Good morning. Thank you all for being here and being in your seats and ready to start this day. I'm Mark Schmidt. I'm the director of studies at New America. And we wanted to start the day off with a real discussion of the nature of the democratic populace at the moment. And it's getting to kind of the underlying questions, not so much the surface questions, but really the dynamics of this popular stage and how we can move it to make sure it's constructive, inclusive, and fully pluralist age as well. So to start the conversation, and we'll start it here and then expand it, I'm joined by Yasha Monk. Yasha is a, most importantly, a fellow in our political reform program, which I launched in 2013. He's been a New America fellow. He's an instructor at Harvard. I think he's still a fellow at the German Marshall Fund, or that may have, I think that's a couple of weeks. But Yasha's been really one of the most acute observers of the kind of threats to democracy, decay of democracy, or decay of liberal democracy, not just in the US, but around the world and bringing a global as well as theoretical perspective to it. And Pete Wainer, Pete is a contributor to the New York Times. He's at the Ethics and Public Policy Center and worked in the Bush White House on mostly on domestic issues, and has also been writing about these issues quite a bit. So I'd like to start by really asking the question of, we can look at the political divide, the American democracy across a number of different dimensions. Race and identity is obviously one. Economics is another. The traditional ideological conflict, big government, small government, which is kind of what we thought we were fighting about for a lot of years. And then I want to make sure we really get to the question of engagement and alienation and what enables people to connect to a democratic populace and to make decisions together, as opposed to kind of the reaction that I think we saw a lot of, which I sometimes refer to from there's a book by the poster Stan Greenberg, where he broke out the American electorate into a bunch of different types. And my favorite types were what he called the FU boys and the FU old men. And I feel like that sort of reaction has played a big role in how do we draw that back in. So I'm just going to kind of turn it over to you. And then we'll be joined by some people who are doing a little more work on the ground and kind of make this a little less abstract. Do you want to go, Gasha, first then? Sure, so there is a lot. I mean, I think there's a few things to understand when we're sort of trying to grapple with this political moment. The first is that I'm always sort of surprised by how neatly people want to explain what has happened. So the temptation is to think in binaries that it has to be either one cause or the other. But what's driving this is either a sort of racial attitude or it's sort of about economic stress. Or it's social media, right? Or it was Russia. And there's this sort of reaction where if somebody says the hacking of the Clinton campaign had something to do with it and there's a bunch of people who are saying, oh, you just want to blame it on the Russians and you don't want to admit that there was any problems with the Clinton campaign. And instead, I think we have to think about how any big social political transformation is the result of an interlocking series of causes. The world is not monocausal. And that's most obviously true for the tension between sort of economic and racial causes, right? I think that two of the great challenges that we face, not just in the United States, by the way, but also in Western Europe and many other parts of the world, first of all, the slow transformation of a set of countries that had a pretty mono-ethnic imaginary of themselves, where in a place like Germany where I grew up or France or Italy, there's a deeply mono-ethnic monocultural societies and they slowly have to learn what it means to be a multi-ethnic society, what it means to have a common identity. In a place like the States where obviously you've always had a multi-ethnic society, in fact, but it also always had a very clear racial hierarchy. And in a similar way, people have to learn what it means to rethink what it is to be an American while we are actually pushing against that racial hierarchy and making some progress in overcoming that racial hierarchy, which is something we shouldn't forget. And then on the other side, you have this huge economic transformation, where from 1935 to 1960, the living standard of the average American doubled. From 1906 to 1985, it doubled all through American history. It was true that people could look at the material, that most Americans, a large majority of Americans, could look at the material circumstances of upbringing and say, my God, I have so much more now than when I was growing up. I'm sort of in a transformed world. And since 1985, we haven't seen that improvement in living standards anymore. And people are really angry about that. So what happens when these two things go on at the same time? When on the one side, they are much more afraid of what the economic future holds, when it doesn't seem natural anymore to think, you know what, I'm doing better than my parents were and my kids are gonna do better than me. But they're thinking, you know what, I've worked hard all my life and I'm not doing much better than my parents were and I have good reason to fear that my kids are gonna do worse than me. And then at the same time, you see that larger transformation and what America is, I think that's when you get a lot of this anger. I was talking to a representative who's telling me that in his district, it used to be that you ask people who they are and they said, you know, I'm a foreman in the factory or I'm a member of a union or I'm a coal miner, right? And the jobs they have now, it's not necessarily that they're that much poorer, you know, perhaps they have a job at Walmart that actually allows them to buy as many things as they could have done 30 years ago. But the jobs they now have don't give them the same social identity. They don't allow them to have an earned identity where what they define themselves by is their professional accomplishments. And so what do they default to? Well, they default to a scripted identity. They now say, well, I'm white and I don't like those people over there, right? And so we have to really think about how do we do a number of things at the same time? We need to, in the long run, actually improve people's standard of living, make people hopeful for the future, make them feel like they have control over their lives and the state is actually helping them take control over their lives so that they have a sense of the political system is on the side and that they can have a better future. And we need to think very seriously and very carefully and I know that there's some great panels about that today about what it means, what we have in common as Americans. Because I think at the moment we often have obviously a very dangerous and disgusting form of white nationalism in the White House, frankly, at the moment. And then I think sometimes a little bit too much emphasis in what divides us on other sides of political spectrum. Really, I think I have to find a new narrative of what we have in common and what kind of common future we want to aspire to. There's also a few things in the short run. We have to beat Donald Trump. But we have to actually reinvigorate the attachment that people have to democratic norms. So some of my academic work, which I'm not gonna go into, shows that there's been a shocking decline in the importance that people give to living in a democracy and even a shocking increase in the openness to alternatives to democracy, both from the United States and in other countries. And I think part of that, frankly, is our thought. I teach at Harvard, nobody there thinks of their job as transmitting the basic values of our political system and the reason why liberal democracy is better than dictatorship or military rule to the next generation of students. Since the beginning of self-governing republics, people have fought carefully about what it means to transmit political values to the next generation. But today what it means to be an academic, what it means in many ways to be a journalist, sometimes even a think tank fellow is to look at the world and say, here's a problem, here's a problem, here's a problem. And there's many things wrong with our world. There's many things wrong with our political system and we need to have a good analysis of those in order to be able to move towards fixing those. But I think part of our job as people and everybody in this room, this is true of, who have a voice, who have a platform, who can write, many of you who teach, is to actually explain to people what in the system is worth preserving and building on and how we can reform it and improve it but also why it's worth having an attachment to the basic values of democracy, of a rule of law, but now under threat here in the United States and in other countries as well. Wow, that's great. I love that idea of that as the mission, especially for academia, would change all the incentives for tenure and everything else, but that sounds great. Pete, do you wanna? Sure, I concur with everything that Yash said and he really is, if you're not familiar with his work, you should be. He's really one of the great and articulate voices about not just what's happening in America but really that's afflicting the Western world. I'll just pick up on a couple of points. I do think that it is important, well, let me start by saying, I think this is a perilous moment for the country. I don't wanna overstate it. There's sometimes a habit for people to think that the problems we face are worse than any other time and they're not. This country politically or political culture is sick but it's been sicker, we had a civil war, there was the Great Depression, there was World War II but this is a difficult time and a dangerous time and I think we need to be alert to it and I think that we've got a kind of ugly populism, an ethnic nationalism that is abroad in the land, not just here but really throughout much of the Western world, a distemper in alienation and in anger and I do think it's important as a first step to diagnose it and to understand what is driving that. Some of it is malicious and malignant. I wouldn't deny that at all. Anybody who's on the internet could figure that out for themselves but that isn't, I don't think what's the dominant thing that is going on and if we begin from that proposition we're not gonna get very far. I think that there are several things that are contributing to it. One is this epic economic shift that we've seen globalization, automation and technology which is driving Americans apart and we've gone from a high-skill economy and low-wage workers and low-skill workers are suffering because of it. Just one data point since the end of the Cold War you've had a billion low-wage workers enter the global marketplace as competition to American workers mostly because of China and other Asian countries. Now I think overall that's good but that creates its own challenges so we have to understand that. I think that there's been a political failure that has happened that there is a sense that our political system, our political leaders and our political institutions aren't rising to the moment to the challenges that we face. I think that both parties are responsible for that. And I'll just speak, I'm a lifelong Republican, I'm a conservative but to speak and address my own side I had a sense for the last several years that Republicans woke up and felt like every day was January 20th, 1981 and Ronald Reagan had just been elected and the problems were the same and the solutions were the same. And indeed over the decades that these supporters in the Republican Party became more Reagan than Reagan so I'll take one example. There was a moment in the 2012 debate where they said if you could get $10 in spending cuts for $1 in tax increases of the 12 people or so who were on the stage would you entertain that and no hands went up because a policy which in general one can defend which is lower taxes is better had become a kind of catechism. And so this happened and I actually think that Donald Trump was in some respects a response to that were sort of categories were shattered but I think both parties I would say for a lot of Democrats they wake up and think every day is January 20th, 1965 and the new deal. So I do think that our political leadership and our political institutions just have not put forward solutions to the problems but I do wanna underscore that these are complicated problems. I mean these people who are in the political class are not stupid and when you have these epic changes and how you deal with globalization that's not a simple issue. I think we have an unraveling of the social fabric and I think that we're seeing the dark side of individualism which is social isolation and I think that that's driving a lot of it and for some people a sense of lost cultural change a lot of people feel like they're being left behind in the modern economy and in the modern culture. In terms of what we do about it the first thing I'd say is this is not beyond our capacity to address. These are not forces that we can't deal with and we're not being attacked from without. A lot of what's going on is within it's within our capacity to address it. I'd say one thing that's just required is political leadership. I don't think that's all that's required but I think it's essential and when I say political leadership I mean it in two ways. I mean one is to come up with a modern reform agenda to address these problems and challenges that are facing people but I also mean political leadership in the sense of our civic culture.  