 So, we have a good 15 minutes for discussion if people want to come up to the mics or raise their hand. Gail. Yeah, so I have thoughts along three lines, so sorry to bear with me. I mean, I do think CSER has an important role as you both outlined in what are the best tests, what are the best indications for which test is it a gene, is it a panel, is it an exome, and that's a really important role and to think carefully about the design and collecting data across sites for that. An area that hasn't been discussed at all is pre-authorization of tests. It's actually a huge work issue in the Genomics Medicine Clinic. It's a big obstacle to care delivery and some sort of activity in streamlining pre-authorization. I don't know what the challenges are because we all have different payers to deal with, but there must be some way to make that a more efficient and effective system. And then lastly, I really think it'd be great to think more about how to document the value of a diagnosis. We saw a patient in our clinic who had a neurologic condition. She was a teenager. She had been seen in 12 academic centers in 10 years with numerous MRIs solved by an exome, and she's not going to be seen 12 more times in 12 years. It's a lot of money she's spent that her insurance has paid for trying to get an answer. So even though it didn't change her management, she's going to stop getting worked up every year by somebody else. So they're ending the diagnostic odyssey. There must be some way to capture those measurements that would be useful in addressing this value of a diagnosis issue. So more comments and questions. Okay. Dave? Sorry. Liva. Go ahead. Yeah. I'll just add to that that I guess another way of even phrasing it is, it was a very nice discussion, certainly educational for me. A lot of it was sort of the kind of the postulate that, okay, we want to do exome sequence, genome sequencing. You have to show clinical utility, meaning that it leads to a positive outcome. But the flip way, which I think the diagnostic odyssey is one, and then in cancer, sort of the expense of therapeutics is another, where you could say, well, there may be equivalence in outcomes, but it costs less. I mean, because there's a hypothesis that given the many of these drugs that in cancer cost $10,000 a month or $120,000 a year, what have you, that genetic testing of whether it's an exome or kind of multi-gene testing could in some instances actually lead to a reduction in costs, even though the outcomes may not change necessarily. So I guess what, how does one, is there a, is there a path there, and would it be different at all than what you described, which was kind of focused on, show me that the test improves outcomes or associated with an improvement outcome? And I would just comment, because some of us talked about it at the break, that many of the CSER sites are interviewing physicians exactly about this decision-making. And so, for example, we have a paper being submitted that shows that physicians are less likely to recommend clinical trials for targeted agents if the exome showed the target's not there, even though that testing is not otherwise required to use the agent. And so I do think we are getting data from physicians that we haven't really talked about today. And in the adult cancer, it's even, the bigger issue is off-level use, because that's where the real payout from insurance companies comes, is off-level use of expensive drugs, which is the very reason why we want to do precision medicine. But anyway, I'd love to hear your thoughts on that. Yeah, I think there's, I think, so I think your question basically, are there some situations where we could show cost savings and not worry so much about the outcomes, assuming the outcomes would be the same, is what you're saying? I think there are some opportunities. The cancer space is, that's a huge area, you know, with the off-label use of targeted drugs, and nobody really knows where that's going to go. There are definitely some opportunities there, I think, with K-RAS testing and colic cancer treatment, that was the fastest adoption of what ASCO issued a provisional guidance statement. It was like, they'd move so quickly, they didn't have time to change the guideline. So there's some examples like that. I think the other one is, in some well-designed panels, I think it's pretty, there's probably some nice slam dunks where you can say, hey, this is cheaper than what we were doing before. And it's definitely as good. It might be better. I think there's probably some cases where we should be careful to take a look at that because that doesn't require a huge investment in some kind of randomized control trial. So maybe looking for those kind of across the spectrum of what CSER is doing would be a great idea. Dave? Me? Bob? Okay. Bob will in an HGRI, Genomic Healthcare Branch. One thing that is the clinical geneticist like me here, you know, know this experience where we see something which is a fairly straightforward economic decision that isn't any harder than economic decisions that families make on a weekly or monthly basis. And yet we're not able to practice medicine in a way that utilizes the benefits of that. And part of that is that what we're taught is that the payer systems are about outcomes and they seem to be blind to the economic benefits. I think several people have hit on this and I think that concept we need to keep hitting on. I'm glad that Dave brought up families because I think the family approach to it is one of those things where economics comes into benefit. And I've been told that over a third of the U.S. population is insured by one or another of the federally funded health insurance programs. And I'm not even sure that includes the ACA subsidies. So but we're not able to use insurance on one person in one of those programs to benefit or reduce costs of our approach to a patient in another of those sectors. And part of that actually ends up being statutory. So it would be valuable to have data to look at that and say how much could we save, how much benefit could we have in order to support changing that to a more rational system. The third point I wanted to make was that as part of the ISCC, the Intersociety Coordinating Committee, I started an insurer education working group and that is with Blue Cross Blue Shield Association. And we have been producing webinars to educate the insurer staff. In part to help them deal with the pre-authorization process more effectively. And in part to be able to become comfortable with the questions that they have to answer about the different testing and reimbursement and coverage. So that process is ongoing. We're at about number six out of 12 of those webinars. We have approval to bring those out of the Blue Cross Blue Shield system into the public and so we're trying to figure out where to post those on an HRI. So stay tuned on that. Steve, no, okay, Jim. So this is a little bit tangential, but I thought it might fit best here and we shouldn't end the day without mentioning that it seems like one opportunity for CSER 2.0 is to address regulatory issues. So while they are directly germane to what you guys are talking about, there's obviously a huge hub of right now about the FDA and regulation of tests. And that would certainly be an area I think in