And now, tonight's presentation of Radio's Outstanding, built of clothes, clear of the rehearsal and the performance of the murder. We call it The Cellar. So now, starring Mr. Eric Snowden, here is tonight's suspense play, The Cellar. Hello. I've told him that it's been a long time, 16 years to be exact. We've been married 20, and I think I owe it to myself to do something about it now. It's the principle of the thing, if you follow me. First of all, I don't like your voice. Jor, jor, jor, I haven't found. She goes at it morning, noon and night. You've never heard the like. Or maybe you did. Go something like this. I've got to tell you, not to put your finger on the attic.  And for heaven's sake. I don't know, I'm sure, why I've got to do everything in the house. It's bad enough that why I scream from side, week in and week out, to keep a close of bread in our man. Never a nope, I'm sure, of having somebody do out with the work. I really don't know why you don't get a better position, always dreaming of what we're going to do. If you'd only ask the back of my house. Bloody awful magic. I've worked it out on paper. There's 60 seconds in a minute and 3,600 seconds in an hour and 86,400 seconds in 24 hours.  Sooner or later it's got to stop and that's a thing. And there's other things. She puts some kind of sheep or a muck on her hands and pour a guy into bed and who gets smeared with it? Who else? Goodness knows. I try to keep myself looking halfway decent. It's not like I can afford a manicure twice a week like Mrs. Climpton. I should think you'd be grateful. It's not a good reason to do in your life. I don't want to tell you, it helps. And she's always put enough feet on me bags. She says they're cold and wants me to warm them for her. They're cold all right. Like a blinking mackerel. She goes my back and she thinks she's hot stuff about keeping accounts. Always guessing about saving. And I get two bob a week spending money. I ask her, how can a man live on that? It's a perishing injustice. So all in all, that's why I got a killer. Everything's ready and I suppose I might as well get on with it. Could you come down for a minute, love? It'll only take half a mile. I've got something to show you down here. Keep your head on, love. It won't be long. What's it you're messing about down here while I'm awake? What are you doing with my cellar? Why is it all dug up like that? You gone bar me? Now you put every scrap of that dirt back in the old this minute. You hear me? All right, love. I will. Don't worry.  I will not have that mess all over me clean kitchen floor. All right, on course drop. I just wanted to get an idea of the size. It looks all right. What you're talking about? Right for what? You'll be there. No way. You've been drinking. You've been drinking, that's what. Not a drop. I'm a cheat open and you know that, Mil. No, Mil, pal. The time has come as the wall was set to the carpenter. Your time. You made this instant and filled in every bit of that old. All right, old comrade. When you suffer all the on and ten minutes, then I will not have it spoiled. Mil, I've got something I've got to say to you. Thank you.  Fed to the teeth and best of that. Yeah, you. Oh, you think you're talking to me?   Oh, I'm going to do you in. Oh, look at you like that.  I'll have the law on you.  I worked it all out.  Oscar, if ever you do anything in this world, do it right. I remember their words as I covered up the mortal remains of my ever-loving ex, milling witching. I did her a corker. One good whack on the air so there wasn't much of a mess, if you follow my meaning. Took me about 15 minutes to cover her up. Nice and neat, lice. And then I went upstairs, and I'm telling you, give me a bit of a turn when I open the front door. I hadn't had time to wash up yet, but I wasn't too worried. Not until I saw who was standing outside. He was a copper. Gormly, my name. He's got the beat on my square. Mr. Witchings. Evening, Mr. Gormly. Sorry to have to trouble you. But I had a complaint. Sorry to hear that, Mr. Gormly. Complaint states that an audible vowel was emanating from your ears. A vowel? The screams, more like. Screams? Those. That's the nature of the inquirer, Mr. Witchings. I'd be obliged if you could shed some light. Happy to, if I knew how I could help. The missus at home? No, she run off to the picture palace. You know these women and their ruddy pictures. What time did she go? Don't know. About an hour ago. No one else here. Not a living soul set myself. You've been doing any screaming, Mr. Witchings.  What do you take me for? All of the nature of the inquirer, Mr. Witchings. No offence, I hope. None at all, Mr. Gormly. She and his hour has me duty to perform. I hope you'll allow me to have a look about the premises, Mr. Witchings. Seems to me a man's got his right, but I always alter aid in the law. If you're looking his aid in, help yourself, Mr. Gormly. Your mind's telling me what you're looking for. Do napers swear the herbs or sounds coming from here? Maybe it was on the radio. It's not on. Saves me making a report, Mr. Witchings. What are you bludgeoning at, you, I'm sure? Well, I don't think there's a need to bother you anymore. I'll just, uh... Hello? Cut yourself? Huh? Oh, that and how. Cutting up a bit of beef for Grubb. Thought I'd give the Mrs. a nice surprise when she gets home. I was in the kitchen when you knocked. Sorry to disturb you, Mr. Witchings. All right. Makes the bloke feel safer now than there's law nearby. Nice that you think so, Mr. Witchings. Good evening. Evening, Mr. Gormly. Handled it nicely. The worst whip was over. Copper had been then gone, and... I'd have at least 24 hours to clear out. May be longer.  