You can either try and channel that anger and that alienation in a constructive way or you can do the other way. You can take advantage of it and turn up the temperature and throw logs on the fire. And we have not had political leaders enough certainly who are willing to do the former and far too many that are doing the latter. That is the kindling is out there and we've now got political leaders who are putting that lighting matches to it and we have to recognize that and we have to confront it and ultimately we have to change it. There's two other quick things. Civic education I completely agree with Yash on that. We have to be able to transmit a respect and reverence even for democratic norms and traditions and a kind of civic comedy. There's a lovely line in the prelude, a Wordsworth poem where it says what we have loved others will love and we will teach them how. And that is in some respects one of the tasks of education which is to transmit to others what we love and revere and that's not going on. And if that doesn't happen then you're gonna raise a generation of people who don't have respect. And the last thing is as individual citizens we have to engage with other people who don't think like us. And in the abstract I think most people would agree with it but when you get down to particular cases it actually doesn't happen very often. And people need to learn to listen well to one another and we just have to and we can go into this more during Q and A but people have to bring into their orbit, into their life people who don't see the world exactly like they do and they have to be able to listen well because one of the problems we have in politics today is this extraordinary dehumanization and when you get to talk to people and get to know them and if they begin to have a place in your own life it's just a lot harder to dehumanize them. You may disagree with them but you'll at least understand where they're coming from and that can be the beginning hopefully of coming together rather than apart. Okay, I think this is great. I think we both laid out a lot of the issues and we'll continue this in a broader discussion. I felt like both of you reached to a language of transmitting and the idea that elites whether it's political elites or the kind of people we are in this room can play a positive role in kind of bringing values downward. I wanna make sure what I wanna get into is make sure that we can look at the question of like is there a possibility for a kind of bottom up populism that's not ugly populism. You know, populism has two faces in the American tradition. So we're gonna bring out three other people and I'll introduce them who have either from their research or their other work have some perspectives on how people are actually bringing this up. So other people. One day we'll have the people will just magically appear but we're not there, we're not quite there yet. Hello other people. All right, I'll introduce the rest of this group. Actually, although these are folks who are all doing a lot of significant engagement with citizens, they all happen to be political scientists which is okay, they're the best kind of political scientists. To my left, Dorian Warren is at the Center of Community Change and Center of Community Change Action Fund. He's been a professor at Columbia, he's been a host on MSNBC and a colleague of mine at the Roosevelt Institute. Lydia Bean runs an organization called Faith in Texas. She's also a Harvard educated political scientist who's taught at Baylor and Vanessa Williamson is a fellow at the Brookings Institution and has a wonderful new book called Read My Lips which is about how Americans actually view taxation and paying taxes as a kind of civic good which I think has been a really revelatory and important book. So you heard some of the conversation here and I'd love for you to, I mean you can challenge, you can pick fights, that's all encouraged but if you can talk a little bit about how you see some of this kind of education in democratic practice and the sort of healthier kind of populism if you wanna use that term in your own work and you're nodding Lydia so you can kind of go. So I come at this problem from the context of Texas in large, second largest state in the country, a majority minority state. It's a state in which I am the last age cohort in which white people are the largest ethnic group. And so it's a shift where we're economically growing. We have a very low unemployment rate. We're an urban state. So in Texas, this issue of answering this rancid form of populism, it's impossible to talk about that without also talking about race and ethnicity. And Faith in Texas is part of the Pico National Network which is the largest faith-based organizing network in the country. We're predominantly made up of the largest religious communities in Texas which include black Protestants, Hispanic Catholics, white evangelicals, white mainlanders, and we also have a large growing Muslim population in Texas. And what we've found working with John Powell is that really it's impossible to address the economic anxiety and pain that people are feeling across working class communities, including white working class communities without also talking about two other dimensions of this anxiety and uncertainty. And John Powell talks a lot about the belonging, this crisis of belonging, and as well as political powerlessness. So you have belonging, economic anxiety and pain, and political powerlessness. And what made Trump so effective in a value-neutral sense is that he addressed all three of those forms of anxiety and pain at the same time and blended them together and said, we're gonna make America great again. And what has been missing is a really vibrant answer that addresses all three of those axes in an inclusive way. So in a Texas context, what we're practically talking about is creating a new people, a new Texas, since we're nationalists and we have our own Texas nationalism, creating and forging a new people that really brings together African-Americans, Hispanics and working class white people, as well as white professionals. But those folks always find their way to the table eventually. So let's just talk about African-Americans, Hispanics and working class whites, which sounds crazy, but it can be done in Texas is being done and so there's no excuses anywhere else in the country. If we can organize working class white people in the suburbs of Dallas, Texas, you can do it where you live. And what we've found is that some people think you can just sort of substitute identity politics for economic populism, that's not the case. Practically speaking, what we've found is that you can organize economically struggling white communities, but you have to address this crisis of belonging that white Americans are feeling right now. And in some circles, that can be a hard pill to swallow. It doesn't mean coddling fragile white people, but world's tiniest violin playing. It's not, you know, we're not saying that working class white people or white people in general are suffering that they're true victims. That would be very, very silly indeed. But what we found is that until you name that, that sense of cultural dislocation and crisis of belonging, until you offer a really strong, vibrant sense of new community that's forged, that decenters whiteness, but includes white people, that is really sort of a new America, no pun intended. And you offer a really clear vision until you address that people aren't open. And when you do address it, people are open to lean into those hard conversations about race, about the economy in a way that they aren't, if you don't address that first. A great example of this, faith in Texas has been leading a statewide fight to a limit payday lending, which is a practice that really targets disproportionately blue collar community. So folks who have a little something to steal, right? And it preys on people across race and class lines. And when we started organizing around this issue in a variety of working class communities, including white communities, a lot of working class whites were genuinely surprised that this was a political issue. They just thought it was their own private shame. And so economic pain is also, sense of isolation is also a sense of shame and isolation and political powerlessness. And so what we were offering these communities was not just sort of an economic agenda, but also a new community. That the idea, join us, join this movement where your private shame is actually a public problem. There are people who made decisions to steal from blue collar communities. And there are public officials who made a decision to take basically bribes to make this to change laws, to allow this theft to become legal. And this is a multiracial, multi-faith movement that has your back. And that's a very powerful recipe for organizing in economically struggling white communities. And when you don't address it, it's always wrangling beneath the surface because Texas is really just an extreme example of what's going on in the rest of the country. But there's no way when you have a group of people who have been in a majority and who have had the culture, the shared identity of Texas to find around them, when you change that, what you're gonna have is a bunch of sad white people next to a Confederate monument being torn down, chanting, we will not be replaced. And as a white person, that's just embarrassing. We can't have that. You have to address that sense of displacement. But when you do address it, we find people are willing to lean into the work much more quickly than you would otherwise expect. One more thing. This is gonna be really important in Texas as we respond to the passage of SB4, which is kind of an Arizona law on steroids. And it's gonna be nothing short of apocalyptic for Texas because it basically deputizes every single agent of the state from the local on up as an agent of ICE. And our response, we can't stop this law from being implemented, right? There's not a policy fix. So our response is collective suffering basically. That's our strategy, collective suffering. And so with everything we do within faith in Texas, our answer to the current crisis we find ourselves in is just forging a new people. So in our case, it's so that we suffer the consequences of SB4 together. And we're making sure we're involving as many white Anglos, African-Americans, and citizen Hispanic people in the suffering of our immigrant communities so that together we're forged as the new people. One final thing, when you lean into this, the sense of belonging as well as powerlessness and economic pain, we're often surprised at how quickly people can be transformed. So transformation is possible, but it's a human need to have to feel hurt. So just one example, I was leading a training at an African-American megachurch in the suburbs of Dallas, Texas, and we were joined by a young white Republican operative who was a friendly guy, really nice, scouting us out for a local Republican candidate. Just wanted to figure out what we were about and make a pitch for his candidate at the end, which he didn't get to do. And in passing, it was a mostly black audience. I kind of felt bad for this one white guy sticking out. And so I just mentioned in passing that one of the things we have to address as a state is the sense of dislocation that white people are feeling and how a lot of white class parents are afraid to send their kids to the public schools because their kids will be in a minority and they don't know how to do that.  