 Let's see right there. So this is the report with the authors. And I think I can point out, you can see that Les Beesiker and Robert Green were really the conveners and did the real heavy lifting in the discussions that we had about this topic. I'm glad Les is here and he's going to be making comments. Also point out that Amy McGuire, who's here on the council, was also a co-author, as well as a first author of an interesting paper that was published in Science recently on some of the ethical aspects of this set of recommendations. And I'm very hopeful that Amy would be willing to make some comments as well. So the ACMG recommendation is that all laboratories conducting clinical sequencing should seek and report expected pathogenic mutations for a short list of carefully chosen genes and conditions. And the reason I put this up is because, as you'll see later, this has been a report which has been met with a lot of, I'd say, some misunderstanding and perhaps some miscommunication. And I think it's important to remember what it is that this recommendation was about. The idea was to generate a minimal list. The importance was to establish a precedent for the idea that incidental findings needed to be reported. It is a recommendation and not a requirement. So why did ACMG feel that there was a need for guidance? Dr. Mike Watson is here in the audience as well. I saw Mike and maybe he would like to also comment on this. But I think it's because there was a felt to be a lack of consistency and consensus on what to report in the face of growing clinical use of whole exome and genome sequencing for specific indications. So these would be children who had an unsolvable developmental delay problem, or you may have a family in which there's an unexplained familial cancer syndrome for which no genetic basis had been found, and a variety of other sorts of applications where you're taking a whole genome or a whole exome approach to try to understand a disease and recognizing that in addition to perhaps finding the underlying basis for the problem, you're going to find other things as well. And it just didn't seem to be a general consensus as to what the laboratory's responsibility was. So the idea was to provide guidance for the laboratories. So what's in the ACMG report? It defines obligations of laboratories to report incidental findings that meet a high threshold of clinical utility. And that high threshold included high penetrance, pre-symptomatic intervention was beneficial. It acknowledges that this is a work in progress, and it recommends a mechanism for ongoing review and revision. So the report's not without controversy. Some people say the report asks for too much. That's sorry, TOO much. I know these things you don't want to hear, but I'm joined the hell out of saying them. So the idea was that we were forcing information down people's throats. The report does not say that patients should be forced to learn information they may or may want to know. What the report does say is that these are recommendations for laboratories who have little of any relationship with a patient. And it's not recommendations for the physician whose professional relationship led to ordering the test. It does put a lot of extra burden on the physician. On the other hand, the physician has ordered this test. And I think this emphasizes the importance of appropriate clinical consent when a patient and a patient's family and physician are deciding to undertake such a kind of broad genetic sweep in trying to make a diagnosis. The other thing is that the report contradicts previous testing policies for children. This is something else that has been said. And I have to say, the report does not recommend overriding the autonomy of children, deciding whether to be tested, when families know that children are at risk for an adult onset disease. So in the classic situation where a parent might have, let's say, a mutation for BRCA1, and they have a child who's two years old, that the recommendations are. And I think many people accept that that child be given appropriate autonomy and for a decision to be made as to whether that child wishes to have testing done, so the child can do that when he or she grows up to the age where they can make an informed decision. But the report does not recommend overriding the autonomy of children in that situation. But it does weigh the beneficence of alerting families of risk versus respecting the child's decision making autonomy when the families don't even know they're at risk. I think it's just a completely different situation where instead of saying, yeah, you know you're at risk and we're going to force you to have that information, versus it's sort of difficult to respect the autonomy of somebody to make a decision about something that they know nothing about. They don't even know they're at risk. And so it's still a very different situation. And so I disagree with the claim that this report contradicts previous testing policies for children. Another complaint has been that the report asks for too little that we left out pharmacogenetic variants, carrier state for recessive disorders. We also left out variants that might be of some personal utility, but with some question as to their action ability. And the idea was to try to have a limited list, one that most people would agree on, constituted a set of information that people would really need to know and would be unhappy if they suffered a clinical event later on which could have been anticipated and intervened on and prevented if only they had known that it was present in their whole exome or whole genome sequencing. Another complaint was that the report was developed in an IV tower with no outside input. The authors spent over a year discussing the issues. The authors reached out to a panel of domain-specific experts to comment on the recommendations. The authors held public fora. So I think as one person said, we all sat around and drank the Kool-Aid, I don't think that that is really an accurate description of the process by which these recommendations were made. Finally, I would just like to point out this