Oh, what a bit of strawberry jam. Lovely. I'd met her a couple of months before, and I hadn't told her what I had in mind. But I knew she wouldn't care when she heard. After all, it was all done for her, mostly. Oh, Oscar, I do love you. Heavenly ain't it. When you was coming home, I do feel something awful carrying on this way. Aggie, love. Sit down. I've something to say to you.  Run away? With me? But how can I? You're a married man, and what would my mom and dad think? Aggie, love. All I have is yours. You don't have to worry about a blinking thing. Everything is taken care of. I didn't care, though, but how? What's your wife going to say? She ain't going to say nothing. Aggie, for love of you, I've done her in. You've done her in? That's right. Where is she? What did you do with her? You're just about sitting over her now. Be reading the cell. Oh, how horrible. This is from me, Oscar. So you, sweetheart. Oh, how you must love me. Never a truer word. Now, listen here, duck. It's all arranged. In the morning, I'm taking the savings out, and you and me are buzzing off. There's a boat sailing for South America to the Argentine at eight o'clock tomorrow night. We'll be on it. No, I don't know what my mom and dad will say. Don't tell them. Write to them from the Argentine. Oh, Oscar, you make it so odd for a girl to say no. Give us a kiss of no more, R.G. Bartz. How may you use that?  Eh, you open the kitchen. She won't be a sec. Can I, Oscar? Oh, if you. Where is my daughter? Out. Out. We'll be home for a bit. Then I'll wait. Oh, close the door, Oscar. There's a drop down the back. She put that out of the low cow, Mrs. Quill, poor old Millie's mother. And when she says she's going to wait, she means it. Last time, it took two weeks to get rid of her. Now, what was I going to do about her? The cellar, the night's presentation in radio's outstanding theater of thrills. Suspense.   Still daydreaming, our stage. Not much improvement in you since the last time I was here. Bill and me, we was going out when she came back. Why don't you drop in over the weekend? She'd love to see you. You can stay for a bit, if you'd like. I've travelled across, all for London to visit me daughter. I've no intention of going home tonight. You can go out if you want to, Oscar. Millie'll stay here and talk to her mother. Oh. I don't let me suffer yet. I've bought a nice bit of smoked daddock. I'll go in and put it on. No.  You? Don't make me laugh. You think I want me attic ruined? I said, mother dear, I'll cook your ruddy apple for you. Take it or leave it.     Just wait till Millie is about this. No. You wait. Matter of fact, this is my house.  You've been drinking. Once and for all, I have not been drinking. Now buzz off. I will not drink this house until me daughter comes in that door. I've got to give you 10 seconds, mother dear, to opt it. Then I've got a land you want you won't forget. Huh? One, two.  Three, four, nine, ten. Put her along. All clear, Aggie love. Oh, Lord, I was very frightened. And don't you worry, you're pretty yet. Everything's right as rain. Now you'll have to be yours. I wouldn't do to have anybody else snooping around and find you here. Now, not a word to anyone, say. You need to get the marble art station at four o'clock tomorrow, say. What about me planes off to marble art? Where I'm going? Leave it to me. I'll buy you all the clothes you want. That's one thing I've got to say for poor old Mary. She wasn't a very nourishing woman, but she was a saving one. I've always wanted to go abroad. Oh, that's awful. Amazingly, going for the married man and the murderer.  Marry you? What a question. I've got memorials same as the next one. Of course I'm going to marry you. Oh, Oscar, I know it's wicked, but I can't wait till tomorrow. You dream about it, love, and before you know it, it'll be tomorrow. Now go on. You better leave by the back door. Next morning at 10, I was in the bank. I had my slip made out to withdraw my savings and a nice little drop it was, too, 800 quid. I was waiting for the money when a tallish bloke comes out to me from behind the gate. All smiles and trickle he was. Mr. Widgen? That's right. How do you do? I'm Mr. Fawke, all the manager. I understand that you wish to withdraw your savings. That's right. I trust you've found no fault with our service. No, just what's mine? That's all good, of course, of course, naturally. Now, I inquire as to the reason you're withdrawing the fund. Is there have to be a reason? No, no, no, not at all. But since you've been such a faithful depositor for so many years. Oh, well, the truth is, Mr. Fawke, for me and the Mrs. Fawke, we take a bit of an olives. You know, the Riviera. A little sunshine and Pollywood. Oh, yes, I see. Oh, then, of course, you want me for some tea with us? No, I want it all. But, my dear sir, you can't spend it