And this guy basically almost jumped out of his seat. He was like, yes, yes, that's what we're feeling. That's it, that's it. And the black leaders were kind of looking at him like, what, really? And one older gentleman says, welcome to my world, buddy. Welcome to my world. Really, this is new to you?  But we were able to have a real conversation about that. And once you're able to name that, the problem that has no name, that Trump has now given a name, people are suddenly very open to what you have to say next. So sometimes after the Trump election, there's this fear in the world of, my world of grassroots organizing that if we're talking about white pain, that's gonna come at the cost of silencing people of color. But what we've found is that it's actually possible to do both very well at the same time and to build a movement that has a white working class base, a white middle class base, but also in our organization, it's predominantly black and Hispanic millennials. And you can lean into topics like police violence, like immigration, if you're willing to also take the crisis of belonging seriously in white communities. Great, that's fascinating Lydia, thank you. It's a good sign that there is outreach actually to a black community. I mean, that's I think a very hopeful promise because if you just have a politics that's our group and the other group without any attempt at that kind of outreach, we're stuck. Dorian, I think Lydia covered a bunch of issues. I wanna make sure we have time for Q and A, but you work with a lot of groups that are organizing around immigration as well. What's your perspective as a scholar and as a doer on how we bring those, the kind of connections that Lydia's talking about or that Yasha and Pete were talking about? Thanks for the easy question, Mark. I really appreciate that. It's a really difficult issue, especially if you see the Washington Post this morning. There's an article about the increased number of deportations under this administration, which is literally tearing families apart and communities apart and in some ways erasing the history of this country in terms of this nation being partly an immigrant nation. So it's hard because we hear stories every single day of people in fear of agents trailing kids from schools to get to their parents because they suspect that they're undocumented. So there's one question around how do you, and I think the big theme here is how do we link people's fates together so that they do see themselves as belonging to the same community or nation? And so how do we link the fates of immigrant families and people with non-immigrants, with native-born citizens? And it's a challenge, and we've seen some signs of hope. If you remember after the executive order with the Muslim ban, the protests at the airports, those are mostly American citizens who are showing up to say, no, this is, we're gonna create a circle of protection around our immigrant and Muslim brothers and sisters. So there are lots of signs of hope. I wanted to pivot to a few things Lydia said on this theme actually that the both of you talked about as well. And it is this theme around how do we create linked fate among people that, whether they have a different descriptive identities, Yasha, as you described it, or just don't see each other as part of the same community. So I just got back from Cleveland, Ohio where I took some very rich friends of mine from San Francisco and New York to get outside the blue bubble and actually meet some people that are not like them. So we went to Warren, Ohio in Trumbull County. That county voted twice for Obama and then flipped the Trump. It hadn't voted Republicans since 1928. And we made them, I and my friends made them, made the folks I took, we made them doorknock to actually talk to people which was scary for folks. And it was fascinating because you got, and we did the same in East Cleveland, which is a predominantly black community. Warren is much more working class, poor white, but it's somewhat integrated. And the stories we heard from the people in East Cleveland and the people in Warren are very, very similar. Deindustrialization wasn't like an abstract concept. It was a lived experience. And it was a very, very common theme of how when jobs literally left, the fabric of the community fell apart.  One of the things I learned is, and this creates the opportunity for linking fates. So everybody on the doors talked about heroin and opioid. And it's fascinating because I grew up in the 80s. I remember what happened when jobs left my community and black people were unemployed and turned to drugs as a way to soothe the harm. And we locked those folks up. And we're much more tender and caring now and I'm all appreciative of that. But it is fascinating because one of the things they said and I learned in Ohio is, one of the highest rates of incarceration are white rural women because of the drug epidemic. So how do we think about creating some linked fates between the folks in East Cleveland who have been subject to the war on drugs, which apparently the Attorney General has restarted for decades with folks that have experiencing the same kind of harm and pain a few decades later and are being caught in the criminal justice system? So how do we create those bonds of linked fate to try to transform and change it? So that's the first thing. And then second, I do think we need to figure out what is the new economic vision for the future and how are we gonna create economic security for people when there is just sheer hopelessness? Because I was curious, why did this twice people voted for Obama and then split the Trump? And actually it wasn't a national story about Clinton or anything else. It was actually a reminder that all politics is local because for decades they're local democratic politicians have been telling them that they're gonna make things better and things have only gotten worse. So you do that for 30 years, you live like that for 30 years and then you get this guy who resonates emotionally he's speaking your pain. Of course they flipped the Trump. But it's actually not that hard to figure out, why? Because the democratic local politicians have been promising things for decades and decades and decades and not being honest about saying maybe I have no agency about the factory that left. Maybe I can't bring that back. Maybe we gotta figure out something else. So it was just a reminder that in some ways all politics is also very local as we're having a national level of conversation about political transformation and this administration and what could be next in 2018 or 2020 if we're not building and developing people at the local level to solve their own problems and to run for office and to build leadership then I'll say it this way, I'll say it this way. The route to national power and transformation is through local places and states. And unless we refocus on those local problems what happens at the national level we're gonna always be stuck. That's fascinating, thank you Doriana. I think it's interesting to think that people would instead of realizing maybe politicians don't have this agency over the economy they would turn to somebody who's actually promising a different level of agency at a totally different and totally different zone. Vanessa I feel like you've kind of uncovered some undercurrents of civic capacity in your work and I wonder if you can talk a little bit about how you see that capacity and how to draw it out in service of a positive populism. Yeah I'll try and add the positive note a little bit. So I think that my previous book was on the Tea Party so I spent a lot of time thinking about older white conservatives primarily who were very involved in the early years of the Obama administration of posing the agenda coming from the Obama administration of posing the person of Barack Obama. And frankly motivated by things that are very much things that motivated Trump supporters a lot of concern about immigration and about cultural change. And then I kind of took my eye off the ball because I did this work on the Tea Party and then went on and did some other things and then it seemed like the aspects of the Tea Party that were so interesting, first of all the motivations of white people who work were very conservative but at the same time the sort of media world in which they lived, right? It was a very unique media world and very much a media world that Donald Trump was good at operating in. And so I went to do this other work and the work I did was actually driven by an experience I had at a Tea Party event where I noticed that these people who were very angry about what they thought government was doing very, very angry, very angry about ACA, very angry about the sort of idea that they had lost control of their government. Nonetheless, describe themselves as taxpayers and that seemed funny to me, right? Because at the end of the day you're mandated to pay taxes and how could that be something you're proud of even when you're so very unhappy with where you think the money's going? And so I looked into this in more detail and one of the, a really interesting sort of thread in American history, both on the left and the right is to talk about for citizens and non-citizens to describe themselves as taxpayers as evidence of contributing to their community and as evidence that they have a right to be represented by their government, right? And so this can be a very exclusive language, right? And I think you see this sometimes on the Tea Party side of things that I'm a taxpayer and someone out there is not. Someone else is not paying taxes which requires you to ignore sales taxes, payroll taxes, property, all the kinds of taxes that low income people actually pay a lot of. But it can also be a very inclusive language and you see this sort of more on the left over the course of our history. I mean, from the founding of course, the idea that if I am taxed I deserve representation. Well, that same language was adopted by the women's rights movement. It was adopted by the civil rights movement and it has recently been adopted by undocumented immigrant groups talking about the fact that they're chipping in their share, right? So they contribute to this country too. They want to be part of America. And so I think that, you know, and what shocked me was the strength of this sentiment across the political spectrum. I mean, something like 95% of Americans see tax pay as a civic duty and they feel that quite strongly. And what shocked me about this was how that civic sentiment had survived what must be what, four decades now of really profound anti-tax rhetoric, right? So it's interesting to me and Trump is in some ways an exception at the very end of this time period where he actually, it is common for Republicans to oppose high taxes, right? To say taxes should be lower. It is not common for them to say they don't pay taxes. So we're really at an unusual moment where there has been a profoundly strong civic tradition of tax paying and a sort of use of the symbolism as evidence that one is a contributing American, one's doing one's part, right? And then now