Debate: Genomic information is essential to clinical assessment of complex disease risk – Discussion



one thing one thing when we had a pre call both acknowledged that they could they could argue either side of this and so I really appreciate their willingness to take on the the the side that they were given as opposed to necessarily those and secondly want to open it up to Joe's inform a comments questions for the debaters whatever you want to you're having fun and we had fun too so let's say we want to test the water with education with getting clinicians used to it which disease or trait would you take out and implement first which okay well let me be clear contrary to my explicit position I think there are some areas now where where it's not complex yeah where it's not where it's not complex where we can and should use genetics today but it's not complex and so for newborn screening for specifically about apologetic apologizes for okay Steve you you go first well I think I think breast cancer is a very good place to look at this I think when you have again there's a there's a part of the equation that we don't talk much about overtly and that is the absolute risk the incidence in the population and when you have a devastating disease like breast cancer and you have 500,000 women a year being diagnosed cardiovascular what 700,000 looking on the web this morning you know of three or four hundred thousand of whom will ty do their cardiovascular disease I think the stakes are very high I'm just using us statistics so that I think we need to not study you know a rare pediatric epileptic condition or an autoimmune disease but go at these places where we do have a fair amount of data and when we have modifiable risk factors because I I mean it's my very strong conviction with breast cancer it's trying to identify those women who are in the higher des ├«les that would benefit from extra effort we already say don't smoke you know keep your BMI down exercise be careful about HRT s and the like but really pushing that message and I think in those populations is very important the other place I would consider this is I thought that the data today was very compelling of looking at obesity with the Ellison's back in etcetera and thinking about how we start to educate because you know we're basically all over the hill okay we're looking at conditions that you're 50 and over I've trained as a pediatrician and I much rather this make it into you know you know newborns and early adolescence and the like that are changing lifestyle decisions it may have tremendous implications in terms of heart disease diabetes cancer and the like so I think we have to we have to go at the pediatric as well as some of these very large absolute risks in either breast cancer or our heart disease I think you're far enough along to really do that so first of all I think breast cancers a is a good one again for the future I would not use that risk or today to influence any decision-making but I think it's really important because we see for example that the meaning of bracket 1 bracket 2 is different if you have a family history or if you're asking Ozzie so there's something there about genetic background and so sleuthing that seems like a priority another area that I'd like to look at actually roughly small but not so small hemochromatosis so this is disease that we used to think of as being very penetrant recessive then there was that great a study out of Kaiser Permanente when they look at all the recessives homozygous recessives for HFE and one only one out of hundred fifty one of the patients who were recessive out of population the forty thousand actually had any evidence of ayran overload more recently studies done with a UK biobank so some shows some may be some muddy symptomatology so there again I think we can work things out I also want to say that it's great to go after pediatrics and again training paediatrician where the understudied area but at the same time let's study things that we know how to treat what I don't want to do is write a carte blanche for everybody to start giving let's say statins or bariatric surgery to a bunch of kids instead I'd rather spend those dollars in obesity on modifying the environment I know the bang for the buck will be much much higher step further I think you know behavioral genetics and sort of physiologic genetics really overlap particularly the obesity world and I think that's where the kinds of interventions for younger populations could be very interesting to not only study but I think to educate because what we also face is you know just this tremendous revolution going on around us with 23andme ancestry.com all this panel testing people getting this information and going to Google and coming into their physician's office and saying you know gee I have this brca1 mutation you know should I have body altering surgery when it's a V us but the self referral or coming from a place where there's not very good assessment per se so I think we have to think really hard about this educational component with each of these places that were that we're gonna do this because there's no question that there has to be feedback the system will get better I don't think it's got a 50 percent error rate as you suggested for the use of genetics in breast cancer or in heart disease but it will get better with time and the alternative to do nothing for you know the 11.2% of women who have breast cancer who don't have brca1 2 or picked up because of their family history I I think is doing just as much harm or if not more by not at least giving them an opportunity to understand and modify those things so let me just give you an example of why I'm not looking for a big wall although I guess the the king in games of thrones didn't like the ball either anyway thank you oh yeah sorry sorry sorry no that was no that was last season member he broke through the wall last season yeah some of us haven't even seen any of that and they're mighty okay sorry oh I'm so sorry okay yeah so a bunch of pediatric endocrinologists had to make a big societal decision that they were gonna test everybody and they did and they got a huge reduction in intellectual disability and they did it by actually calculating responsibly true positive false positive true negative fossa and the cost of the test and who was that I could name names because they're some of my heroes at Children's they defined thyroid hormone screening that changed but they