abroad. Who says I can't? The government, sir, the government. A maximum of 50 pounds need be taken out of the country. Yes. What are you giving me? But, surely, you know that it's common knowledge. To me, it ain't. It's my money. I can do as I please with it. Here in England, yes. But you can't take it out to court. It's a ruddy injustice. That's what it is. A chance, I'll give the point, sir. I'm conservative, and that's your hard luck. Now, you and over my money, see. What I do with it is my business. Up to it. Just as you please, Mr. Widget. I've done it. They've done it. What in blazes am I going to do now? I shall be 800 quid in the pocket and went home. And that's what I should never have done. Because when I got there, the old cow was standing in front of the door and the copper gormly was with us. There he is.  Ask him. Ask mine, you meddling old egg. Now then, now then. No language of euclation to Widget. There's a lady's upset because she's not down the door and there's no answer to move in. Well, what's that to her? She's worried about Mrs. Widget. It's me own flesh and blood I'm worrying about. I've got a right. She ain't home. That's all. Then where is she? She went out shopping. He's lying. She went out last night and he put me out by force. Threatened to do me a mischief. He's done something to her. You mark my words.  Now then, now then. Look here, I ain't got time to stand here arguing.  He wouldn't let me in the kitchen last night. Outside I'd see the blood and gore where he's access to pieces. You go in there. Mr. Widget wouldn't do a thing like that, Mum.  And by the time you're finished, your daughter will be home. Just like Mr. Widget is. That's right. I ain't moving from here till I see her alive with me own eyes. Yes, it's all one with me, but she won't sit in front inside. I'm not having you break up my happy own. He's afraid. He's afraid to let me in. He knows what I'll find. He knows. I'll look at him standing there.  You seem to yourself, Mr. Gormley. You sing last night. You're the law. If you can't be satisfied, who can? I'll ask you. I'll get him. He's got few hypnotised eyes like he had my poor Millie. Talk a winkalore for Billywood, but not Mace. I'm not doing I am. But Mr. Widget, to oblige, let her have a look at that. Well, you'll blimey what I have to put up with from this old gas bag. All right, all right. But it's the last time. Don't say I didn't warn you. Went through the house like a ruddy bloodhound. And there wasn't nothing, not an air out of place. Mr. Gormley followed her with me and I could see it was a very aggravated position for him. Mr. Gormley likes to keep the peace. But by the time we got to the cellar, he was clear out of patience. Well, satisfied? Are you satisfied? You want to look in the cold wind? Go on. Get your hands nice and dirty. This is sorry to have troubled you, Mr. Virginia. Don't mention it. As for you, Mrs. Quill, I don't want to see your nasty face around here until I give the word. You stay out of Millie's and my way, see? And if you don't, I'll have you put in charge. Them's my right, ain't they, Mr. Gormley? In the matter of speaking. Disturbing the peace, Mr. Virginia. Right. And she's disturbing my peace. Now, I'll thank you to leave my house. When you come right down to it, I suppose they're right. In a way, I am a dreamer. Always have things to tell the truth. I ain't got no 800 pounds. Not even 80. I ain't no Eddie Jones. But I wish there was. There's only Millie's mother and Millie. And then greasy hands and cold feet and jaw, jaw, jaw. And if I end for what I'm going to do, it'll be worth it. There. That looks about right. Millie. Millie. Could you come down for a minute, love? In the cellar, please, huh? It'll only take half a mouth. I've got something to show you down here. I've seen it to the bone.  Are they not? You think I haven't got anything to do with that thing? It could air on, love. It won't. It won't. It'll be a good consideration. I'm fair, well-out. I'm sure I'll get the wire put up with it. I'll go with you. What are you doing with my cellar? Why is this old dog up like that? You've gone, Barney. Now, you put every scrap of dirt back in the old, this minute. You hear me? I just wanted to get an idea of the size. It looks about right. What you're talking about? Right for what? For you, dear, which Mr. Eric Snowden starred in tonight's presentation of The Cellar. Next week, the story of a handcuffed man and the woman who holds the key to his freedom. We call it Give Me Liberty. That's next week on Suspense. Produced and directed by Anthony Ellis, who wrote tonight's play. The music was composed by Lucia Morrowick and conducted by Wilmer Hatch. Richard McCast were Jonathan Olin, John Boehner, Betty Harford, Paula Winslow, and Ramsey Hill. This is presented by the United States Armed Forces Radio and Television Service. Forces Network.