it's very interesting to see whether we're at the moment where that, like other civic norms might break. But the fact that it has survived so long I think is actually a sign of hope. That's good. I know we want to really open it up to Q&A. If anybody, if anything you, anybody heard that you want to challenge question, ask a question about, otherwise we'll go to Q&A. All right, let's open it up. Please wait for somebody to bring, raise your hand if you want to ask a question and wait for somebody to bring the microphone to you and say who you are. Nobody wants to be the first question of an American conference. Yes, over in the, like by that exit sign over there. Is somebody taking the microphone? Over there. Thank you and just say who you are please. Hi, my name is Benjamin Lee from the Carney Endowment for International Peace and my question is about the urban rural divide within the United States. How do you think that has shaped the political culture and the civic culture within the U.S. and are there any possible solutions to address this problem? Thank you. Or maybe anybody, all of you can start with that. But maybe you may deal with it more often Lydia, more directly. Yeah, yeah. Now it's a common misconception that Texas is a rural state about 75% of Texans live in just basically three urban areas. So you can talk to a vast majority of Texans without driving off into the boonies. But I think that the urban rural divide is huge and there are solutions. But first I want to say it's not really an urban rural divide. It's like five cities where Democrats sort of hold themselves up and then the rest of America. So that's a different problem if you're like we have the cities, our people have the cities and you people can have like the little town. That's a very condescending and somewhat delusional view of doing the problem, to be quite honest. When you lose the suburbs, which are cities in their own right of 400,000 people, you have a problem, right? It wouldn't, even. Well let's not do it so much in partisan terms as in kind of culture and engagement. Yeah, yeah, you have a problem. It's kind of bigger issues that we've been talking about. So I will say that they are possible to solve. I think if you're talking specifically about rural, I was talking with Dee Davis and one of the things that's really clear if you spend time in cities under say 25,000 is that there's a complete collapse of civic infrastructure and a lot of what's left behind is Christian radio and talk radio, low tech. You don't need civic tech, it's very low tech and extremely polarized and these are spaces where there's not contestation, there's not dialogue. And if you have a sort of civic infrastructure that's basically just in five very big cities, right? And again, this is not just a partisan problem, this is a civic infrastructure. If you're part of a sort of civic community that wants to engage most Americans but you're just in five major metropolitan areas, you're having a problem with suburbs as well but you're also not reaching these very small towns. And one of the things that happened, and Dorian, you really alluded to this earlier is this slow atrophy of small town papers and then democratic institutions, the precinct chairs who remember the New Deal are starting to die. They're basically a whole generation are just gone. There's no one to replace them. Many of the churches are in a full state of collapse. People forget that the most rapidly secularizing population in America today is working class and rural white people. Not because they're deciding they want to be atheists but because churches are unraveling as institutions outside of wealthy areas. And that is a very dangerous place and that was happening long before Trump came and no one can say that we couldn't have seen it coming because you totally could have seen it coming because we've been telling you for 15 years, you could have seen it coming. So I think fixing that is about, it's not just about who you're talking to but also where you're talking. So it's about being outside of these major five cities and having presence and speaking to that audience and recognize they're an audience that a lot of folks haven't talked to in a very, very long time. Yeah, there is, I think, if you look at some of the things that Jim Fallows has written about communities like Erie, Pennsylvania or whatever, there are other than those five cities, there are a lot of smaller cities and communities where there is a little bit more civic capacity. Yasha, you want to- So as we have so many political scientists here on the stage, so I think all of us will agree that the way to try and understand the phenomenon of comparative, you have to look at other countries as well because if you just look at the United States, you might think that a story that seems really prominent here explains the rise of populism. When in other countries where that story isn't happening, you still have the same outcome. And so I struggle with that because I'm trying to, I just finished a draft of a book that does try to explain the rise of populism, not just in the States but in other countries as well. But most of the factors that seem to be present in nearly every country, there's a good count example too. So we very complacently in the United States want to think, you know, Trump, that's a problem of old people, right? Like only old people voted for Trump and young people didn't. And like, A, that's not true. Young people in the United States, white young people in the United States voted for Trump 48% or 43%. The most shocking fact about the 2016 election- Just put an exclamation point on that. An exclamation point. But also it's not true in other countries. So you look at France and actually 20% of people 65 or older voted for Marine Le Pen in the second round of a presidential election, 44% of people below the age of 25 did. So it's not true that only young people voted for it, right? One explanation- Well, the Brexit was much further in there. Right, so Brexit and Trump where it was true that old people mostly voted for it. But France, Poland, India, it's not true that young people don't vote for the populists, right? So it's complicated. Stagnation of living standards. I think that's a really big cause, right? I always talk about it. But look, you look at Poland, the GDP increased six-fold between 1990 and now and they have a huge problem in their hands. So there's a counter example there, right? You look at the difficulties of transitioning a mono-ethnic society into an equal multi-ethnic one, right? While you look at Eastern Europe, we have a populist problem in the huge space and there's very, very few immigrants. So there's a different form of it. They have demographic fears about it. They see what's happening in Western Europe. They don't like it, but it's not straightforward. The one story that's actually straightforward everywhere and this is how it relates to the question is the urban-rural divide. I have not seen a single electoral map in the United States, in Britain and France and Poland and Turkey and India and Russia where it's not the case that a lot of this populist anger comes from rural or ex-urban areas and where the sort of liberal-democratic candidates do much better in the cities. So there's something really universal going on here and it makes me a little skeptical about how much we can do about it actually. I think it really is driven by some very deep technological drivers that are difficult to confront, but yes, the urban-rural question I think is crucial and it's the one thing that really is universal so far. There's also, I mean, for the entire scope of American history, rural has been overrepresented from one way or another. I mean, one person, one vote, which was kind of a miraculous ruling, began to break that but didn't really do that at all. There's a sign that says stop, so. You know, anybody have any, I don't think we'll do another question. Anybody have any last comment?  Because it kind of came up suddenly. Oh, I know, I just think that this point about the rural-urban divide is critically important, one aspect of which we might have some control is what visions of one another we receive, right? Because one of the big challenges I think is that the image of the cities in rural America and the image of rural America in the cities is a nasty stereotype, right? That's what we're seeing a lot of the time and a lot of that comes from the fact that when you were talking about corporate, like talk radio and these sorts of, the vision you get of people you don't see is so toxic in this country right now and I think that that's probably something that crosses national boundaries. Yeah, I just wanted to say, I think much of what has driven this is economic. I think a lot of the data supports that and we talk some about it, but what's happened is this sort of economic divide has transmuted into this tremendous cultural divide and I think a lot of this election, a lot of what's happening today is this kind of cultural alienation from each other and apropos what Vanessa was saying, I spoke with Arleigh Haaschild who's a sociologist at Berkeley and she wrote a lovely book called Strangers in Our Own Land and she went actually to Louisiana, the bio country to understand the Tea Party, she's a liberal and she came to really like the people there. They were very kind to her and she was struck by that but she said that what was driving so much of what they felt was a sense of dishonor and humiliation and when people feel humiliated, that leads to anger and anger leads to bad things in a self governing country and I can't underscore enough how important and some of the people spoke eloquently about it. It is that people feel heard. They have to feel like you don't and this goes on both sides that you don't look at them as subhuman or driven by maliciousness and that's just not going on right now. We have these to the extent that I've never experienced in my life and I probably is rare in American history because of technology and all the rest is we're living in political silos, we're living in cultural silos, we're living in theological silos and as long as that continues to happen this kind of fierce anger and alienation is going to be with us and there's not a magic wand that's going to solve this and it's not going to be a leader coming in. We are a self governing country and in the end, this has done a person at a time and a community at a time and some of the people here are doing something about it but that has to happen and we don't have any time to go into how that can but I really do believe this notion of hearing and even of friendship, which is friendship not just people who see the world the same way but see the world in a different way and appreciate each other for that because it helps widen the aperture. None of us has a perfect angle on the truth and the whole idea of democracy is that there is such a thing as a collective wisdom that we're a fallen people that none of us can fully ascertain the truth and the reality of things and we have to model, including political leaders, this idea that we have something to teach each other. Thank you Pete, I think we're literally going to get the hook.  Just really quickly, I think one thing besides comparative analysis, it's also helpful to do historical analysis so I've been rereading, Sabil will know this, I've been rereading the great book by W.B. Du Bois Black Reconstruction in America written in 1935 which is about the same distance from the Civil War that Anne-Marie Slaughter mentioned earlier that we are now from the Civil Rights Movement in the 60s so it was very freshly written and so there's some lessons there about what happens when your community and economy is destroyed and what are some experiments to rebuild those political bonds and what happens when they fall apart, especially around race. So there's some lessons historically as well as comparatively that we might learn about how to rebuild our democracy. Reading assignments are good. Okay, well hopefully the rest of the day we'll build on some of the questions raised by this panel and I would please give everybody here a big round of applause.


