 So, I think Steve did a wonderful job covering, as he put it, the responsible path forward and to clinical sequencing. So, I guess that leads me to cover the irresponsible path. And more seriously, I'm actually, I'm grateful to be here. I'm glad that you've invited a patient to comment on the effects of clinical sequencing. And, but I also have to warn you that as a patient, I'm not here to make your life any easier. And in fact, I'm actually here to make your life much more difficult. And the reason for that is that I think it's actually somewhat challenging to define complete definition for patient-centered outcome. What exactly does that mean? And I think it's actually really important that we get this right. And because if we don't, it's going to be, we're going to miss a lot of what is happening as a result of sequencing. So, what I really want to do today is present some examples of why it can be very challenging to define what an outcome is in a very systematic fashion. Now, Steve was actually kind enough to give a very broad and somewhat vague definition of whatever is meaningful and important to patients and caregivers. And I think that the challenge here is that, you know, if we work with a broad definition like this, we actually can capture a lot of outcomes. But when you work with a broad definition, measurement is what becomes difficult. So, I think measurement of this definition is actually going to be the most challenging component. And the important thing I like about that definition is that it doesn't strictly rely on a notion of clinical utility. And it sidesteps issues like actionable. Is it an actionable result that you're giving back to a patient? It's really about what matters to the patient directly. I think that's critical going forward. Because I would say, and I hope to convince you of the fact, that from a patient's perspective, any information you can give them that they didn't have before is in some way actionable. And if you work with patients, then there's a lot they can do with the information you return to them. But again, it's going to make measuring these outcomes in a very unifying way somewhat hard to do. And I've actually, I've looked at some of the literature on this. This is part of the work I've done with the End Diagnosis Diseases Network. I've looked at some of the surveys given to patients to try to measure the outcomes of sequencing or genetic counseling or these sorts of things. And I always find them falling somewhat short of what I'm witnessing out there as a patient and in the patient community. So, towards that end, I'll give you six data points from the patient's side of what can happen when you get your genetic data back and what patients can do with that. And I'll start with my own story. And I know a lot of you have seen my story before. So I'll keep it brief. I'll try to summarize seven years of my life in about two minutes. So my son is actually, he ended up being the very first case of an ultra rare genetic disorder. And so I would say our story was more or less standard, at the start at least, beginning on this undiagnosed island where many families who have a rare undiagnosed disease start. And then we had what I would call sort of the standard diagnostic odyssey, which I'll just sort of show you the pictures for right here. And up until we got to sequencing, our journey wasn't all that different. We had seizures, movement disorder, developmental delay. And the one odd thing in our case was a strange inability to cry tears. I think that was what was sort of the standout feature from the phenotype that really distinguished us from a lot of the other disorders. And that was our life for four years, sort of trapped on that island, not knowing what was going on. We got very lucky. We've been working with Duke University and some of the folks who see here on this slide throughout the entire diagnostic odyssey, trying to get answers to what was going on. So when clinical exome sequencing was just becoming a thing that you could think about doing for research, this is back around 2010 or so, they approached us and they said, we think you're a great candidate for this trial. So we signed up. They did trio sequencing. So what they got from that was that my son had actually inherited two novel variants in his anglyone gene, or at least as yet unseen variants in his anglyone gene. And they believe that this was probably the cause of his disorder. But they were careful to tell us that, hey, this is the first, in fact, only time we've ever seen this gene associated with human disease. So we're not really sure. In fact, until this morning, I wasn't quite sure how to call a variant like this, but then I heard this Vax term, a variant of almost known significance. So now I know what it was. That's a great technical term. So I mean, we were pretty sure that this is what it was, but we didn't know exactly if this was truly it. And I think they had to actually modify the IRB protocol or get permission to actually return this to us as a result. But they did. And I'm very glad that they did, because we could do an awful lot with that, despite the fact that it was called not actionable. This really is a brand new disorder. There's not much you can do for it with knowing that. So what I design, actually using some postdocs from folks in the room, we looked at the genomic databases that were out there at the time. I think it was the Washington database. We realized that there should be other patients out there, if this really was the cause. There should be about 500 of them living out there somewhere in the world. So I thought, well, I think there's a way to actually find them. So to find them, what we did, what I did is I wrote a blog post. And I really wanted this blog post to do two things. I wanted it to go viral, and I wanted it to rank very highly on Google. So if there's anybody else out there with this disorder, they would find us. And then we would know for sure. So this is the blog post I wrote. And sure enough, it actually did go viral. Very quickly, in fact, it was seen by several million. And it did, in fact, rank very highly on Google, so that if anybody's out there searching for the same symptoms or the same gene, we would pop up right away. And what this does, when you start to find other patients, is kind of remarkable. I think within two months, we actually ended up with two more patients in Turkey. A couple months later, we had two more in Israel. And then a few months after that, we actually had another patient right here in the US in Palo Alto. And over the past three years, we have had patients popping up all over the world as they encounter the presence we have set up on the web. And what this has done for us, what it means to get a diagnosis like this and to be able to act on it, is that it sort of washes away that dark night of uncertainty and isolation. And you end up with a community and the sunlight of science in its place. So even though it's in some sense not actionable, I think there was an awful lot that we were able to do with that. Because that community, which today stands at 39 patients around the world, has been very active in pushing the science. In fact, NIH itself has been very active in pushing the science on this disorder through the natural history study that's been established on disorders of Lycosylation. So we're a part of that study. We've pushed 13 patients through it thanks to Bill Gall's support. And I've actually been fortunate to visit many of them as they go through, because I spend