Let me try this again, nice and seriously, I'm just going to set this here. For those of you that are wondering why that's there, I'm not going to tell you. I'll let you figure it out. It has absolutely probably nothing to do with the word at hand, which is independent variable. Independent variable is the variable that you manipulate. It is the thing that you want to find out what it has an effect on, right? So you're going to watch behavior, that's your dependent variable, what you watch, what you measure. Independent variable is the stimulus or the condition change that you want to know what effect it has. So if you crank up the temperature in here, it's going to have an effect on my behavior. Temperature be independent variable. I'm betting that maybe there's a reason I put this out on the table. Maybe that's an independent variable. Sadly, I can't measure your reactions to it other than what you put down there in the comment section. But so I don't know, maybe it is an independent variable. Table's not level though, I can tell you that much and for all of you people that are looking at it, leave that alone. Don't bother me there, all right? I don't really care if the table's not level. We're just making some fun and having some entertaining values and making stuff happen for you, which would be independent variables to try to make your education better. Deget my point.


Good afternoon. My name is Sarah Hull. I am the director of a unit that's known as the NHGRI Bioethics Corps, and I am also the vice chair of the NHGRI intramural IRB. And I share a joint appointment, a faculty appointment with the clinical centers department of bioethics. And what I hope to accomplish today, in the next hour, is giving you a very practical perspective on the ethical and IRB issues associated with doing whole exome sequencing research. I want to note ahead of time that I'm possibly going to use the terms next generation sequencing, whole exome sequencing, and whole genome sequencing a little bit interchangeably, realizing that there's huge technical differences between these, but the ethical considerations maybe not quite so much. So if my use of terminology seems a little bit loose, I apologize for that, but we've been seeing protocols that use all of these technologies, and that's been influencing our thinking. Let's see. So I'm not sure how to advance. Oh, the other keyboard. There we go. So the views and the opinions that I'll be sharing with you are my own and not those of any official perspective of the agencies that employ me. That said, it doesn't actually feel quite right to say that these views and opinions are my own. They're very much a product of many interactions that I'm quite privileged to be able to have being here in the intramural program at the NIH. So I want to acknowledge, I want to do my acknowledgements upfront because I think that will help you to understand all the experiences that my comments are grounded in and based upon. First, I want to acknowledge my colleague, Ben Berkman, who with me runs the NHGRI bioethics core, and that involves providing research ethics consultation to our intramural scientists as well as helping to run and provide the infrastructure for our IRB. And so over the last few years, we've had the opportunity to do dozens of ethics consults related to questions that are arising about next generation sequencing research. From the earliest design stages all the way through to dissemination and questions that even come up at the time of publication or attempted publication. Too many of these consultations to count, but those are very much influencing my thinking about all of this and the evolution of my thinking over time. My role with the NHGRI IRB has also been very important and we've been, in a way, we're sort of a specialized IRB. We've been addressing issues related to genetics and genomics for the almost 13 years that we've now been up and running. And as early as 2006, we were starting to think in an anticipatory way about some of the questions related to next generation sequencing thanks to the ClinSeq protocol, which was one of the earliest ones that was starting to try out some of these kinds of techniques. And we've actually spent the last two annual retraining retreats that we run. We run half-day retreats and we've spent the last two dedicated to exploring in more depth issues that had been coming up around next-gen protocols in our IRB. I also want to call attention to the Clinical Center's Ethics Consultation Service, which is one of the roles that I'm involved with as part of my faculty appointment with the Department of Bioethics. Anybody who's here, who's part of the NIH, can call up our paging operator and request to get in touch with the Bioethics Fellow who's on call to ask for a consult, an ethics consult, to help with questions that might come up at any stage in the conductive research. This is a clinical service that's available to you. A number of consultations that I've been involved with through this referral mechanism have also dealt with questions around the ethics of whole exome and whole genome sequencing. I also just want to call out one additional person, Bashali Meskeri, who I know was here earlier. She's a part of the NISC program, and she illustrates the spirit of cooperation and collaboration between those who are working on the ethical and oversight side of things, like myself and the scientists who are at the computer and seeing the subject. She's become an example of a very good gatekeeper when somebody comes and talks to her and wants to set up sequencing at NISC. She knows when to refer them to talk to us about the ethical