very nice paper that came out in Science Express on Ethics and Genomic Incidental Findings. Robert is a co-author, Amy O'Guire is a co-author, and although they both, as it points out, the disclosure here, although they were both on the original ACMG working group that wrote the recommendations, this paper does not represent the official views of the working group, but I think it's a very careful and thoughtful contribution to the Kool area. And I would recommend people having a look at it. And I think with that I'm going to stop and take questions, but more importantly, it'd be very good to get comments from the other people in the room who really have a lot to say, I think, on this topic. Can I make a list of this here? Last one, do you at least come to a microphone? Because we have free chairs. And I said, well, just come sit here. Because I suspect if we're going to have a discussion about this, you'll be brought in. I suspect you'll be brought in. You might as well be close to a mic. So we'll open this up for Jim. So I support the recommendations. And one of the things that I think is critical that hasn't been extensively discussed is really what is the nature of incidentals. So one of the criticisms is you have said that labs need to go looking for these mutations and these chains. And I think what that fails to recognize is that incidental findings in medicine are almost always arrived at after a methodical analysis of the data that is before you. So if you think about a radiologist who's reading a CT scan of the chest, she engages in a very methodical analysis of the data that's sitting there in front. Incidental findings don't just leap out. I'm going to follow the contour of the ribs. I'm going to look at the pleural surface. I'm going to look behind the heart, et cetera. So I think the thing to remember is that when genome scale sequencing is done, the data has already been generated. And you are going to parse those data through a whole series of informatics filters. And what the ACMG recommendations say is you should also parse it with a filter that looks at these. And the other thing I would just comment on as a physician is that all of this controversy, it's understandable. And it's all the more reason that you should be hesitant to order a broad test. You should be seeking in medicine usually to order narrowly-focused tests that answer a specific question. Sometimes we don't get to do that. Sometimes we need to do a CT of the chest, because there's something wrong in the chest and we don't know what it is. Likewise, I think much of the problems that people envision with this can be gotten around if physicians do not just willy-nilly order whole genome sequencing. That's probably a bad idea, and most of us would agree. But sometimes it's going to be the right thing to do, because we really have no knowledge of where to start. Yeah, Tony. In all the grants that we're looking at this time on newborn sequencing and others, there's always a component of that which says they're going to take this information and try to understand from the patient or family point of view how they're internalizing it, what does it mean to them? So you say that the criticism was done in an ivory tower, but in retrospect, do you think these types of recommendations should have come out without having public fore with the stakeholders to understand their perspective in retrospect? Well, I think there certainly were public fore, but the public fore may have been too restricted in that they were predominantly medical professional fora. And that's therefore perhaps some more involvement with consumer groups of some kind would probably have been a good idea. And perhaps we had hoped that there would have been more of that at the fora that we held. Yeah. So some of the controversy seemed to stem from disagreement with the actual recommendations, but some seem to be misunderstanding of what those recommendations were, clearly clear. Is that all rectified and clarified now? I would say that most of the controversy that comes from a misreading or misunderstanding, the fact that there's been a misreading or misunderstanding has been pointed out. And so I think that part I think is better. I think there's still a fundamental feeling among some individuals that it's just a wrong idea, just from the get-go. The whole thing is just a bad idea. And I think to some extent that comes from a lack of personal experience with what it means to be a clinician and what it means to take care of a patient, this puts a lot of responsibility on the physician-patient relationship. So for example, we had a meeting last week, the ICCG meeting, in which one of the people in the audience got up and said, I come from the Orthodox Jewish community, and these recommendations show a profound misunderstanding of some of the cultural contexts. We would certainly not want certain information passed on to the patients. And I think the issue here is that it's the laboratory that's being asked to report these to the clinician. The clinician should have the culture. I mean, the laboratory has no way of knowing what the cultural background is of the patient on which they've sent the sample. It's the clinician who should understand that, know their patients very well, and know what, based on the basic consent that has gone on between the clinician and the patient, what needs to be communicated and what should not be communicated. So these are recommendations for laboratories. I think that's kind of a fundamental problem that people don't understand and misunderstand the patient-physician relationship. Les. And I think that's really a key observation. And I think the answer to your question is no. And I think the reason why it's no, as I've come to think of these recommendations as being kind of a Rorschach test for how people think about our field. And I think that what we have realized in the process of doing this, and as Bob said, we were working on this for 14 months and wrestled with it and struggled a lot with a lot of these questions and then launched them a bit abruptly, I think, on people. And I think what the reactions