it. In the sports world, there's a lot of concern about hypertrophic cardiomyopathy, and all of the national, certainly every time I would see a young patient in Houston. In Houston, if you don't want your sons to play football, you got to start at about age three. Otherwise, you've taken religion from them. So bottom line was, we'd always get these people to come and see us. And of course, they're often going on scholarship to college or what have you. And if you happen to have HCM, you've taken everything away from them. So I just want to indicate to you a couple of points. Now, the treatment for hypertrophic cardiomyopathy, really definitive for sudden death, is indwelling defibrillator. At the moment, there are about 6,000 indwelling defibrillators in people with hypertrophic cardiomyopathy. I've told you it's the most common cause of sudden death below the age of 36. When are most of the defibrillators put in? 79% after the age of 45, because they die before they get there. And without testing from family point of view, these teenagers die or die on the field because they're not tested. And obviously, as I've indicated to you, the ECG history and physical is not adequate. All of these people would gladly pay to have that done. Now, you've heard about pharmacogenomics, so Dr. Annette pointed out the problems we face there. But I just want to indicate one thing to you. Because I'm pushed and driven by genetics, we develop a little machine to put on the ward to test for the eight or nine variants that alter clopidogrel. This is a little machine run by the nurse. You take a blood out, rather than use the PCR, we amplify whole genome. You put this test tube in the machine, 45 minutes later, it comes up and tells you whether it's resistant to clopidogrel or not. On the basis of that, this was published in Lancelot a few months ago, we then went ahead and gave them clopidogrel. Now, it's true that 20 or 30% of clopidogrel have those people that can't transform the active form. It's a little bit complicated at the moment because some of those people who are resistant still do very well on clopidogrel. But what I do want to say to you is, clopidogrel cost a few cents. And we got four new drugs. Prazogrel cost a few dollars, each one of them. So you could select your 60 or 70% for a few cents on the basis of this simple test. What most cardiologists do, why bother if it will give everybody Prazogrel? Now, clopidogrel is the best proven test anti-platelet therapy for myocardial infarction for stents and what have you, but still will probably go and pick the most expensive tests rather than going back to doing this. But hopefully the new trials coming out, if they show of course that this is a good way to go, then it will probably creep into it. And I would say, here is the field where you probably do not necessarily want RCT, but you can do work to see outcomes and I think it's appropriate. But back to the other genetic testing. It's a tool to do something with. We've never done a randomized trial to see if biostatisticians do better running them or not because we accept their expertise. I think we have to accept genetic screening in a certain way as a tool and as expertise. We're never going to do an RCT on HCM. It's never going to happen. So here I think it is more appropriate because of the fact that it is testable. I'll now run into the polygenic disorders which are very complicated. And let me say up front, there's nothing in cardiology at the moment that I can say you can use clinically in terms of screening for these diseases that affect coronary artery disease which is our bread and butter as Bill pointed out. But 9P21, I want to point out a couple of things about it. First, when we and the group from Iceland came out and identified this back in 2007, one thing was surprising to us is that 9P21 carries a significant risk. If you are in terms of premature myocardial infarction below the age of 55, it increases your risk a little over two fold. Overall, about 50% if you got two copies or 25% for one copy, it is present in 75% of the population but it is independent of known risk factors. If nothing else, this should say to you, it has been said since 1957 that about 50% of genetic predisposition for coronary artery disease is in your genes. And this is done by epidemiologists, not by cardiologists or geneticists and this is clearly coming out. So if you want to prevent heart disease as all of us do and certainly those of us in the cardiovascular world who feel that it can be in fact prevented mainly in this century, we clearly have to turn to get genetics because 30 to 40 to 50% of it is there somewhere. It's not all in your cholesterol or blood pressure. And I think 1921 clearly indicated to us there are other things going on. Now, we realized very early in the game as I think all of us are realized of being here today, that it would require a large collaborative effort to identify them. And because in fact, they do have a small effect and they're not like single gene disorders. Not any of those are necessary or sufficient to induce the disease. They act in multiples. So the bottom line is we formed with cardiogram, a large group, and this involves both the UK, the US, and Canada. And we put together 194,000 cases and controls and we did obviously, we ran every body sample first with two and a half million of the SNPs. Now we do it with about 18 million SNPs. And so we now have 50 genetic risk factors that have been identified, confirmed in independent groups and clearly all satisfied genome-wide significance, et cetera. 