oversight and review. She makes sure everything is in place before they get too far down the pipelines that you've been hearing about today, and that's been just a really important aspect of our work. And there's many interactions with the other IRBs here at the NIH, as well as collaborators. A lot of my own research program is inspired by the kinds of questions that come out of these consultations, and I've listed all of the various collaborators on papers that are starting to come out about these questions, and I'm very grateful for the opportunity to be able to work on. And so let me get to the point. I think many of you here are here because you have a very basic question. You want to know, how do I get my whole exome sequencing protocol through the IRB? And to draw on David's presentation earlier, I think research in general, protocols in general, are all on a chariot race of sorts. Everybody wants to use this technology, get through the process, do the science, get the paper out, and we really don't want the IRB process to hold things up for sure. That said, I'm going to very politely suggest that this is not the right question to start with. First of all, there's actually more than one ethically appropriate way to do whole exome sequencing research. So on the next few slides, I'm including quotations from a qualitative project that I'm working on with Ben Berkman and others. We just started the analysis, but I have a few quotes from a question that we posed. This was interviews with IRB chairs and staff at three different sites, the NIH and academic medical centers in the Boston area and in the Seattle area. And we asked them about policies that their IRB has, either explicit or de facto policies about the ethics of whole exome sequencing research. And in this case, one administrator said, it's much more case by case. What are the protocols? Who are the people? What's the relationship between the investigators and the people whom they're studying? So here we get the sense that there's not a one-size-fits-all approach for handling this. Okay, another issue is that IRBs, and I'm perfectly willing to admit this, we're all still trying to figure this out. We're really struggling with the ethics of reviewing whole exome and whole genome sequencing protocols. So this quote is from an IRB chair. We certainly don't have a policy, and I don't know that we really have come to a firm conclusion. I mean, it gets discussed every time and there's disagreement every time. So this suggests that within the IRB, protocol to protocol, there are some disagreements. And I'll also mention that from IRB to IRB, even here within the NIH, there are some differences of opinion and different outcomes that we see. So I can feel the sense of frustration welling up in some of you, at least, who are here in the room. Another IRB chair said, we do not have an institutional policy. I think we've gone through several different discussions in our IRB for each specific protocol, but I think we're still at the stage where we hear from investigators what their approach is, and then we decide at the meeting if this sounds reasonable. I included this quote because I hope it gives you the sense that the process is a little bit more constructive, that IRBs are actually quite open to hearing from investigators what a reasonable plan is for their set of circumstances and to review it on a case-by-case basis to come work together to come out with the right set of answers and the right protocols and solutions to the ethical questions. Now, we actually do have a policy here at the NIH in the Intramural Research Program that pertains to the ethical review of whole exome and whole genome sequencing protocols. It's not a very prescriptive policy. It talks about the level of review that's required. So the policy states, since there are ethically relevant distinctions between traditional genetic research and whole exome and whole genome sequencing research, the use of these sequencing technologies must be reviewed explicitly by an IRB and or OHSRP. Now, OHSRP stands for the Office of Human Subjects Research Protections. It's an oversight office within the Intramural Program here at the NIH. So existing protocols will need to be amended to include whole exome sequencing and whole genome sequencing. And this was, this is a policy that was endorsed by a group called HISRAC, which is a collection of all the Intramural IRB chairs as well as higher leadership back in July of 2010. So you might be thinking to yourself, well, what if I already have consent to do genetic research on the specimens that I've collected from subjects in my protocols? This would still require ethical review oversight. It might be as simple as an amendment to add the new analyses to your protocol, but those would have to be reviewed by an IRB. Well, what if I'm only using coded specimens that were given to me from an outside, from an extramural collaborator? Or two would need some kind of institutional review. What if I'm not planning to return any incidental research findings? That would solve the problem, right? Well, that might be an acceptable approach depending on the circumstances, but it's an approach that would still need to be reviewed either by an IRB or OHSRP. So now you