 Great. Thank you. Good morning. So we thought we would just sort of summarize what we thought worked some of the key points and if we got them wrong, y'all could correct us and if we missed some things, you could also add those. So that would be great. So kind of walking through these are very word-heavy slides, my apologies. Some of what we heard from the laboratory sessions, obviously sharing genomic data, very critical. Many labs are willing, but the fact that this requires resources is often not identified. So Dan, are you having trouble hearing me or? They just turned it off. Sorry. You know, I think I'm close enough to the microphone, but who knows. And then this issue of not putting things into clinical care until they're well-established is a real challenge when, as Heidi pointed out, some of these things, the vast majority in fact, are found only in one family. So you really only see them a few times and you can't get them to be well-established. Delivering information from available sequences takes resources. So going back and querying it, updating it needs resources. Categories were changed as we heard 300 times, I think, at one point, and about 4 percent of doctor reports change per year, which is pretty astonishing. We also heard a little bit of concern about how one can get CLIA-certified labs to do sequencing, and that requires resources as well. And we also heard that much of the recent growth in genomic testing is in infectious diseases and also to some degree in cancer. Any disputes here? You all just stop me if you want to dispute a point. How's that? Pardon me? Okay. So this was in genomic testing, is my understanding? Right. So when you say and genetics in genomic testing? The highest growth rate is in cancer and genetics, although infectious disease is the largest in volume currently. Okay. And projected in- Okay. No, I know it's the last bullet, but I thought this was within genetic testing or genomic testing. The two things that were increasing were infectious diseases and cancer, but I guess maybe you're suggesting Mendelian diseases as well? Is that right, Debra? What do you mean by the genetic and genetic? Because we already have germline. So if you talk about all molecular testing, which includes the high throughput sequencing. Infectious disease is the largest volume of molecular, including next gen sequencing, but the highest growth. So it's growing at about 11% per year, whereas cancer and germline, I call that genetics. Okay. And I call cancer somatic. If you want to parallel them, I'm not quite sure how to do that, but genetics and or germline and cancer are growing at about 18% per year. Okay. I think if I remember my slide correctly. Yeah. And we'll check your slides and make sure that we've got it right, but thanks for that correction. So I'm having trouble. Germline and cancer is 18%. So, and we'll pretty these up here. So, but thank you much. 18%. Okay. Great. Yes. Please. Clea certified labs are doing sequencing. We're doing a lot of sequencing. So. Okay. So. Pardon me. Illumina. Illumina would be one of them. So isn't the challenge really then hospital, Clea certified labs? Is that what we're, Deborah, I think this was your point. So it's really the next gen sequencing technology. We're using CE for doing a lot of sequencing and there are selected labs that have moved into using next gen sequencing technology. But I think the vast majority of academic laboratories. I mean, I put a question out on the association from like a pathology listserv recently saying, what do you think of this instrument versus this instrument for a clinical laboratory? And I got more answers back saying when you find out, let me know rather than an answer. So. Wow. All kinds of labs are trying to figure out the technology to go with and how to adopt this, how to justify it. The business plan for a hospital laboratory is very, very difficult. So would you agree then with this formulation of it, how to get hospital and academic or maybe just hospital, Clea certified labs to move to next generation sequencing? It's more how to get them to pay for next gen sequencing instrumentation so that it can be incorporated into these labs. That's a subtle difference. But we want to. I mean, clearly it's very cool. It's new. And it's, we think more cost effective, but we don't have the opportunity to test that out necessarily. So. Okay. And I might add enable as opposed to get. I don't necessarily think we want to get them all doing it, but enable the ones who are capable of doing it. You know, in talking with Illumina in distribution of their myceaks, which are meant to really target the hospitals, smaller labs, pathology labs. One of the biggest struggles is the whole confirmatory process that's not built into a myceak. You know, and they're hoping their instrument is sample to report end to end. But that confirmatory process is not yet supported in the clinical labs. You're like, well, how do I do that part of it? So I think it's how do we enable these labs to be able to support the process? But most labs who would be doing next gen would likely already be doing CE, capillary electrophoresis, Sanger sequencing, so, or have real time PCR, I mean, and have technologies to be able to do that confirmatory process. So maybe. I think most labs do. Yeah. This is a great discussion and it's very helpful, I think, to have it. I do have 50 slides. No, I only have 11. And this is slide number one. So if we can live with this, at least for the moment, it seems like that. Okay. Great. Then whole genome is potentially a concern. It may imply that it's complete or infallible. And that we just need to be aware of that. There aren't any FDA or CLIA standards yet for next gen sequencing. No