46 of them is in the paper in Nature Genetics we published two weeks ago. The other four just came out, they're mainly in Chinese. So a total of 50 without question. Now, this certainly will make it look more difficult,ologist. And I want to indicate very clearly at this time, it is difficult to know where we'll put this in terms of clinical practice because at the moment, we don't really have a ready place for it. But we have identified, as I'm sure many of you and other diseases have shown, it's no longer like single gene disorders, it's not which gene you have, it's how many of them you have. If you look here, this is done on a population that we have of about 15,000 that we have followed for about four years independent of genetic risk factors, known conventional risk factors, whether it's blood pressure or hypertension or what have you. And so it clearly tells us we must pursue them. I'm sure of those 50, they probably only act in two or three pathways, but we need to know what those pathways are. And I think the time for genetic testing for Mendelian disorders is certainly here now. Even though my colleagues won't always do that, the time has come and it's no longer looking to the future. I think comprehensive prevention will require we do it all the way through. Personalized medicine, it will be difficult to really realize it given the fact that genetics is the basis for it. And having spent 20 or 30 years in the field, I think at this moment, unless we have, everybody here from the different societies agreeing some kind of structured education for my colleagues, I don't think it will do. And neither are we here to teach genetics. You're not going to make them. I think it was well put by Michael when he said, you got one or two hours. We have to embed it into their curriculum. They're not going to spend another year in cardiology. We already have about nine sub-specialties in addition to cardiology. This is the way I think we have to go. Thank you. Great, thank you very much. Okay, so Mark. Yeah, this is for Bob. My understanding is that in Italy, they are actually doing prospective screening for hypertrophic cardiomyopathy and long QT syndromes as a routine part of any pre-participation, physical examination, at least from high school and above. I was curious if they have been generating any outcomes data as to avoidance, identification and avoidance of sudden death. Yes, the data in Italy very much confirms that if you look at the death rate of people who were turned away in high school from participating combatant forces, the death rate is about one third of what it is in those people who were not screened out and continued. So on the basis of that data, certainly it is a retrospective analysis, but a little bit prospective in that it was done beforehand, they show it is a save lives. Great. Gene. Another question for Dr. Roberts. It seems to me that there is a tendency among cardiologists to ignore this business and has it stretched to everything? I mean, if you ignore it in hypertrophic cardiomyopathy, do you ignore it everywhere else? I once was told by an expert that I was entitled to my own opinion but not my own facts. And what you seem to be saying here is there are facts that very strongly support careful screening. It's very interesting because 9P21, as you know, also accounts for about 26% of attributable risk for aortic aneurysms and also for intracranial aneurysms. We are getting many more requests for 9P21 from the people in stroke and neurology and in the peripheral vascular people than we are from the cardiologists to do HCM. So it's a very interesting story. Now, when I ask them why would you want 9P21 for an aortic aneurysm and not be tuned in for otherwise? It's because they don't know enough about aortic aneurysms, it's the first piece of data they put their hand on. Interesting. We have John Harley. I'm sure among your 50 genes that there's a substantial number with odds ratios of 1.1 and 1.15, the idea that one in nine of the patients that you see or something on that order or one in 10, the gene that you're finding actually contributes. I mean, what would happen is that people are gonna look at the same data and a professional will say this is critically important and other professionals will look at the same data and say, no, we can't use this for clinical application. It just doesn't make the kind of difference that you can rely on to make either therapeutic or diagnostic decisions. I agree with everything you said and you're absolutely correct. And that's why I emphasized in the beginning when talking about this for coronary artery disease, it is clearly early in the game. All I would say to you is that it took from 1954 when cholesterol was shown to be a significant risk factor, then the 72 Brown and Goldstein isolated the gene for the receptor and showed