might be getting the sense that we're actually proceeding very cautiously deliberately when it comes to the ethical oversight of whole exome sequencing research. And you'd be correct about that, and that leads to another question, which is what's the big deal? What is so different about whole exome sequencing that everybody's taking it quite so seriously? Glad you asked. Here's the now somewhat familiar curves that map out the extraordinary speed in which sequencing technologies are able to generate kilobases and the extraordinary decline in costs that we've been talking about. And what this means is that it's much more efficient, much more accessible to use next-generation sequencing technologies. Investigators are scrambling to incorporate these into their protocols, and it's going to result in much, much more, exponentially more genetic and genomic information being generated about individual research subjects. And it's that magnitude that presses on some of the ethical questions. So in general, my colleagues and I have argued that these technologies don't actually alter or raise new ethical concerns. The concerns that we've been talking about in relation to genetic research, issues around adequate informed consent, how to protect confidentiality, how to minimize risks and maximize benefits and issues of inclusiveness and fairness, these are all still stable and intact and still apply to whole exome sequencing research. The issue is that because of the magnitude of information that's going to be generated, this will in turn magnify and make more concrete many of the concerns that were relatively hypothetical or theoretical until this point, and it's this that has implications for how we conduct ethical review of whole exome sequencing research, especially in the context of the regulatory framework that we're working within. So I think that these, the ethical issues that emerge from this context can be sorted out into three general categories. There's issues related to the management of all of this information and specifically what we do with individual research results. Both those that are considered to be primary or research related results as well as those that we've been calling secondary or often people refer to these as incidental, in other words incidental to the core research questions being asked. There's also a lot of interesting and challenging questions around the ethics of broad data sharing requirements and how that will play out in the context of large scale genomic sequencing. And then important questions to ask about the content of informed consent and whether it's adequate to cover all of these new kinds of plans and issues. And in some cases perhaps whether re-consent, re-contacting people and giving them new information might be required. So this is going to, I'm going to use this framework to organize the remainder of my comments this afternoon and I'm going to focus in mostly on questions around incidental research findings, incidental genomic research findings and whether or not they should be disclosed to participants because this is really where some of the most challenging questions have been coming up for us and where we've been spending a lot of time and effort in our work with investigators. So just a couple of conceptual clarifications in the world that we've seen shift in the last 13 years from a candidate gene targeted approach to genetic research to now next generation sequencing. A couple of our assumptions have changed. So an existing assumption is around traditional genetic research is that it will produce relatively few clinically significant incidental findings. It would be relatively rare to see these in the context of research and our revised assumption now that it's not so much a question of whether we're going to see clinically relevant results emerging from research and how many and of what character they will be in individual participants. A second assumption that I want to put out there that we've had is that it's actually really easy to distinguish between so-called incidental or secondary findings and those that are explicitly related to the original study hypothesis or disease focus and I think as research evolves over time and as we get focused on broader models of genomic medicine I think it's at least arguable that research that uses next generation sequencing is going to blur the distinction between what counts as incidental and what counts as related to the research. It's all going to be there and related to the research in some way and this distinction might become less meaningful over time. A third assumption is one that I've, and my colleagues informally refer to as don't look, don't tell. I understand that phrase is now available and what it refers to is that researchers generally, the idea that researchers don't have an obligation to be clinicians and to affirmatively search actively for incidental findings in their data. This was put out for example by Susan Wolfe and her colleagues in some of the very important papers they wrote early on about incidental findings in genetic research. The first assumption is that the nature of this technology makes it such that the act of looking for all possible results becomes much more practical. It's all there and