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attending to that time, and we'll be happy to start taking questions. Anything that folks can think of, although we may reserve the right to defer some questions into the afternoon session if it's something that we have programmed in. Yes, sir, on the right. Hi, Dr. Biserker. I'm Jonathan Epstein. I'm with NICHD. So, like you, we face this problem with DB SNP, where it's hard to trust it, and it's hard to dig deep enough to know whether you can trust it or not. Now, you internally at NISC have your own genomes, your own exomes, and I've heard that you might release some of that data for other people to use for quality control and SNP filtering, and I just wondered what the status was of that project. Yes, so we're in the process of depositing those data into DB GAP, the database of genotypes and phenotypes, so that will then be publicly available quite soon as well. We can't transfer the entire results set to people for collaborative use, but on a reasonably sized throughput basis, if people have inquiries with respect to the frequency of variants in particular genes or smaller sets of genes, we're happy to download those and provide summary statistics on variation detection in that cohort, and are you using NISC for your sequencing? No, we're not. Okay, so there is this thing about, I think, a platform compatibility. Ideally, what you want is, I think, a sample set for controls that was generated under a similar set of conditions and processes as possible, so this would be less than ideal, but it is certainly available to you and to other practitioners in the audience or online. If you have requests, please do let us know, and we're happy to share those data for control purposes. You want to say something, Jim? I'll just, a little further in what you said, yes, it'll all be deposited into DB GAP, but we're also submitting just the variants that we have discovered in ClinSeq and releasing the frequency data on those into DB SNP as well, or something like that, a VCF-type file that you can work with, so it'll be available that way. Eventually, it would come out through the DB GAP method as well, as frequency information for all the samples. Thank you. I have a question for Dr. Mulligan, and I'm Bojik Husser from Clinical Center. You mentioned the depth of coverage, let's say 60 times or 100 times, and then you mentioned the MPG as the measure of quality, and you went pretty fast through your talk, and I didn't really get that, let's say, one year into the future. What is the good measure of quality? Because I'm not an expert on the genetics, I work with data, with clinical data, but this will be increasingly more important. My other question is, I understand there's always this error in reading the bases, so kind of a naive question. If I take the same DNA and send it to your lab in January and send it again in December, what's the likelihood I will get the exact same data set back? And I'm meaning not those 15 terabytes, so many reads, I just want the one, the kind of the cleansed, aligned, and perfect read. Yeah, so that's a very good question. And in fact, it is a challenge for certain projects that have a very long duration is that the technologies that we used a year ago, we don't even have access to now, for example, some of the chemistries that are used on the Illumina machine, they outdate and you have to move to the next one. So you're going to have different sensitivities as things move forward. Now Illumina, as the example here, I'm sure it happens with other technologies as well, is they're always trying to improve things so that they get better balance between high GC and low GC regions of the genome. So to answer your question, if you sent a sample in January of this year and then sent one again now, how similar would the results be? There won't be exactly the same because everything's changed underneath, it may be a different capture kit, so you'll have better coverage, so you'll have new sites that have variants that were never interrogated before. So now, let's see, and other things change too. It's a changing field, it's just rapidly changing. I could go on and on about other things that could change, but the direction we're moving in is that the samples that are sent at a later time should have a better set, overall set, than the ones earlier because things have been improved upon. I hope that answers your question. Just might add, I think, remember when you're sequencing a genome either by shotgun or exome, there is an inherent randomness to that process, where those reads come from and where they come from and how much coverage you have at any given position is a function of probability. So I would say that the chance of getting exactly the same result with all of the same calls and all of the same MPG scores for two different genomes, the chance of that happening is zero. And so you should take that into account, and I think that's a factor in your decision about how many samples you want to sequence for your project because there is a variation in the assay that's intrinsic to, you know, multiplex sampling of a genome that is going to vary from one experiment to the next, and you have to decide how much money you want to spend, how many times you want to sequence, how many samples you want to sequence, and how deep you want to go to make those determinations. Well, hopefully the old data has already yielded results, so it's enormously valuable because it's already published. Now, if it's something that did not yield a result, then you may want to go back and try it again or, you know, think of a new experiment. Is it maybe a translocation instead of, you know, maybe it's a small change in the genome that isn't being able to be, you can't pick up with the capture, exome capture. So you just need to rethink your approach for samples that have failed in the past. There may be later presenters talking about what you can do for those families, for example, that may not have succeeded in the past. Hi, Anelia Horvath from NICHD. So I have no experience with the Illumina, but I've been using solid from applied biosystems for the last year. And it seems like one of the biggest challenges we face is that when we apply two different analysis pipelines on the same data set, we never get more than 70% overlap in the results. And actually, this is illustration how many false negatives we have, and it addresses the question of sensitivity. So I just want, and again, it doesn't address the capture or incomplete capture or missing gene or something like that, because every time when we look in the IGV files, we are able to see the mutations there. They're just not caught by one or the other, another pipeline. And we were considering approaches like making a union of the different, applying different pipelines and making union of all of them. So I was just wondering if you see something similar, and how do you handle it? We haven't seen anything that severe. We have investigated different aligners. And when we tried to use the BWA aligner versus the DIAC CM one that we've been using for a long time, we saw a number of differences, maybe more like a 90% overlap, so not the low 70% that you have, but we decided that it was best just to stay with the system that we had been using all along and try and switch and maybe throw things off. We thought what we were actually doing was better than switching to a different aligner. So you were testing the alignments, not the post-alignment calls, I mean steps? So if you're working from the same alignments and getting different calls after that. Yeah, that's what we observed. That sounds very challenging, and I don't have experience with the solid data analysis. I would just follow up. One thing that we did do, which gives you an idea, though, about variability is I don't think anybody talked about where we did the genome, the shotgun, and the exome from the same DNA sample. Was that mentioned? We didn't talk about it. Jamie has done some comparisons. Yeah, do you want to just summarize that very briefly about what you saw on one versus the other? So in this particular test, we did a whole genome sequencing and then exome sequencing and used the same analysis tools to compare and there is sort of a different question. In this case, the concurrence, the agreement was extraordinarily high, I think, with discordance of 1 in 10 to 20,000. So applying the same methods to even different capture, the same analysis methods to different sequencing methods, in our hands, seemed to give a high agreement. However, that's sort of different than the question of different analysis methods on the same data. And a lot of the some of the different methods do use different assumptions and different dials and knobs to tweak different parameters, and that can make a big difference. That's a challenge. Max. Max Munker, NHGRI. Les, I was very intrigued with the examples that you gave for the different inheritance patterns. And of course, it was very instructive to go through them one by one and to think about the families that we have in the lab and what we might want to do. I was even more intrigued by what you said that other colleagues shared their data that, in essence, really, it was only about 30 to 40% that led to success. So that's really the bottom line. And what I wonder if you could expand on that a little bit, what the pitfalls were or what people were guessing. If you don't have a solution, it's hard to guess. But then the other question that I have is, what is technology and what's biology? And with biology, I mean, what would you expect to be found in exons and what would you expect to find in non-exonic sequences? Yes, so I think the ceiling ought to be probably in the 80 to 85% range. I think our experience, and you've done as much of this as we have in positional cloning, when you have a trait and you are certain that it's Mendelian and you know you have mapped it to a locus and you have a family and you know you've sequenced the genes, you know that 10 to 15% of the variants are not variants that are assayable by PCR and 3100 or by exon interrogation because they are control elements, deep splicing elements. So there's the biology that pushes out a good number of them. Copy number variants, as I mentioned, are not readily assayable by exome sequencing although some efforts are being made. And as well, all of the foibles that I listed of not recognizing the genes, not completely targeting them, the capture, that distribution that Jim showed of that wide distribution, did you notice on the left side it slipped upwards at zero? There is a decent amount of the exome that has zero coverage when you do an exome experiment. And that's an issue. And as well, the graph that Jim showed with the tail off of alignment for base pairs of indels. So a six base pair indel, which we know we've seen in Mendelian disorders, it's very difficult to find those. And so those are, there's just plenty of reasons for that. And then I think the other considerations are, you know, it may just be some of these families that have been selected for these projects that just really weren't good candidates. Maybe they're not as Mendelian as we think they are. Maybe they're teratogenic for all we know. So environmental causes, we are not going to find with the GA2. I think maybe you were alluding to also is the, if you're just going after the exome, how much is going on in the rest of the genome? So we're only interrogating 2% of the genome with good coverage like Les just talked about. But is there something else going on in the intergenic regions or like some diseases could be an insertion in the intron of an aloe element or a deletion that will cause skipping of that, of an exon cause of disease. We wouldn't pick that up necessarily by exome sequencing. So there's various classes like that. If we aren't interrogating it, we won't see it. And you may not see it well with whole genome sequencing if it's an aloe repeat, a recent aloe repeat. You won't get coverage there anyway because your reeds won't align nicely if you did a whole genome. So there's challenges all around. Exome is a good first step as I pointed out in my initial statement. Just one more comment on that. There is certainly there isn't completely useless. I don't know if Dr. Adams is going to talk about an example later on. There was an example where no variant was identified, but in carefully looking at what was covered and what was not covered, it suggested some follow-up experiments with Sanger sequencing that then did uncover the correct variant. So sort of knowing what you, or I guess you do know what you haven't identified has value in itself too. My question is about Exome capture kits which you mentioned. One of them is Illumina truce capture or something like 62 megabases kit. So is it possible to capture the DNA using Illumina 62 megabases kit and then do the next gen sequencing on a platform other than the Illumina? Or is it a platform specific? I'm