hypercholesterolemia was a disease and the first drug appeared in 1987. Things have speeded up today. We're not gonna take us 50 years to find out how these things are important in finding new drugs. So I would say to all of us, it is on us to try and educate them before these genes find a place. Whatever percentage of them do, some percentage will and new drugs will come out. It's clear there are other pathways other than the ones we know. I'll give you another example. Right now our guidelines, both American Heart, American College, as well as European, Canadian, Cardiovascular, all say if you have a cholesterol or LDL, a 160, and you don't have any other genetic risk factors, not that. But if you have one other risk factor, such as hypertension or smoking, then we should lower it to at least 140. If you got two, we'll go down to 120. And then with more than that, the disease will go to 100. Right now, 9P21 is being concerned to be present in 4.5 billion people. It's an independent risk factor. Everyone across the continent has practically shown that. So if I said to you today, your cholesterol is 160 and you're almost, I guess, 9P21, should I act to decrease your cholesterol down to 140? Everyone will look at me and say, you're crazy. But if I said you got hypertension, which is just as unrelated, yes, you can drop it down to 140. That's the kind of reasoning I think we have to prepare them to get out of in the near future. Excellent point. We have, I think Bill Powell had a comment and then, oh, you didn't, I'm sorry. Oh, okay. Yes, please, Wolfgang. Yeah, these polygenic models with rare variants, they're all by necessity additive because we cannot test just what you said with the two risk factors that are more than additive. And they really don't add up, even with 50 genes and rare variants, you don't add up to more than 15% increased risk. So I think what we need to try to find out how to look at the dynamics of the interactions among this, which is right now statistically very difficult because you don't have the numbers, even with 200,000 people. So there are still other factors there that we haven't looked at at all outside the rare variants. Yes, I agree entirely. And I think many of those who don't reach 10 to the minus eight, and there's about 180,000 in this group that don't, and certainly many of those are, and you're right, we add them together, but they probably interact in a much more collective way in the body, and so we're stuck with that situation. But be rest assured, ordering up a test for a chip that's got 100,000 genes are just as simple as ordering up for your electrolytes. Excellent point. Bill, did you wanna make a comment? No, I mean, ultimately we have to put it in a patient context. And we have limited resources at this stage of the game. It has to bring value to our value equation of taking care of patients. So yes, we did not go for the sake of time through all the educational things that the college does, but it is along the line of most of the other professional organizations that we need to engage in that equation. And at this stage of the game from Bob's point of view, one is the single Mendelian-like genetic disorders. This is really a must nowadays to be able to do this. And I think we have to communicate that to our physicians, our total health care team to be able to do this. The polygenic ones are still big areas of research and hopefully down the line it will be cost effective and also changes our management down the line, Bob, with all the data that is coming forth. So I think it's very exciting, a lot of area of research. Jeff. I think I just wanted to make the comment that I think it's great to communicate about Mendelian disorders, but I think most of the cardiology practicing community will need something a little bit more, the clinical decision support tools and understanding how to access the tests and some of the interpretive services. So I think that's a great start, but I think to really get it to effective use in the clinic, it's gonna require more along those lines. And we talked about that. I think the college is embarking on a big digital strategy to have at the point of care the tools for the physicians. So whatever we communicate should be available at the point of care through their smartphones or pads or whatever it is available for them to be able to at least to help them going through this decision process. Great, I'm reminded that we have at least 65 if not more live stream watchers and I don't know that we have a mechanism for them to ask questions. So do we know if we have a mechanism? I'll ask my colleagues in the back. We do. There's a live chat running on the first one. Okay, so if live streamers who are listening want to ask questions, how do they do that? Can I wonder if they can hear you? Probably not. I was just trying to be like, Mark. So if there are live streamers that are out there that want to ask questions, go ahead and sign into the chat and put your questions in and I'll forward them to Terry. Or I could speak them for you. That would be fine too. Okay. That'd be great. Super, thank you. All right, thank you very much, Bill and Robert. That was terrific. We really appreciate it.