 I think my job right now is in addition to welcoming you to basically introduce Daniel who's done all the work on this except for the cracking of the whip which we get to do here. But a lot of this was Daniel's inspiration, it was his idea to kind of come up with this and we're delighted that you've all come to join us in it. So Daniel, take it. Thanks very much, Terry. And thank you all very much for coming at a relatively short notice to DC for this meeting. Hopefully a very constructive meeting and in fact a huge amount of work has already been done as all of the working groups can testify in preparing for this workshop. So the goal here is in our minds is really to think about in the situation where you have large scale sequence data from a patient or from a disease case, how you can actually determine the mutation or combination of mutations within that particular individual which are causal for that individual's disease. And determining this causality, oh actually could you flick my slides on, yeah thanks. Determining, ensuring that we have good standards for inferring causality matters for a number of crucial reasons. As many of us who've worked with databases of known disease-causing mutations can testify, these things are littered with incorrectly reported causal mutations due to relatively small sample sizes or other errors. Once these things creep into the literature it can be almost impossible to actually purge them from the record and from databases of these mutations. And the existence of these false positives is a major challenge in a number of settings. Obviously they waste research time but more importantly they can result in incorrect diagnoses for patients and they can influence, falsely influence therapeutic and also reproductive decisions. I think we'll hear Heidi and David later on this evening talking about some of those implications in the clinical setting. Now obviously we're also in an era where the capacity to do large-scale sequencing is increasing incredibly rapidly and so that raises both the power to detect real mutations but also the power to generate false positives. So I think without clear standards for establishing that a mutation is actually disease-causing it'll be relatively easy for the literature and for the databases to become overwhelmed with false positives. So for the purposes of this workshop I just wanted to be clear about what we're discussing in the context of causality here. So that is, we recognise of course that it is typically impossible in a strict sense to fully demonstrate that a particular variant or a particular gene actually plays a causal role in the sense that we can't actually replace that gene at least not yet in a diseased individual and show that their disease is actually corrected. And while we all accept that there are mutations that are as close to 100% confident causal as we can imagine such as Delta F508 in cystic fibrosis for instance, we also recognise there is a spectrum of evidence for causality. And what we plan to focus on here is what we call implications. That is the process of inferring with some level of confidence that a particular variant or combination of variants contributes causally to the development of a particular disease phenotype. And that occurs obviously through the accumulation of multiple lines of evidence and each of the different working groups will be providing their own perspective on that on that process. And just to help define the scope, we felt it was useful to focus particularly on rare germline variants. So with the frequency typically of less than or equal to 1%. And also to consider the full spectrum of disease. We really, we want to acknowledge here that there is a continuum of disease between common complex disorders right the way through to monogenic or oligogenic disorders and that the process of inferring causality, although it can, it may be quite different at the different extremes of that distribution, there is still much we can learn from combining information across the whole disease space. And of course, we're also interested in considering the implications of causality definitions in both the research and also the clinical settings. So the key outcomes that we're seeking for this workshop will be firstly to identify definitively the key challenges associated with implicating variants as playing a causal role in disease. Secondly then to establish guidelines for investigators, reviewers and editors to consider in assessing the evidence, implicating variants or genes as causal in that specific situation. And the final outcome which I think is critical is to generate a manuscript then disseminates these guidelines and these more subtle discussions about exactly what causality means to a much wider biomedical community. And we, the schedule for the meeting as those of you who've looked at the schedule will know is relatively brutal tomorrow. So we'll be getting up fairly early, finishing relatively late. Each of the working groups has an hour for their own presentations. And each of you has already, each of the working groups has already done a phenomenal amount of work in generating draft guidelines. And there is a, the full, a summary of the full draft guideline process is available in the folder that you have on your table. And we also have the individual summaries that were submitted by the working groups which often contain much more context and subtlety than the summaries are also available on the website that was emailed out previously. So this evening after I finish and we've all introduced ourselves, we have Mark Daly and Heidi Rehm and David Dimick will be speaking to help frame the challenges associated with establishing causality both in the research