not sure about that. I'm sure there could be a way to do that because it is just DNA probes that are hybridizing. It doesn't necessarily have to have the adapters of the Illumina kit around it to pull that out. Jamie, you might have a sense of that. I'm actually not sure either. As Jim alluded, it should be possible. Definitely I believe they make the whole protocol available online. So have a look at that and then contact them because I believe it should definitely be possible for any platform to sequence given that your library was prepared appropriately for that platform before the actual capture. Steve? Mark's NIDDK. Today we're dealing with a very powerful wealthy methodology. It's all from the NIH and I wonder a little bit about other centers. First of all is there redundancy with other centers? For example China and second of all are there areas of major disagreement that we're not hearing about? I'm sure there are. This technology is so new. A lot of the things that we are doing are the polite term that my informatics and computational people use is called a heuristic. I sometimes call it making things up as I go along and see to the pants and we're trying and I think I hope I gave a flavor and I think your Dennis presentation was the same. We're trying lots of different things and I think some of the things we're trying probably really aren't all that clever which is probably an answer as well to Max's question which is that the variants are actually there and our analytic algorithms and our filtering are not allowing us to see them and so we have to work on that. One of the things I've been intrigued with that we've talked about a little bit is the unaligned fraction. So we are all focusing here on what aligns to the genome that we can look at and compare to the reference sequence and there is a fair amount of sequence that's generated by these instruments that's sitting in the computers as the unaligned fraction. One of the potential reasons that it's unaligned is that there is a genomic variation substantial one that's preventing that alignment from occurring and that that is the variant that's causing the disease in the patient that you're studying. What about the question of controversy I mean are there people that say you guys are doing it all wrong and it should be our way. I haven't been hearing a lot of that. I just met with a group from BGI last week and we were talking about all of the analysis methods that both groups are using and we're both faced with the same challenges and we're both excited about the same possibilities so there wasn't anything that came up in that meeting that was any disagreement at that stage. Just to add to that it's nice when other groups use different methods and find the exact same genes and the exact same mutations and I think that in itself is just a replica and a good control that things are being done right by different groups. I think it's also worth saying that we're not here to effectively represent all approaches and all viewpoints on these questions what the four of us each described is how we have chosen to solve the problems that we have been faced with these are one or a couple approaches and there are more approaches and other people are using different captures and different sequencing instruments and different aligners and different base collars and different filtering strategies and there's a universe of variables out there and I'm sure that there are some that would work better than ours but ours are working fairly well and you are free to take from us what you think would work for you and ignore what doesn't. So I have a question to Dr. Biesiker you presented an interesting research agenda to focusing on all those 2,500 diseases and including maybe the functional side of it but basically getting some exams or families affectance was an interesting term and let's say we kind of went through all of them and you also mentioned an interesting example what can we learn from this hereditary osteoporosis which has impact on general osteoporosis so once we have kind of used up all the diseases, the monogenic diseases we can go after what's the next step or is this the end of that we can go, what's the polygenic diseases, is there any hope to go after these in a similar fashion? And I think the other whole domain that you didn't include in your question is the somatic question which Jardena's talk exemplified so I think we have a huge amount of work in front of us and I was careful to try and use the phrase a recognized clinical entities because I don't for a second think that those sources of knowledge represent all clinical entities and as you well know and a nice paper that was published that showed and I can't remember was it exomer whole genome, the medical college of Wisconsin case? I can't remember but it was next gen sequencing used as a clinical diagnostic tool because the patient had a very atypical presentation of an autoimmune inflammatory bowel disease that was not clinically recognized by the clinicians, they sequenced it found a high penetrance variant in that gene and then in retrospect they could say oh yes, this is an unusual presentation of a disease we in fact know and recognize and so I think this technology will diffuse out and be used for all dimensions of analysis both in the research lab and in the clinic and I think essentially forever in the cancer somatic sequencing world. Another application as Les was alluding to is that in the clinical domain in cancer for example you can imagine that these discoveries will be applied at some point to the clinic, there will be drugs, there already drugs are being given based on these mutations, this resistance that develops after that drug is given and to find out what the resistance mechanism is, again these technologies could be used to find out in an unbiased manner what that resistance is and so this keeps rolling over, it will be applied again and again in the future. Oh there's plenty to do I mean the Mendelian disorders are really just the low hanging fruit of the heritability of human disease and we and our colleagues I think internationally I think are focusing on Mendelian diseases because it is a more tractable problem mathematically and statistically for analyses of these data sets and it is only a matter of time before this starts crossing over into the multifactorial polygenic world but will need much larger control sets and case controls type study designs to extract that kind of information and as you all are well aware for those of you who take care of Mendelian disorders the determination of the primary genetic variant that is causative of a Mendelian trade is far from explaining all of the variation of that disorder in an individual and there are modifiers that affect those traits and those data are potentially extractable from exome and genome analysis as well we have plenty of work to do I'm not worried about us running out of projects at least in my lifetime so I think it will be fun. Yeah it's a start, exactly. Hi this is Rinki from NEI and I have a question about the exome data you presented so you said there is a need of a different variant collar because of its hemizygous status and because I did one SLRP family and what I'm seeing a lot of heterozygous variants I sequenced three affected males and very few homozygous which I would expect and I was using the standard variant collar which you would use for autosomes and so I was not even aware until I heard from you so can you elaborate on that and what variant collar should I be using. So it's very important to know what part of the genome you're analyzing and if it is a male sample and you're looking at the X or the Y chromosome you do need to handle those carefully. If you have the wrong information somewhere in your pipeline I think it's a female sample and it's really a male and you call heterozygous on X you're going to get things that just you're going to generate false positives because the model is going to try and find something that is potentially heterozygous from the data and will call things and those will clearly be wrong because it should be homozygous in those regions unless it's something else strange going on in the genome that can happen. But the collar that we're using is the MPG package it's available online through NHGRI's research web page so you can download the program it's called BAM to MPG and it has a flag that you can use in there and state I want to call this region as a single copy hemizygous region and you can give the coordinates and so if it's a male sample then you can just give the regions of the pseudo autosomal, non pseudo autosomal regions on X and Y. And also that the capture in that X chromosome it was less compared to the other autosomes. Do you see that also in your samples? Like my average capture was around 90-92% but in the X chromosome in the region where I was looking for my gene of interest there I saw at least 30-40% genes not being covered could it be because of the X chromosome or something like that Was this the Agilent XXome kit? No, I used the whole Xome kit because I was doing X chromosome as well as some autosomes so I just ordered one kit and I did the Oh you did the whole Xome? Yes. And only looked at the X? Yes. For one family? Yes. Maybe it was just a depth of sequence and another answer is that or possibility is that if you analyze the data with a heterozygous collar X chromosome will only be covered half as much because there's only one copy of X for two copies of Y. So you're going to have lower coverage and won't have enough coverage to start to call the heterozygous that you don't want to look at anyway. No, but I was looking in the genome browse like IGV for the capture and the depth of coverage and I saw like a lot of exons because I went by exon by exon because I knew this is the so it was already positional mapping family so I knew where I am expecting my mutation to be and when I looked at gene by gene I saw less coverage compared to Well, you only have one copy of X for two of the autosomes that could be the answer. No, I should be trying that thing you mentioned. Thank you. I think another thing that points out as well is again we're working towards because we're at early days and we're not the only part of the genome that people have a single copy of, right? We know that there's copy number variation throughout the genome and one thing we all want to be able to do is to recognize a point in the genome where we have one allele that we are deleted for and the other allele we have one copy of and in fact we ought to be if we could recognize those and implement single allele base calling when they're in trans with the deletion that would be our power and those are things we're just not seeing as well and the converse is when you have three copies of an allele what is your call are going to do? It's not going to call those bases, right? And you're going to make mistakes so that's a refinement that needs to be implemented for more ways from that. And I'm sure your agenda is quite interested in having if you could just figure out the copy number across your tumor sample then you could correctly call it each location and that's something we would like to get to at some point but it's a more way to process tumor samples. I'm sorry I may not have fully understood like the previous conversation but I have a more specific question about my project. I was looking at a region of homozygosity where I was expecting all the homozygous variants and I have found that there are quite a few heterozygous variants and I was thinking it could be because it could be simply false positive or platform error or something like that but is it possible that there is actually a copy number variation and that's why I am finding those heterozygous variants because I am using I'm not using the... So if it's homozygous theoretically all the variants in that region... How is it homozygous? Because I have a well defined linkage region for a recessive... So then it's identity by descent in that region so then again you should there you could be using a heterozygous collar in that region I mean a collar for diploid samples but if you know it's really identity by descent the only thing that will be real will be anything that's somatic changes between the two copies or not very recent changes between the two copies yet so again you should see a huge reduction in the heterozygosity did you see that in that region? Well I am actually seeing heterozygous more than expected heterozygosity We should talk about this maybe afterwards, yeah If there are no other urgent questions I think we should break for lunch we look forward to having people come back and I think our start time start time and as well we welcome encourage the web viewers to rejoin us at that time Thank you all very much