arguments with that, I don't think. Do we need a genomic medicine specialty? An interesting thought and one that we might want to pursue. What's regulated under CLIA versus what is sort of the art of medicine in interpreting the sequences, an important point raised. Try to capture the marked variability and interpretation to understand it. So one of the, I think, issues that was raised was that, gee, when you send out these variant files, actually the BAM files, that people interpret the variants very, very differently. And if you can capture that, I think this was a bioinformatics point, you can actually learn to model it and kind of learn something from that. And then we need bioinformaticians incorporated into pathology groups and other groups doing this kind of work. Any corrections? Great. Okay. I made a slide for you in terms of the Frukey criteria, which I thought was a nice way of going about it, but you may want to look carefully at this one. And actually, I think what we heard, we were looking for those who do this kind of work as well as those who pay for it to tell us, you know, what kind of evidence do you need or how do you make your decisions? And most of them came down to points very much like this. So you need well-controlled, adequately powered studies demonstrating analytical validity and clinical utility. And that was sort of a, you know, a sine qua non and also pretty undebatable. It would be helpful to have clearly actionable results. And I think in most cases, all of the people who spoke on this felt this way, either that you could prevent drug toxicity, you could identify a treatment path, diagnose rare heritable disorders, and possibly carrier testing. So those would all be examples of actionable variants, although there might be other things as well. There should be some kind of a path to a reasonable level of reimbursement. There should be freedom to operate in terms of IP and patents and other things. And an interesting note, which is maybe something that we want to think about is that adoption is slower if a test replaces some procedure that physicians can bill for, which was a, you know, sobering comment. You want to take that out? Oh, really? I think it's an excellent, you know, it's on tape. Okay, so we will do that. No? That's fine. Okay. Great. All right. And then the sequencing working group, was it was its usual energetic self? Yes. Oh, yes. Sorry. That last slide, the clinical utility part. I mean, there's a nuance missing here. And we can't show clinical utility for three billion bases. Right. So I'm not sure what the solution here is, but there's some element of, yeah, we want, all this has to be done, the proving, you know, the evidence that's required. But then again, there's also this element of, this is the whole genome. And so how do we handle that? Good point. And I think maybe we want to qualify this first point, you know, sort of like where possible or where feasible or that, because I think your point, and you should make it yourself, was that when you have this, it's great, but a lot of times you don't. Isn't that right? Yeah, I think the problem is getting, you know, the payers aren't here maybe today, but that's what they're looking for in terms of reimbursement. And so if you don't have that, I don't know what the solution is for reimbursement. Okay. Great. So we'll just call it what payers looking for. Okay. If I could type it would help. Okay. And again, you know, these are, it's not like these are instantly going to end up in a, you know, a paper somewhere. It's just, we're trying to capture a lot of the discussion today. Okay. They'll just end up on the internet. I'll be looking for a job. Yeah, that's right. We could, well, maybe I should be fair then and we'll just take that out. So I wanted to make sure that you were paying attention. Great. It worked. Yes. All right, good. Because we do want you to come back and still be employed. Okay. So that was the, all right, sequencing working group. There was talk or hopefully plans of perhaps producing a white paper, laying out research and policy agenda for implementing sequencing in clinical care. Recognizing that this already been done, but can one do it in a more perhaps systematic or provide kind of a roadmap for doing that. Focus with a lot of work and a lot of potential tasks to be done, it may be appropriate to focus on the areas that aren't being done currently or that are gaps so that there's not overlap or duplication. And then the highest priorities we may hear from the sequencing group after they've had their working group meeting. One high one sounded like was how to assign clinical relevance to variants, especially with this problem that Brad pointed out as did Heidi, that you only see a couple of them and how in the world do you get enough to know what it means. Howard seemed to feel that the wet lab was moving so fast that this was not a gap area and not an area that you needed to do much in. And one point that was made, I think by the lab group, was considering genomic critical values. So what are the critical, maybe that was Deborah's point, what are the things that you absolutely have to report just like you have to report a potassium of 2.0 or whatever. Determining what the legal requirements are for data return which varies by state, which is an interesting thing and might be something worth trying to compile in some place at some point. And there was no substitute for knowing what the patient and the clinician really want to know of making decisions on what to report. Yes. If I could make a comment and it might be a minor semantic comment and if so I'll stop after saying it once. This term return of results or data return for me is a research term. In clinical