reflect is as much a consequence of how people view the field because people have very differing views about what medical and clinical genetics is or should be, how exceptional it should be compared to the rest of medicine. And I think what I underestimated is how high and strong the walls are that we as a field have built between ourselves and the rest of medicine. They're really impressive. And I think people are shocked and dismayed that we may have actually taken down a couple of those walls and people are upset about that. And we struggled for a long time and no one in our group could come up with good reasons, no coherent reasons that I can recall why a number of these situations we're talking about returning are any different from imaging or routine clinical chemistry or the physical examination even. There isn't a good distinction and no one has come up with a coherent reason why these kinds of conditions should be handled completely differently than all those other things in medicine. There just, there aren't, I haven't heard one. And so I think what it reflects is people have notions about what medical genetics is and is not and it's a challenge for us to change some of those perceptions because this is a microcosm of what we're really talking about when we say genomics needs to move into the mainstream of medicine. That's the challenge that we are now facing and I think it is a bigger challenge than I initially anticipated that it would be. So I think this is a wonderful problem. The response is fantastic because too often when we put these things together no one cares. No one hears it, there's no, but even bothering with it. I remember when interventional radiology started out where we were talking about the radiologists or other. The idea that radiologists would actually do something with a patient. I mean these aren't real doctors, they're people that read films. These are photomap people, not doctors. And yet they're gonna stick a needle where. And so it's very similar now that geneticists are people that go do some things somewhere and now they're actually interacting with patients. So the fact that there was a response, the fact that so many different types of people cared, I think reflects that the field is starting to move into maybe not mainstream, maybe not even close, but at least towards something that is gonna be more widely perceived. And hopefully now the question is, can we maintain that and push it to the point where people see the usefulness and get past just the laboratory but also the doctor part of it? Yeah, so I think there's, I think Jim, this has already been touched on, but I think there's two fundamental issues that are kind of at the core of the controversy around this. And one is, what is the nature of the test and this issue of incidental findings? So I think some people view this as dictating the scope of analysis, which is typically an expert type of judgment that you make in terms of analyzing a test, how broadly do I analyze it, how deeply do I analyze it, what do I look for, those sorts of things, which is not something we usually ask patients about, it's a pretty technical question, versus whether you're actually doing something outside of the scope of the original test and this is something different that you then need to get permission for. So I think that's one fundamental piece of technical controversy that really informs the debate. And I think that the second piece is the nature of these results. And so there's developed from the ethical standpoint, there's developed a really long history and discussion about sort of the right not to know and the role of patient preferences and pre-test counseling and stuff in genetics. And most of that discussion revolves around the types of results that are late onset, you can't do anything about, a lot of people have expressed that they don't want them, the uptake for genetic testing is very low. And the recommendations really address things that are supposed to be actionable, highly clinically beneficial. And so I think there's debate about whether there's evidence to support, whether in fact we have that level of clinical benefit to justify what went on the list. But that's a question of is what's on the list, what's the right thing or is it not the right thing or do we have enough evidence yet or have we not built enough evidence yet, et cetera. But in terms of the ethical issues that have really been I think the crux of the debate around this, the question about how much we should be asking patients their preferences for what we look for when we do the analysis, I think turns on those two things. And I think that the presumption of the group, if I don't want to speak on behalf of the group, but my understanding of our conversations was that just like any time a patient goes in for a comprehensive evaluation, you can presume that a reasonable person is going in there for an evaluation and would expect to be informed about things that are clinically relevant to them that they can do something about. And we all the time do diagnostic workups on people with a general consent to treat under that presumption that we will give them back information that the clinician finds to be relevant to them. So I agree these are recommendations for laboratories. I would say that I think it's a little bit strong to say that the group didn't say anything about the physician-patient relationship. I think they did leave room. Just like when anybody goes in for any other type of diagnostic test, patients always have the right to refuse information and that gets negotiated, whether the physician feels comfortable continuing a relationship with that patient, if they're not gonna give them information that they think is important, that they now have possession of and what kind of position does that put them in? So there's always room for that and there's always room for negotiation, but I don't think that they were completely silent on or agnostic about whether this goes from the laboratory to the physician to the patient or just from the laboratory to the physician. No, I think what I was trying to say