I have this glass of water here and between me and the water there are no mirrors, there is no cause for reflection and yet if I show you the water from the underside and then I point my flashlight, my phone flashlight from this side you can see the surface of the water begins to shine that is in fact reflecting the light from my flashlight and creating an image of my flashlight on the other side on the upper side of the surface it looks like light is coming to you from somewhere here when actually my phone is below the surface of the water this is the phenomenon of reflection that is associated with mirrors but there are no mirrors here this is the case of water air and glass three materials that are completely transparent and transparent means that the light on the other side of the material is brought through the material to this side which means there is no chance for reflection whatever reflection does occur in a very small amount and a large proportion almost all the proportion of the light is transmitted through these materials then why are these transparent materials why is the surface of water behaving like a mirror when I point my light from underneath this is the phenomenon of total internal reflection which you all must have heard of plenty if you are studying for JLE then you have definitely heard of total internal reflection you know what it takes for total internal reflection to happen you need the light going from a denser medium to a rarer medium and you need the angle of incidence to be greater than a particular value which we call the critical angle now this critical angle can be determined from the refractive index of the denser medium with respect to the rarer medium if this value is new then the critical angle is given by the sign inverse of 1 by pin now in the case of the water the last experiment which I just showed you the light from my phone enters the water performing a regular refraction but then while traveling through the water it encounters the water air surface and when it hits the water air surface it becomes a ray of light traveling from a denser medium water to a rarer medium that is light now what happens to this ray is that it is hitting above the critical angle and therefore it reflects instead of refracting following the traditional reflection loss that the incidence angle is equal to the reflected angle but why does this happen you all know that above the critical angle psi by psi are equal to mu no longer has a solution the formula based explanation but what is actually happening inside the material which causes light to suddenly start reflecting this phenomenon of refraction and total external reflection were explained traditionally in two ways one of them was by Newton who assume that light consists of tiny particles that are attracted to different media in different amounts another explanation which one out in the end for a long period of time was by a scientist called Christiane Huygens this person assumed that light is a wave and if you observe these crest points of the wave it's a 3d wave such that from a source the crest points spread out in circular shapes as you go further the radius of the circle increases and the crest points approach planar shape this plane is called a planar wave front and the consequence of planar wave fronts is that when this wave front approaches when a planar wave front approaches the boundary between two material then this wave front continues to go undisturbed but the material the boundary points of the material will release their own little spherical waves now if the wave front is parallel to the boundary of the material all the spherical waves are released simultaneously and depending on the nature of the material the waves may either constructively interfere with the original wave on this side or this side and destructively interfere with the original wave on the opposite side if it constructively interferes on this side the wave passes through which is a transverse medium and if it destructively interferes here and constructively interferes here the wave reflects back which we call a reflective medium like in the case of metals now this is the case where the incident wave front is parallel to the surface separating the media if the incident wave front makes an angle with the surface separating the media now these points correspond to the crests of several waves that are one after the other side by side in space different crests reach the border of the media at different times which means these secondary waves the wavelets generated by the border points are now not going to be generated at the same time in fact this wave will generate first then this then this and so on and you can see the edges of the wavelets will form and inclined surface and depending on the speed of these waves compared to the speed of these waves and on the intensity of the different waves there will be some amount of refraction which is which means this line of crests will get over at a different angle or there might be some amount of reflection which means the line of crests is going to reverse and propagate in this direction now if this side is an optically denser medium and this side is an optically rarer medium the line of crests is going to bend away from the medium surface and propagate in that direction and what happens after a certain angle is that the newly generated waves the newly generated waves will not destructively interfere on the inside of the medium and constructively interfere on the outside of the medium in such a way that a pure reflection occurs and all the energy is kept in the same medium this is the wave phenomenon of coated internal reflection explained originally by Christiaan Dragons and developed upon by the great scientist Frejana so it is the effect of interference between the incoming wave and the wave produced by the particles on the boundary which causes refraction as well as total internal reflection so my question is just like light is a wave sound is also a wave light is an electromagnetic wave which is an oscillation of field the electric and magnetic field is inside a medium but some is a pressure wave it is the up and down of pressure over a mean value within air enclosed in a space if sound is a wave can we apply this theory to sound as well in other words if sound crosses the border between two media does the sound refract and if it crosses from a denser medium to a rarer medium is there a chance of total internal reflection and the answer to both of these questions is yes sound is a wave just like light and snails law is not something that is specific to light it is a general law that applies to all kinds of waves traveling in any medium not just light and sound but also water waves traveling on the surface of water the ripples that you see produced when you drop something in water those ripples will also follow snails law if you go far enough from the source of the ripple so that the ripples tend to become straight lines or clean waves as we call them so now sound also undergoes refraction sound also undergoes total internal reflection but there is one important thing to keep in mind number one what is the refractive index of a material when speaking about sound you see when talking about light we define the refractive index as the ratio of velocity of light in that medium to the velocity of light in vacuum unfortunately sound does not travel in vacuum so we can't apply this definition to sound directly but refractive index is also defined for refractive index for a pair of materials the ratio of speeds of light in these two materials basically the speed of light in vacuum gets cancelled out when you take the ratio of refractive indices and the refractive index for a pair of materials is simply the ratio of the speed of light in these two materials the same thing you can do for sound which gives us the refractive index in the sense of sound as being the ratio of speeds of sound between two materials but an important point to make here is about density when we talk about refraction we talk about light going from a rarer to denser medium or a denser to rarer medium now a rarer medium in the sense of light is a medium where the speed of light is higher and a denser medium is a medium where the speed of light is lower which means an acoustically denser medium to take the pattern of optically denser media we find acoustically denser mediums have a lower speed of sound but the conventional sense of density is that solids are denser than liquids which are denser than gases but if you look at the speed of sound travel it is higher in solids due to the height of the bulk modulus of solids and slightly lesser in liquids and much less in gases which means solids are less acoustically dense than liquids and liquids are much less acoustically dense than gases and gases are acoustically denser stop all this is the reverse progression as to what we think of when we speak of light so solids are very much optically dense liquids are slightly less optically dense and gases are least optically dense but the order of acoustic density is reverse this is an important thing to keep in mind while calculating matters regarding to sound waves. The reason why total internal reflection of sound is not so easily demonstrable as light is that you don't commonly find an interface between two media where on one side you have a acoustically very dense medium and on the other side you have a very acoustically rare media. You see densities of media usually tend to vary slowly and it is in these examples where we find a sort of continuous total internal reflection of sound. What do I mean by this? Take an example of the phenomenon of a mirage shape an object that is in front of you will send light rays will reflect light rays from the sun in such a way that the light rays initially head downwards then the density change in the layers of the air causes this light ray to bend away from the model because the air is being heated up by the ground the lower layers of air are rare which means the light is travelling from a denser medium above to a rarer medium below which bends it away from the normal until total internal reflection occurs and the light swings around upwards to our eyes. Our eyes retrace the path of the light as if it is a straight line and it looks to us like the object is coming from there and we automatically interpret it as a reflection of this object in some body of one when in fact there is no water their reflection is actually a total internal reflection or a curved total internal reflection from the layers of air that are closest to the ground. An important application of this kind of curved total internal reflection is in the detection of submarines by ship using sonar as well as sonar stands for sound elevation and reaching it generates sound pulses and then looks at the echo of these sound pulses from different objects by analyzing the input from different objects it imports a graph of which object is where depending on how long the echo has taken to reach from that object to the receiver. Now in a sea you know that water is very slightly compressible so as we go deeper under the surface of the sea the water at lower layers is much more compressed than the water at upper layers which means the density here is less and the density here is greater because of the compression of water at lower levels of the sea. Now if the density is greater that means the speed of sound here is less the speed of sound is less than it is here if the speed of sound is less that means this is a denser medium or this is a rarer medium with respect to sound this means that as a ship on the surface releases a signal from its sonar this signal travels down into an acoustically denser medium which means it bends towards the normal and it hits say a submarine at this level. Now on the surface of the submarine reflects the sound back what happens is it reflects it in all directions because the surface is not smooth it is rough suppose a film extending at this angle reflects it back in a direction that seems to be heading towards the ship. At this point this rise traveling from an optically denser an acoustically denser medium to an acoustically rarer medium which means it bends away from the normal and this curvature continues until it hits the critical angle for this pair of densities once it hits the critical angle it begins to reflect back and go deeper into the sea rather than hitting the ship. This means submarines can hide themselves and they do in fact hide themselves by ensuring the presence of a large number of films of the submarine which would send off the signal from the ship in such directions that total internal reflection of the returning song is accomplished at a certain depth of water below the surface. This will help us hide the submarine which is an important application an important military application of the total internal reflection of sound which is something we haven't been able to hear much about which is something we don't hear much about compared to how much we hear about the total internal reflection of light. Nevertheless it is very important and has real world applications.