really figured out they didn't say Oh 50% false positive rate that's okay for the time being cuz in the future it's gonna be great no they said we're gonna make it work today and because of that very few people got hurt boss got saved contrast that with thee what's the the ACMG had some criteria about mutations that you should screen for one of the mutations that they said that you should screen for in Pediatrics before the data was fully in but they thought probably pretty good about it was a gene that what for which if you were home as I guess you were likely to get cystic fibrosis I can tell you I was spoke to the guy from ACMG who contributed to that decision how he has been heartbroken ever since because it turns out that a significant portion of that particular mutation the kids don't develop cystic fibrosis and he knows that several personally knows that several pregnancies want the pregnancies were terminated because they thought their kid was gonna have cystic fibrosis it speaks to me that this is loaded this is loaded weapons we should not create a wall we should look at every bit of data when we do those big cohort studies for actionable real stuff that we know could not possibly be wrong and think about it like real Public Health people sense to be specify seed tilty instead we're showboating we're saying because I can let's do it and it's not just the industry that industry is abetted by our triumphalism and we as doctors we've previously been very very sober but because of for right reasons we feel we have to showboat and that's hurting our patients mark you were next in it it's this pantheon of pediatricians I've heard Pangloss Pandora pandering pan pandemonium I'm pondering the antipodean views between rare disease and polygenic risk scores and I'm wondering if these two competitors can find common ground on use cases combining rare disease pathology there were scores breast cancer is the perfect example for that I mean that that's why I would start there because I think we know an awful lot about a good fraction of the highly penetrant mutations responsible for breast cancer in the general as well as special populations how we identify not until Chuck Schumer and Mitch McConnell get together and start us down nationalized health care and we really have genetics built into our system that will that really effectively be done we have to still go through this Wild West of testing analyte which has its challenges but I think that it's changed the nature of clinical practice okay there's no question about it in many places but it has not filtered to all parts of the United States alone you go to you know rural parts of Arkansas and Kentucky the idea of clinical testing for breast cancer or colon cancer risk is pretty much non-existent the moonshot from the NCI just as a small advertisement is pushing this and trying to develop these kinds of things but it's we still have a long way to go so I agree and in fact I see breast cancer as one of the more advanced examples of the kinds of things that so we're closer to reality where some of the other projects I think are not there and that's why I get more worried about them for me yeah so coming back to misdiagnosis and doing harm so you would have thought that by now we would all have learnt the lessons about variants that are just rare because they belong to minority populations in this country and so the question then is how should we prioritize where we spend all our energies in terms of really promoting equitable distribution of resources because I bet if you wanted to sequence every patient who goes to a minority serving institution and get their electronic health records you could probably accelerate what we're doing here yeah and but we all really still want to do the convenient samples that's already assembled and so my question to our sweaty wrestlers is that you know you have to think about the harm that's done by not finding patients with actionable mutations because they're poor they have no actually you just but you just actually reminded me of something most important them the most powerful snip the snip were the biggest odds ratio of any and we haven't mentioned today this snip is has a bigger as observation on the end things have been mentioned here is poverty if you are poor you will die no matter what your genetic background you'll die faster from cancer you'll die faster from any other disease and that's what the data tells us so guess what as a public health oriented people that tells us about something where our investment has to go I thought you were gonna say the Scottish national but yes so that's number one number two is I couldn't tell whether you're being reluctant reluctant or not I do think we actually need to go into our men our minority populations I'll speak as a Jew we actually are the first people to have committed Auto eugenics by screening a sacs people who are dating and it got gun that down and so I do think we should focus on various minorities and because all of us originally evolutionarily came from Mother Africa that's the mother lode of genetics and given the fact that we have a huge number of african-americans as a population seems negligent not to sequence them so that we have good sense of what the frequencies of these different genes are because they may not be represented in some of our studies although I have to say NHGRI has done yeoman work in trying to to get that representation but it's not for lack of trying on their part your ops you write about the problems of convenient samples such so much but I think we need to redouble we need to redouble those efforts and I'll spare is very entertaining conversations I've had with with Gary at the NHLBI about this topic all right let's think one more time thank you the great debater and then / – great well thank you thank you both we had talked about having a sort of a vote as to you know who won the debate but we decided not to do that yeah that's right that's right well let them choose who won and let Steven we'll let you get off to your your appointment on time so we can end early unless people wanted to continue some discussion but I think we probably are it's been a long day already so we will start again tomorrow at 8:30 promptly please there is breakfast starting at 7:30 again in the in the room behind us and then we'll will take it away so thank you all very much and we'll see you tomorrow [Applause]

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