was that I thought that these recommendations actually put a greater emphasis on the patient-clinician relationship. So for example, in the last year, if you wanna think about a whole genome test that's being done fairly routinely and I would say under the presumption that Amy just described, which is that you're treating the patient, is a race EGH. We're doing lots of race EGH for children who have autism or children who have a developmental delay. In the last year, I've had two patients, one with a deletion of unhippo-lindow and the other with deletion in P53. So now I made a leaf romani diagnosis and a unhippo-lindow diagnosis and you better be sure when you order a test like that that you warn the patients or the parents in advance, we may not find what the cause is, we may find the cause, we may find something you didn't anticipate, we may find things that you may not even want to know about that we may find out. So you and I, in ordering this test, we have to be sure that we're on the same page as to what the test is being done and what I'm gonna look at, what I'm gonna look for in this test and which I'm gonna feel I need to communicate to you. You may have brought your child in for developmental delay but now we have to worry about unhippo-lindow. So I want to echo that I think it's incredibly important that this report came out and that you guys clarify that it really relates to sort of standards for labs versus the patient-doctor relationship. One question I had was in your internal discussions were there concerns about false negatives and how those would be interpreted? So is this a question about, in order for you to be able to return ex-home results, you must meet the criteria that you could find all known or expected pathogenic variants in these tests because when the doctor gets it back, they're testing for ex but they see that the patient is cleared for why that they may return and say, well, we didn't see any BRCA one or two mutations but in fact, since that wasn't the primary aim of the test, it may not have met that kind of criteria. How did those discussions come about? Go ahead. It's a big concern and it's very, Robert Green has unearthed the term, it's called opportunistic screening because the data present an opportunity to detect a subset of things that are highly actionable and they're obviously not a complete set of highly actionable things that you might want to do for a patient nor are they even nearly complete as to the list of variants in those 57 genes that you might be concerned about but we were very concerned that we wanted to keep the positive predictive value high because the prior probability of having the disorder is low and so we focused on raising the threshold quite high so that we were confident that if a secondary incident on finding was returned, it was highly likely to be correct, acknowledging that we're sacrifice sensitivity in doing that and that's an issue and we deal with that in the clinical setting all the time, clinical research setting in that people who've undergone genome or exome sequencing in my protocols call me up and say, oh gosh, I had a nodule in my colon or polyp in my colon, did you find anything in those colon genes? And I say, whoa, we are not screening for those genes. If you have a clinical indication for that single gene test, you have to get that single gene test. This is not a substitute for that and just as newborn screening is not a substitute for working up a kid who has a metabolic collapse. If a kid has a metabolic collapse, you use them newborn screening results if they're positive. If they're negative, that does not dissuade you from doing a complete workup of that baby for that phenotype. So it's exactly the same, but it's a great question because there's a lot of presumptions about that and we have to make sure that patients understand that that's not what we're doing. So did you come up with any language that my company reports or something that could be communicated to that degree even sort of what's the confidence in the genes that had been screened and that sort of label that might come? We didn't come up with any specific language in the report, but of course all laboratories do report their level of sort of sensitivity and specificity. So I think it's going to be implicit in that, but we didn't come up with any specific language. Maybe that would be a good thing to do, but we would do that with the laboratories in continental laboratories. Mike? So I thought I was gonna panel up first. Oh, sorry, okay. So I just wanted to follow up on something that Les said because I think that it's part of the why there was misunderstandings. And so on the one hand, there's the argument that although many people have tried to find some essential difference between what kind of findings you produce from a test like this versus the kind of findings you might produce from radiology or from physical exam. And so if you can't find an essential difference, then why are you treating it essentially differently? It's an argument that makes sense. On the other hand, I think that one of the issues is that there's also a contradictory sentiment that overstates the importance of genetics and genomics and that there's a lot of enthusiasm for these tests and a lot of interest in these tests. And although presumably other technologies when they were new also had too much enthusiasm and too much interest. But I think that it's the fact that that is as true as recognizable as the fact that there is no essential difference, right? That people still treat them differently. And so what needs to happen, which people have said, but I don't think was emphasized in the report is that yes, this speaks to the need for a very strong relationship between the doctor and the patient. It also speaks to and to create that requires an incredible amount of education because that is not typically available right now. And so you can say we're gonna put the burden here, but you have to be very aware that it might crash because people can't necessarily pick up that burden. So like the issue that Carlos raises is their language to talk about