Hi, I'm Chris McCormick, GB Soapstow and Big Air Skiyer. I'm also a member of the Ellsberg and Freeski team and today I'm going to be teaching you how to do a 2-th down rail here. So yeah, let's get started. So first things first, before you get started, you want to find a nice down rail somewhere in the park that you feel comfortable doing a ski slide in both directions on. The reason for this is that when you do the 2-th down, you're actually going to be landing into your unnatural ski side, so you already want to be pretty confident with that. So as you approach the rail, you want to be coming in at a slight angle to the take-off in a good solid ski position. So this means with your knees nice and bent and also with your weight pushing into the front of your boots. So moving on to the take-off, as you come off the lip of the jump, you want to try and push your noses up and over the rail as you initiate the rotation for the 2-70. Once you've done that, you're going to keep that leading arm pushing around until you've completed the rotation and landed on the rail. Once you're on the rail, it's straight back into your solid ski position, so that again means knees nice and bent, core engaged and also plenty of weight onto your leading leg on the rail, which for me in this instance is my right leg. As you're coming to the end of the rail, all it takes is a nice little pop-off, looking where you're going into the landing and making sure that when you do land, it's with nice bent knees and your skis pointing straight out. And that's pretty much it for how to do a 2-70 onto a down rail. It's a great trick to have and once you start to feel comfortable with it, there's loads of different variations you can try, maybe a switch-up while you're on the rail or also a 2-70 out. Thanks very much for watching, I hope you guys find this useful and good luck with your 2-70s on.


All right, so before wrapping up this notebook, let's quickly recap what we've learned about reinforcement learning so far. So we set up the formalism of Markov decision processes, and we said Markov decision processes have S, A, P, and R, where S is the set of states, A is the set of actions, P is the transition probability, P of S prime given S, A, and R is the reward function that maps from S, A, S prime to some scalar reward, right? And we've learned techniques for dealing with these MDPs. So if we know the entire MDP, then we know how to compute the optimal value corresponding to the optimal policy, the optimal Q function again corresponding to the optimal policy, and given that we know how to learn the optimal Q function using the Q value iteration that we saw just a few slides ago, given that it's easy to then compute pi star because pi star is simply the r max of Q star, right? So we know exactly how to do all of this if we know the full MDP. Plus we know for a given fixed policy, we know how to evaluate it as well. We saw this as one of the sub-routines in policy iteration where you evaluated a policy and found it's corresponding V value function or Q value function. Now, if we don't know the MDP, we've just begun to deal with the setting and we said if we don't know the MDP in particular, we don't know P and R, the transition probability and the reward function, then we've seen this idea of temporal differencing where you can actually learn to estimate the V for a fixed policy pi that's a policy evaluation through temporal differencing. And then we saw our very first RL algorithm, which also uses the same temporal differencing idea, but this time to actually learn the optimal Q function, Q star of SA, corresponding to the optimal policy. So we've only really begun to scratch at the surface of reinforcement learning and so we've seen in particular Q learning as an example of what's called value function reinforcement learning, but we haven't yet really seen how things like neural networks that we've been dealing with in recent weeks actually help us with this type of value function reinforcement learning. And so we will see very soon deep Q learning where neural nets will help us in Q learning. There's another entire class of methods called policy search reinforcement learning where you don't really bother with learning this optimal Q star like we did in Q learning because after all at the end of having learned Q star really what you're interested in is computing pi star which is equal to r max over A of Q star. So can't we directly learn pi star? Why do we have to go through this whole process of learning this state action value function or the Q star? That is a class of methods called policy search RL. There is then a third class of methods that tries to kind of bridge the gap between value function reinforcement learning and policy search reinforcement learning. This is called actor critic RL. And the idea there and we'll see this in more detail later is to take policy search methods and use value functions to help them along, to help them learn faster. So these are actor critic reinforcement learning approaches where the actor is a policy and the critic will be a value function. And finally another fourth type of reinforcement learning which is very different from all of these approaches is to say hey we actually started all of this discussion by dealing with MDPs where all the quantities were known and we said we could do policy iteration, value iteration essentially dynamic programming techniques to solve those MDPs. And if the only difference in the reinforcement learning setting is that we don't know the transition probability p and the reward function r can't we just learn to approximate p and r from experience and then use the same techniques from before the same dynamic programming style techniques. So that's model based reinforcement learning. And aside from all of this we could also cheat and say let's not actually do reinforcement learning at all but instead train agents to perform sequential actions the same tasks that we want to solve like driving or cooking but train them by mimicking an expert like ourselves. So we would perform some demonstrations for the agent and then the agent would learn to mimic us. So that's a class of approaches called imitation it's not strictly a reinforcement learning approach although it can be blended together with reinforcement learning approaches.


The hyper pack pro and this is the one I wound up going with this one also has a find my module it It has all of the pockets that are important both of them have the strap that will Let it easily sit on top of your roller suitcase So that you don't have to wear your backpack if you're rolling a suitcase through your air through the airport So they both got that I Just liked the configuration of the multiple pockets on this hyper pack slightly better Then the then the other one, but I think it's you know, that's just a judgment You know personal preference kind of thing, but I this hyper pack It's I like a as you might imagine saying I want you know three separate pockets plus the laptop I like a backpack that's big You know, I want to be able to carry stuff with me And I want to be able to buy a sandwich in the airport and and put the sandwich in my backpack before I get on the plane I don't want to have to carry an extra bag on the plane But but this this hyper pack pro it stayed with me I used it obviously for CES because because that was the choice I made and it was frustrating First it's switching to a new backpack is it's something. I would rather do over like a You know a Low-stakes weekend getaway kind of thing where if I decide oh, I don't like the configuration of this Or even I need time to adapt to this I I would rather do it on a thing where I'm not like relying on it all day every day Yeah, you know that the frustrating part is Yeah, you know, you have to learn how the zippers work You have to learn where you put all the things and so it's like oh, I need that one quick thing I know it's in my backpack I need a minute, you know like that, you know that it's just these things work their ways into our lives and and That's why I've used the same suitcase for 28 years exactly, you know I because I can get up in the middle and I in a hotel room in China and go I know where the Tums is it's I know which pocket it's in I can get it without turning on a light and yeah, yeah Yeah, yeah, exactly