which the LC component of CSER going forward could make some important contributions. I would also echo that maybe it would be within the domain of CSER to have an educational component directed towards the payers rather than the clinicians or in addition to the clinicians and patients and their families. We've all experienced, you know, denials for insurance or pre-authorization denials when you want to do a panel that's cheaper than doing five individual gene tests but you have no trouble getting the individual gene tests approved because that's met their criteria. I've had a very dismaying meeting with a payer that will remain unknown that actually made the effort to come to our institution and review the use of arrays, copy number, SNP arrays, and brought their expert who was denying it flatly because arrays were shown to not be effective. Of course, the papers they have were on expression arrays, not SNP arrays, but I think it's also failing on our part to educate those parties because it's a huge time sump for us in our clinical activities and maybe that should be incorporated into CSER going forward as well. Yeah, Bob. Now that Eric's back, I can ask a question about the NHGRI staff in general and that is, to what extent are other institutes taking a look at clinical utility studies of genome sequencing as applied to their diseases? I'm not sure. I know Terry has been leading or co-leading a working group of other program directors. I would think that would be one route to get some sort of insights. Right, so there's been very little work in that area as in any of the, you know, assessing the implementation of genomic medicine. But I'd call on my colleagues from other institutes who might have other information to step up. And I should say when we talked about kind of our vision of CSER 2.0, several of the sites talked about partnering with cohorts from other institutes to try to introduce genomics into those cohorts as one method. So I just bring up the point that this is a huge area. It's obviously of great interest and there's been a problem with the NHGRI being saddled with what I really, what I think are NIH-wide responsibilities, but with an NHGRI budget to do it with. Well, you've been waiting for a while, so did you have something you wanted to say? Naomi Arons and Blue Cross and Blue Shield Association. Thank you, Dave, and thank you, Pat, for those presentations. I'd like to make a few remarks from our vantage point in the Center for Clinical Effectiveness. We provide the scientific analyses of the evidence for our 36 plans and 106 million beneficiaries. So the first remark I'd like to make is I believe that the underlying issues here are really not about the test. It's about the cascade in this broad array of information. And I think you'd agree with me that maybe we haven't completely, you as clinicians and scientists, grappled with that cascade. And that, I believe, is an underlying caution around here, around a payer's approach. So I really would like to emphasize that. Second, I'd like to- Just so we're on the same page, why don't you define cascade? Cascade would be findings with respect to other conditions that then go on for more examination and more testing. And believe me, you are living in the wake of the impact of imaging, which had a huge impact over the past several decades on health care costs. And nobody really wants to relive that. And in fact, I don't think we can afford to relive that anymore in the current environment, particularly if we want to expand access to health care coverage. So it's critical to maintain affordability. One way affordability is maintained, unfortunately, is passing more costs on to the subscriber. That is regrettable, but unless there is some clear focus on what is necessary and what is useful, that will probably continue to be the easy way of managing this, because it's terribly difficult. Second, I really do want to emphasize that that medical necessity definition is not a whim, it's not an opinion, and it's not a philosophy. It's contractually based. That is the product that has been contracted for. If you want a product and insurance that covers another level of information, rather than that which alters a clinical decision, then that is a different contract. It is a different benefit, and it will be a different cost. So be careful what you ask for, because the consequences may be unanticipated. Finally, I do really want to take issue path. Perhaps there has been an expression of we want randomized controlled trials, but that is certainly not what we're saying in our evidence analyses. One, it's well understood that in diagnostics in general, most evidence is indirect, meaning it's pieced together in a chain of evidence from various sources, both performance and understanding the consequences of a test. Certainly, clinical validity information in itself can often permit that kind of inference from indirect evidence. Not always. It becomes more difficult where you're going to areas where there is really, the definition of a disease is changing, and that is the area you are stepping into. So I want you to understand that this is not just a limitation of what payers know, but it's kind of a limitation of where the field is at. We have no ignorance of adaptive trials, of the use of archive samples. All that is accessible to us, and we make it accessible to our plans. I do believe, once again, we have to go back to this fundamental underlying issue being one, understanding what the contract covers, and it doesn't cover. As a social policy decision, one might change that, but you need to understand the consequences. And then understanding some of that reticence, however it may be expressed, is being around what is the cascade and its consequences. Thank you. Okay, so Debbie, quickly, as Katrina gets up. So I just wanted to bring up something related to what was just said, but before I do that, I just wanted to say that the NCI with TCGA made a big investment that's led to a lot of the information that's been used with the NHGRI, the TCAGA. NHGRI. NHGRI, right. But the NHLBI is also making a big investment in genomic medicine by large-scale sequencing in the top med program of... But Debbie, I mean, I thought Bob's question was a little more clinically downstream than discovery where TCGA was all about discovery. Right, but I think the discoveries are leading to more, and I think we need to bring that up, and I think they are going to some of these. The other thing is on the healthcare providers and passing the costs off to the individual in the program, I think we need to carefully look at the ethics of this. I mean, I'm involved in Mendelian disease, and parents would pay anything to find out something that could help their child. I think that's an area that needs to be looked at very carefully and the ethics of this and how it's provided, but it sounds like that's one of the areas that the groups are willing to think about. But I'm very concerned about that area and the ethics of it, the same way with cancer and family members. Great, thank you. And I would just say one theme about the cascade is we also talked about the cascade of diagnostic tests, and I think you have to balance those two. So Katrina, who's a member of our CAP from Mass General, is going to kind of summarize.