and also in the clinical settings. Then tomorrow, as I mentioned, each of the working groups will be giving their presentations. We would urge the presenters in each of those sessions to try to keep their presentations to 20 to 30 minutes preferably even less to allow as much time as possible for discussion. This is really an opportunity then for each of the working groups to present their thoughts on the particular area that they were assigned to explore. And you will notice that there are actually laptop cords available on basically I think all of the settings around the table. So you can just plug in, you just need to call out the number that's present on that cord and you will then be connected to the projector. So in fact, if at any time during the meeting you have a particular slide or something that you're interested in showing, you can just stick your hand up, let us know that there's something you're interested in projecting and we can get that up for the whole group to say. So shall we demonstrate that since Mike is there? Sure. So please, would you turn on number 16? So your number is just right there in the corner of your little thing there. So and there I am. And then we can basically switch to anybody. So you do have to be connected in order for this to work, but it should work reasonably well. So thank you. Thank you, Mike. You can go back to 17. Great. Thanks. And then we would also ask presenters, if possible, to email their slides, their final slides for this summary, to either myself or to Chris Gunter to my left. And we'll also to both would be ideal, actually, as a backup. So during the process of the meeting, we'll be attempting to distill as much as possible some of the key messages that emerge from the working groups to add to add to the summaries. And we'll also be attempting to edit some version of the manuscript on the fly. We'll see how that works. I just like to finish then by thanking all of the people who've been heavily involved in making this workshop a reality. So all of the members of the planning group, in particular Chris Gunter to my left, who was involved in the conception, the idea of this workshop, which stemmed from a conversation between Chris and I on Twitter, in fact. And a huge thanks to Terry Monoglio, who really was a driving force by actually getting this workshop together and ensuring that we did manage to bring such a smart group of people into one room. But all of the members of the of the planning group named here have participated in a whole series of conference calls. In fact, I think I believe all of us were present on almost every single one of those calls, which is quite an achievement. So I'd like to thank all of them for participating so strongly in this process. And then finally, of course, all of the working group chairs who helped to pull together the summaries for their particular section. They're named here. So you can see for those of you haven't yet looked through the summary. This gives you an idea about the breakdown of the different groups and how the order in which they'll be presented tomorrow. OK, now with a further point, so you probably have seen Ian's name in your email and he's our program analyst extraordinaire. So if you could just let people know what we need to know about eating and leaving and sleeping. OK, so as everyone saw, there are drinks available or refreshments available out in the lobby. That'll be probably for not much longer. So if you want to grab something, go ahead. You do have to pay if you are staying at the hotel, you should have filled out food forms for to include breaks and meals. If you haven't thought about that form, you can get it at the registration desk right outside. If you're receiving reimbursement, you should have had a form for reimbursement in your folder and just return that voucher back to Sandra by the end of the month. And if you need her email address, you can contact me. If you need transportation back to the airport tomorrow, sign up for that at the registration table. Let's see. And if you are worried because your cell phone isn't working, it's probably just because we're in the basement of the hotel. And that's all I have. I guess it makes sense now to start by going around the room and having each of the participants introduce themselves. Starting with Jeff over in the far corner, maybe just by state, your name and the institute, your comfort. Ben Voight, University of Pennsylvania. Nancy Cox, University of Chicago. Suzanne Leal, Baylor College of Medicine. David Goldstein, Duke University. Russ Altman, Stanford. Les B. Secker, Intermural NHGRI. Greg Cooper from Hudson Alpha. I'm from Madison, and I bring women's hospital in Harvard Medical School. Steliados, Antonorakis, University of Geneva, Switzerland. Ian Marperi, NHGRI. Heidi Reim, Harvard Medical School and Partners Healthcare. Eric Green, NHGRI. And I should pause and personally thank all of you on behalf of the Institute for coming here and participating in what is a very important topic and important workshop for the Institute and actually for all of NIH, to be honest with you. Thanks. Terry Minolio from NHGRI. Daniel MacArthur, Massachusetts General Hospital and the PART Institute. Chris Gunter from Hudson Alpha. Jay Chandra from University of Washington. David Dimmock, Medical College of Wisconsin. Wendy Winkler, the Broad Institute. John Stamontarianopoulos, University of Washington. Len Fenaki, Lawrence Berkeley Lab. David Adams, NHGRI. Ewan Ashley from Stanford. Mark Daly from the National General Hospital and the Broad Institute. Don Conrad, Washington School of Medicine. Mark Daly, Nescape on Nature. Orlea Bacall, Nature Genetics. Beth from Mr. The New England Journal of Medicine.