laboratories you talk about what do you report to the physician and all of the professional societies and regulatory bodies give guidance on the structure of clinical reporting, the content of clinical reporting, what's primary and what's secondary in a clinical report. CDC has taken the lead in developing some recommendations around molecular, genetic, clinical reporting guidelines. Return of results for me at least implies a research study deciding whether or not to return information and which information to return. So in all areas of developing guidelines or what legal requirements are I think they're two separate issues and we should try to keep them clear. Does everyone agree with that? Yes. Yes. Okay. Great. Hopefully I don't think I use those terms at all here. So I should be good but your point is well taken David and I think what we then want to sort of focus on is when we're talking about the pathology labs which we often don't talk about unless we have pathologists in the room and when we're talking about what the research study does. Although presumably there is some return of results from the clinician to the patient that was based on reporting. So they may intersect there. No, that would still be part of medicine and we would not use that term. Really? Which is again for me that's a concern. It's an ELSI concern. It's a topic of debate and grants and research. It's a research issue. In clinical medicine whatever goes in the clinical report the physician chooses how to deliver that information to a patient. And that's still reporting? It's reporting. As long as you all agree with that. Well it's reporting and it's also communication of results to the patient and how that's done. Is it only done by the physician treating the patient? Is the pathologist or geneticist involved? Does a genetic counselor have to be involved? And does it go into the personal health record? Because we all now have personal health records and so where do you put it there? Mike, you had a comment? Just more terminology. We've been calling that the disclosure visit the physician to the patient. So maybe there's not... No, it's a good point because I think Dave is right is that people do use return term for that piece and maybe we can get them not to. We can certainly try but disclosure is an interesting one. Okay, and Dan, yes? Yeah, I think our group talks about this a little bit and I think it really the same value. It depends on where it comes from and the clinical contextualization. You know, is it... You know, you got a test in the clinical setting and you found maybe a little add-on versus this is getting something out of a biobank and you find the same thing. So I think this disclosure visit concept is great. This sounds to me a lot like a clinical research interface issue and maybe one that that group could address and give us something that perhaps would be a little more coherent than we can come up with with me standing at this podium. Is that something we could ask? Sure, I have 40 minutes to get there. Or at some subsequent meeting which we hope to have. No, it sounds like it's a real issue. Great, thank you. Okay, the financial reimbursement discussion was certainly lively which we very much appreciate. It doesn't look like any of them were able to make it back today which is very unfortunate. The point was made that utilization of imaging was driven by regulatory approval and reimbursement rather than evidence of benefit and that example has been brought up numerous times and saying why is genomics being held to a different standard. I guess some might say the problem was not that genomics is being held to a different standard. The problem is that that was a mistake but regardless it is an interesting point. Evaluation of evidence needs to work from a clinical problem rather than starting with a test. That was an excellent point. Several of them gave kind of their principles for coverage which is pretty much similar to what we heard from the labs that the services are related to prevention, diagnosis or treatment. The information will affect the course of treatment. The care and or treatment is likely to improve the outcome. An interesting one is attainable outside of investigational settings. So this is the real world setting not just in research. And then the services are consistent with the design of the plan and I think there are aspects of plan design that we weren't able to get into and that I certainly don't understand but it's a reasonable point. Comments? Okay. Great. And also there were suggestions in terms of what the evidence standards should be. Obviously analytic validity, clinical validity, clinical utility. Final approval from appropriate regulatory bodies is very helpful although it's not, again, a sine qua non but when it's required then obviously the payers would expect it as well. It wasn't clear to me how you know when it's required and when it's not maybe you all know that and we could expand on that. And there should be demonstrated benefit. Also the point made that having genetic counselors available by phone was actually quite an advance and made it much easier for physicians to use these tests. Any comments here? No? Yes. I think that final approval bullet has to do with when the FDA needs to require something like if it's a kit or whenever FDA will, that's what that's referring to. Oh, great. Thank you. Okay. Super. In addition, we heard that unit costs were the biggest driver of the escalation in healthcare costs and not utilization. So bringing down the costs of individual tests is probably, and again, tests were only, you know, a small proportion. I think 0.5% we heard overall healthcare costs but this is an important point. Costs from molecular