very sifter. You just enter in the variance right into a computer program and it's a more fundamental component of the analytic approach. So it's going to be harder to tell people that you can just avoid, avert your glance and not see the incidental findings that are right there in the computer before you. This leads to some really interesting questions. The fundamental question here is whether all of this new technology changes the scope of the obligation that investigators have to disclose incidental genetic research findings. And I want to give a very cautious view on the answer to this question that I think that there's an emerging consensus that yes, there is some obligation to now be actively and deliberately disclosing incidental findings of genomic research to subjects, at least sometimes and in certain contexts. And that seems to be a trend that I'm seeing here across the NIH and that bioethics colleagues elsewhere are also talking about. So this represents a paradigm shift in how we think about incidental findings. And so given these new technologies, what does this mean for IRBs and how we review investigators' protocols and their approach to managing incidental findings? What I'd like to do now is present you with a case to chew on. This is a composite of a few investigators who have come before our IRB, but it's very realistic and grounded in their actual experience. So I'm going to present you with how they approach their protocol and I'm going to present you with the specific concerns that the IRB raised in response to the proposal. And hopefully that will illustrate for you how this is playing out in practice. So our investigator, and I call her well-intended, but I want to emphasize that everybody that I've been talking to is very well-intended here and wants to do the right thing, even while they're really enthusiastic about incorporating these technologies into their research. So I don't mean to single out that feature, but just to highlight it and be grateful for it. So a bench scientist, a PhD scientist who studies a common complex disorder and it could be cardiovascular disease, it could be diabetes. That's not quite so important, but to understand that it's more common might be helpful. This investigator wants to collect samples prospectively and to use whole exome sequencing analysis to help pinpoint some of the variations that they're interested in. The protocol that she puts together involves a one-time blood draw here at the clinical center. And the intention is that there's not going to be an ongoing clinical relationship or even research relationship between the subjects and the researcher team. And although the researcher's done a good job of partnering with some clinical investigators and certainly is working within the clinical center, there's nobody directly on her team who is a clinician and very relevantly, there's no genetic counselor that she has access to or counseling resources immediately at hand as part of this protocol, nor any funding to be able to bring one on board. And she very much wants to do the right thing, but is conflicted and a little bit ambivalent about what this actually means in practice. So she does her best to put together a protocol that tries to straddle this balance between disclosing results and doing it in a way that is practically feasible. So this is submitted to the IRB, and the IRB returned with a couple of comments in the category of whether or not the investigator should be engaged in disclosing incidental findings. The IRB felt, picked up on the fact that the protocol didn't clearly and consistently address the study procedures and most importantly the plan for providing genetic findings to subjects. And what they were picking up on here is the consent form and the protocol weren't exactly consistent with each other and even in the consent form it tried to both say that this probably wasn't going to happen but might happen and they were concerned that it just wasn't a coherent and internally consistent plan. The IRB went on to say that it's the decision of the investigator to determine which genetic findings will be returned to subjects. So this was in effect saying that the investigator has latitude to figure out what it is that they're going to be focusing in on and needs to come back to the IRB with a reasonable plan. So we didn't want to, there is no set list of variants that we could provide the investigator and it was up to her to come up with a plan to figure out what that was going to look like and come back to the IRB. Some other issues that came out around informed consent. The investigator has a duty to inform subjects clearly during the consent process about the possibility that using these techniques the study itself may identify genetic variants that could be of relevance to subjects but only some of which would be of known clinical significance. So it need to put out there and inform people that stuff is going to be learned basically through these techniques and then the consent form would also have to address whether or not the subjects would be provided with any of these results or perhaps if they would be given a choice about whether or not they wanted to be recontacted and to receive some of these results. And then some