how much confidence you have in is their language to talk about false negatives? I think that's the feeling that there was sort of a prematurity to the announcement because there are all of these steps that still remain to be gone through. Just to respond, I think those are all great points. And I think all that being true, I think that we've been in a cycle for a fairly long time of my perception is trying to convince the wider medical field that genomics and genetics is relevant to them. And they're saying go away, come back when you have something useful for us. And so I think there's a catch 22 there. And I think this part of my reasoning for pushing this pretty hard is I think we just somehow have to break out of that cycle and it's going to be awkward and difficult wherever we break out of the cycle. But I think one of the ways to do that is to put something in front of people and they're using the test. Those results are there and they're sitting in front of their patients and the labs are looking at these variants and the patients are sitting in the offices. There it is. And whether we like it or not, whether we're all completely ready or not, we're doing it. And so we just have to, I think, our feet are in the fire now, we have to figure out how to solve it. Yeah, I think one of the sticking points in all this has been the issue of patient choice. And it's very seductive to say, well, patients should have a choice and before they have the test, they should be able to decide what gets reported and what doesn't. I think the real problem with that is I'm not, I think that's kind of an illusory choice. And I think that holding somebody to a decision they make, even if there was a half an hour of counseling, which is probably unrealistic for every one of these tests about that particular subject, and holding them to a hypothetical decision that I don't wanna be informed about something that we as a community think is probably, could be life-threatening and preventable, is hard for me to do. I think the other thing I would just bring up is, I worry more in some ways about false positives and false negatives. I sat down with a patient just last week who is in our CSER study, and I told him, as are the terms of our study, that we found an MSH2 mutation in you that was utterly unexpected. We had sequenced him because of a visual deterioration. And this was in our class of genes where we had said in the consent that we're gonna tell you if we find a mutation. Now, the reality, as I think we all know, as we begin to ascertain people through sequencing as opposed to family history, that the penetrance for most of the things we're dealing with is gonna drop, right? And that's a real concern. And those are data we have to collect, but nevertheless, as Bob said, we have to make decisions now, and as Liz said, about how to integrate these things into medicine. And the best evidence we have now is that a clearly, what appears to be a clearly deleterious mutation in MSH2 is going to carry with it a very high risk above serious but preventable disease. And I think we owe it to patients to act on that while continuing to collect evidence to see are we so wildly wrong about penetrance estimates that it would obviate that responsibility. I doubt we are, but I think we need to entertain that as a possibility. Turn on the mic. No, it's... Hello, hello? Yeah, there it is. Okay, so just to answer a couple of the questions, this report was, this group did not operate in complete isolation on this topic. There's another group in the college that's working on technical standards and guidelines for the laboratories that include sample reports. I think it was approved by the board. It's just delayed in publication. So a number of issues related to the clinical laboratory have been addressed and should be out pretty soon. I think we acknowledge that there's a lot of system issues in place that are going to make this difficult for many labs. You can't get paid for all that extra work right now. So there's a lot of changes that would have to take place for this to be fully realized. And we often wonder if we should have been a little bit more emphatic about that need for system change for a policy like this to really be enabled. And then I would say, echoing what Les said, there is a lot of this clinical testing already going on and the bars got pretty low on the kind of results being returned. And I think it was important to set some parameters around what's going to be acceptable in a healthcare system. Otherwise, everybody's gonna get another follow-up test that's gonna cost the system a ton of money. So those two extremes aren't gonna work and finding that midpoint is what we're gonna be looking for. Now, I think there's a lot of things that we need to do downstream and Jim alluded to one already, which is we have to figure out how we're gonna capture this data. This is the ultimate unbiased ascertainment population that came in for one indication. It is not what this incidental finding is. It's unrelated to what they had. And if we don't find ways of capturing that unbiased ascertainment data to really understand the risks associated with these people in their particular medical and family histories, then we're missing a huge opportunity because it is really the pilot for what's already starting to appear on the horizon, which is primary genetic screening. None of us think that the cost equation fits that at all, nor does the data right now. But this is the kind of incidental finding data is the kind that can really inform how that whole part of genetics develops over the long haul. So I think it's gonna be very important as a research institute that we begin to think about, how are we going to capture this data to inform future indications for how this kind of information is used? We are putting together the system by which we wanna be able to maintain this list over time. I doubt it'll be done before July when we'll be ready to accept people's recommendations of what they think we should take off the list or should be added to the list. I think those are my main comments. Thanks. Good.