diagnostics have risen much faster than other costs, 14% per year, just in a two to three year period. The point made that payers shouldn't fear innovation even though it always seems to cost more but look for those that will replace more expensive and less effective technologies. Certainly if some of the DNA testing for chromosome abnormalities becomes widely accepted, that would replace amniocentesis which would be a major advance and certainly would replace more expensive and at least riskier technologies. And there was an idea suggested and seemed to be resonating with the group as a whole that we find a way to make public-private academic collaborations to design studies to produce the decisive information that will convince payers as well as others to, you know, hospital labs to buy the equipment and as well as payers to pay for it to do these kinds of studies. And I think we'll hear a little bit more about potential plans to move that forward. Any changes to this one? Good. Okay. In public health, Toby talked about potential partnerships in genetics and chronic disease leadership in the state health departments. I think a group that we have not included in these meetings and one that we may want to consider doing. Local cancer and heart disease coalitions, national professional and disease related organizations. I think we recognized yesterday that the professional organizations are, again, a group that has not generally been at this table and perhaps is a stakeholder group we need to address. Patients, obviously. Genetical lines are patients like me. Considering cross-cutting goals and impact on health disparities would be wonderful to the degree that it can be done. And there was an interesting example as a potential sort of a use case scenario of hemochromatosis homozygotes who have signs and symptoms suggesting they might actually have the disease and yet are still getting iron per their medical records. Changes to this. Okay. Then we had the working group reports and we will have their reports and they'll be posted, but just to kind of summarize where we are, one suggestion was perhaps using a small business mechanism with Epic or one of the other medical record systems to incorporate some of the family history tools. Considering social network software and infrastructure for collecting or correcting family history information from relatives. So as a relative reports it, can they support it over to their relative and say you should know what's happening to me and I'd like to know what's happening to you, that kind of thing. A variety of interventions could be tested, optimizing collection and use or action on family history information in emergency settings such as those regarding a potential monoclonal infarction, bringing to other environments such as rural and underserved areas, educational environments such as residence and training. And of course the ever present question does the intervention work in usual care. And then the hope that the family history group would link to the sequencing working group both on Mendelian and complex traits and of course in the reverient space. Jeff did I get that right? Okay. The periodontal group, thanks Murray for keeping us to task here on this one. The management of patients with diabetes and periodontitis sounds like it's an active area certainly at Marshfield and with some other partners that you're developing. Management of dental patients is an area where genomics can contribute, especially in pain management and coagulation. There's an interest in bringing pharmacogenomic data to dentists with computerized decision support tools and ways of developing those. There may be an oral systemic personalized medicine model that could be developed that would again build on this link with diabetes, periodontitis and maybe other diseases in periodontitis. And the hope or the expectation that sequencing might replace culture in the microbiology laboratory which has potential for a huge impact and I think we could note that in clinical care it already has replaced culture in many cases. So this may be something to do in dentistry as well. Does that seem like a reasonable summary? Great. And I'm done. So many thanks to the planning committee and to... Oh, yes, Deborah? Can I just say that I think for the laboratories there also was something not captured and I thought it might come through in other areas and didn't think about it. Which is the uncertainty of regulatory oversight of all this testing in the clinical setting. We don't know what FDA is thinking about this. We don't know... While you said there aren't CLEA and FDA guidelines standards in this area, FDA has been talking about IVD-MIA which they've now done away with that terminology so we don't even know what to refer to it as. But the CAP has created some standards. But standards are kind of different than the regulatory oversight and whether we will be allowed to do this under an LDT process. Can you explain that? LDT. Laboratory-developed test. So we can validate tests in a CLEA-certified laboratory under CLEA standards and bring it to clinical use without going through the FDA. And then... But the FDA has just waived its oversight at the moment but it may step in at some point and regulate it. Which we don't know what that would do to using next-gen sequencing technology in clinical laboratories. So this is a huge clinical dark cloud. And our FDI colleague is going to make a comment in a second. Just one second. Have I captured what you said about it in that third bill there? No, it's actually uncertainty of regulatory oversight. Oh, sorry. That's what I just saw. The standards is a different thing than oversight. It's oversight. So just regulatory oversight rather than standards