way too much time in this city. And so it's been a real powerful moment for our community to have that ability to participate in this protocol. And what it's giving us is a tremendous amount of actionable data on the disorder. Lots of biomarkers that are driving the fundamental science and driving our push towards ultimately a treatment. And at the same time as this, of course, we paired up with scientists right off the bat. We want to push the basic science, since we know nobody understands the disorder, let's do that. So we went to Dr. Hud-Freeze, an expert in disorders of Lycosylation, and we said, let's do this. And it's been a while now, but we've made a lot of progress in the basic science. We actually have a pretty good understanding of what's happening with this gene, and most critically, what's happening when this gene isn't there. It causes an accumulation of misfolded glycoproteins in the cytoplasm. And over the past few years, we had a much better understanding of what that accumulation is looking like and what it's causing within the cells. In particular, it's causing a deficit in one particular metabolite represented by this little blue square right here. And it turned out this little blue square is actually available on the internet for about 25 cents a day. So I bought it. And after a particularly nasty bout in the hospital for my son, I actually decided it was time to try it out and to give it to him. And the amazing thing is, after about three days on the substance, of course, I tested it on myself first, I should say. He actually cried his very first tear. So this clearly was actually involved in the pathology of this disorder. And so it may have been one small tear for him. And in fact, he's cried many tears since. But it really was sort of an ocean of science for the disorder. And of course, when he cried that tear, I collected it, packed it on dry ice, and shipped it to a lab in California for analysis, which is more or less what any parent would do in that situation. And I myself, I'm actually a computer scientist, but I've been shifting a lot of my research into the intersection of biology and medicine and to the extent that computation intersects that as well. And in fact, I even over the summer got my first grant proposal funded in biology. And we're actually building a planarian-based drug screening platform for Anglia I back at the University of Utah. So we made a lot of progress. And I would ask you all, does that constitute action? Because I certainly think the answer is yes. And I was asked to comment on the economic effects. And so I can tell you that just getting a diagnosis alone will drop the medical bill substantially. Because there's all sorts of stuff you stop doing. I think our medical bill is dropped by a factor of 10 after getting a diagnosis. Because we just stopped doing a lot of stuff that we knew wasn't actually going to work. I actually think that the net economic impact, though, was roughly zero. Because everything we were spending on medicine was now going into postdocs, which insurance does not cover. So the question is, can other people do this? Is this replicable? And the answer is actually yes. Other people can do this. And I'll share with you some very quickly some examples of other people that actually have. So after we found patients on the unit, other patients have been reaching out to me and asking, hey, can you help us do the same thing? So a few years ago, Milo's family reached out. I helped them put this website together. And in 29 days, they found a matching patient. And the mother is now a co-author on the resulting paper. And about a year after that, another mom said, hey, I want to find patients on the unit, too. And so she put up her own blog post. And in two weeks, ended up finding other patients out there with the exact same disorder. Again, another novel disorder discovered by moms. And then just a couple of weeks ago, there was yet another case of this where I helped a family put together a website. And they put this together out there to find patients. And they shattered, I think, the world record for patient matching. They found seven more patients in 12 hours for a totally novel disorder. The reason they found them is that the researchers working in the disorder hadn't yet published their results. So the researchers knew about the pathogenicity of this gene, but it wasn't available in ClinVar or any of the other databases. Just about the only way to figure this out was to go to the internet and ask people what this meant. So over time, my experience in working with patients is that it's taking less and less time to get a variant interpretation done by the internet. Down to the point now where we're at around 12 hours of fully utilized things like social media. And what this means is that the internet itself is becoming this database of variants. Because patients are posting them on Twitter, on Instagram, on their blogs. You name it. But the good news is you can search that with Google. So you can actually query this patient-generated variant database with Google queries. So another story which I think is very interesting is Tracy's story. So Tracy, seen here with her daughter, is, I think, really amazing for what she's done. So her daughter, who's now 19, started having seizures about 17 years ago. And in her daughter's case, or in this case, what's really amazing is her mom only had a high school diploma. But she was just fascinated with what was going on with her daughter and really wanted to help her. And so she ended up getting an associate's degree, then a bachelor's degree, then a master's degree, then a PhD in neurogenetics, and finally became a postdoc doing variant analysis for exomes, all motivated by wanting to help her daughter. So of course, she gets to this point and they actually run her daughter's exo. And well, they actually find something. They find multiple variants of uncertain significance and L-type calcium channel genes. So then the question becomes, well, what does this mean? And I should also point out that Tracy has an amazing YouTube video online. I highly encourage you to actually watch to hear the full story of how this unfolded. And the question became, well, what is this doing to the ion channel in this case? Is it causing a gain of function, or is it in some way causing a loss of function? And she knew from observing her daughter's history over time that it was in fact, most likely, a gain of function in L-type calcium channels. So then what she did is she checked for medications that could actually interact with these channels, and she found a drug for arrhythmias that was actually capable of acting as a blocker for this channel. Working with her clinician, they actually tried it out, and it worked. So the number of seizures per month went from hundreds before down to maybe a couple dozen afterwards. So this is a dramatic improvement in the quality of her daughter's life as a result of sequencing. She'd like to point out that we need to focus, not just on the variance of uncertain significance, and we actually should not be afraid to return these to patients either. I will skip over Sonia and Eric's story, he's right of time, their story is also online, I highly recommend you read it. The short version is she ended up getting, she's now a PhD student researching her own disease. So this sort of stuff is certainly happening over and over again. So if there's anything we should do, it should be to erase the words not actionable from our clinical vocabulary. Thanks.