development? Yes. Perfect. And FDA doesn't do standards. So CLEA does standards. And the FDA can correct me. So in the previous bullet it would be no CLEA standards. Although CAP, ACMG and AMP now do have standards that they're introducing for next-gen sequencing technology including the bioinformatics. And I'm going to send those checklist questions to the sequencing working group. Oh, great. Thank you. Okay. So you think that this captures it now? Yes. I just had a quick question about freedom to operate. We didn't discuss that a lot. But sitting here thinking about returning data to patients, I know there was a recent Supreme Court case, Prometheus, that many people seem to believe is going to invalidate a lot of the diagnostic patents that are out there. I mean when we start to think about clearing the way for every base that we might want to report, I mean, is anybody working on that or thinking about that? May I comment? So I was just at a Cold Spring, Cold Spring Harbor two and a half day conference with a whole room full of patent attorneys. And they were... Look at you. Wow. Wow. That sounds like a lot of shit. Yeah, it does. It was pretty weird. They were talking language that I didn't understand at all, but they didn't understand what I was talking about. But I was definitely communicating the clinical impact of what they were doing. And they heard me and a few others. Wayne Groty was there, Bob Desmic, a few others. There were only, I think, four physicians in the room. So... But the patent issue is huge. And while the statement was made and it was even discussed by the patent attorneys that next gen sequencing may not infringe some of the patents, when you have a quarter of the genome patented, it's daunting. You can't possibly, from a medical perspective, when you're doing an exoma or a genome, think about how to collect all those licenses and pay the royalties and everything. So do you think if we add patent issue is huge? Is that... That's fine. And there actually is someone starting a clearing house for patents. Really? Yeah. And I can give you her contact information if you're interested. Oh, absolutely. She was one of the patent attorneys. Well, again, this Myriad case, Prometheus versus Myriad, some people believe that that kind of opens the door towards invalidating all of those claims. Oh, whatever. Well, I'm not a patent attorney, but I'm very confused by it. So the Myriad case is the one that's challenging the ability to patent human genes and human DNA sequence that's moving forward and the prediction is based on Prometheus that that case could lead to a decision about whether human DNA sequence and human genes are patentable or not. And I'm not sure that there's too much more we could all do while that case is proceeding. Depending on the outcome of that case, problem could be solved or we could decide it's a major impediment to diagnostics using large-scale sequencing and we need to do something else. So it has to be on the list of concerns, I guess. Concerns? Okay. Likewise, coming back to the CLEA FDA regulatory, it sort of is an obligatory bullet item on your list of worries. On the other hand, my view is FDA posture is the same as NHGRI, is learning from the community, coming to these meetings, trying to understand what we're doing and encouraging the community to work together to create databases, to create standards that will make it easier for them to decide if and how they need to regulate this new technology. So I think we should be encouraging more FDA participation at these meetings because my experience over the last five years with chromosome microarray now is sequencing is they come to learn and every time they hear about a community effort to develop standards, they're here to encourage us, that's the right thing to do and their worry is more about individual laboratories being too far ahead of the curve when there are no standards. Great. Yes, last comment? Thank you, David, for that. I just wanted to add because we put the bullet that there is regulatory uncertainty and that's certainly true, but there are many misstatements and that's the other part that we are trying to correct or let people know when we are at these meetings that people assume about FDA and one of them was somebody yesterday said there is no FDA guidance for IVDs. There's number of, that's what we do. We have a number of guidance for IVDs, for instance. So it's the same with standards. Yeah, we don't do standards per se, but we participate in bunch of standards. There are CLSI standards that you may want to add to the list of what you have with ACMG. CAP are in development. So there are a lot of ways to figure out how to evaluate. Sorry, CLSI? Yes, CLSI. And helping, what is that? Clinical Laboratory. We have a lot of standards institutes and they're working actually on the guidelines right now for next-gen sequencing. Great. Dan's going to tell me that we're really, really over time, but Brad, maybe one last last comment? I was just going to say on the patent issue and that territory, we actually have a grant funded research in this area to Bob Cook-Degan and it'd be really interesting to maybe hear what he has to say if he could come to one of these meetings or something. Sorry, use a microphone? He would what? He was at the Gene Patent... Oh, it's a culture and cover meeting also. Great, okay. Yeah, so we'll try and do that. Okay, so we do need to finish, I think. If, Deborah, if you could send that information to me and we'll post it on the website for this, which will be up on the Office of Population Genomics and HDRI website. So, Dan? Okay, no, I think... unless there are burning questions, I think we'll go on to our... a couple of presentations this morning.