other issues as well. If a decision is made to return results they would have to be confirmed in a CLIA certified lab and that they would have to be disclosed with appropriate counseling available to the subjects. And the IRB suggested to the investigators they look into whether their institute, their home institution and or the clinical center might be able to provide some support in the area of genetic counseling consultation. So this came to the investigator in the form of a series of recommendations. The original protocol was tabled and this does happen and the ideas that the investigator can go back incorporate those suggestions and come back to the IRB and receive a full review. So the investigator did that, consulted with the bioethics core about the plan and then resubmitted a revised, a dramatically revised protocol to the IRB which was quite consistent about a plan for disclosing incidental findings and provided some criteria about what clinically relevant might look like. And the protocol also made clear that it was expected that the number of variants that would realistically be identified and disclosed were quite small and this was reflected in the consent form in a consistent way as well. So this time the protocol was approved but with a series of stipulations that still were attached to it. The IRB still wanted more specificity about the process that would be used to review incidental findings to determine which ones were clinically significant. And based on the IRB's review of other whole exome sequencing protocols it made a recommendation that the investigator might want to consider putting together a multidisciplinary committee and this committee would be used to review the variants that emerged in the analysis and help to determine which ones were actionable and would rise to the level of something that ought to be disclosed to a subject or at least that they'd be given the option of receiving. The IRB suggested that this should... The committee should include a broad range of expertise including medical genetics, genetic counseling, ethics and the IRB perspective and it also pointed out that this review should be occurring before any decisions are made about which variants should be confirmed prior to disclosure. And this was in part because we had a sense that the list was going to be a lot longer than the investigator was assuming. So the IRB also felt that it would be beneficial for the investigator to talk to some others who have been involved with this kind of research. People that we've been hearing from today, people who have been dealing with this and know a little something about how to interrogate the sequence data that they're generating for clinically significant variants. And the IRB also commented that their experience... The experience of these other protocols is such that probably a larger number of incidental variants would be identified as I just mentioned. It's really interesting for me to take a step back now and look at that last bullet point because I think maybe as an IRB, our own IRB has shifted somewhat in its thinking about this issue over time. It's clear to us now that the number of incidental or secondary variants that's going to be generated really depends on how hard you're looking. And I think Jennifer's presentation just before gave us a sense of how possible it is to find incidental variants that might be of clinical significance, but also really how complicated it is at the same time. And I think the IRB has developed a more nuanced perspective on this question since these comments were made that suggests that we're not quite sure in different studies we think different amounts of looking might be happening and might be indicated. And so we've seen some more variation in how investigators are now proposing to handle the how hard should we look question. So I hope that gives you a little bit of a sense of what themes are coming up at the IRB. What are some of the principles and what are some of the questions that we're asking? I highlighted the example of a PhD scientist to show that not everybody doing this is trained in the field of medical genetics and maybe we'll have to draw on the expertise of others. But I think some of the same questions and issues that I raised that the IRB raised will apply to other kinds of studies as well. Now what I'd like to do is take a step back and just look a little more deeply into what is behind some of these IRB concerns? What ethical principles are at stake and why is the IRB so concerned about some of these questions or why this is also complicated? And there's good sound ethical arguments in favor of disclosing incidental findings and arguing against such disclosure. And that's the nature of bioethics, the nature of a true dilemma. My colleague, Frank Miller, who's a faculty member in the Department of Bioethics and one of our past fellows, David Shallowitz, argued that an obligation to return findings is grounded in the principle of respect for persons. So they said it would be disrespectful to treat research volunteers as conduits for generating scientific data without giving due consideration to their interest in receiving information about themselves derived from their participation in research. So some of what's behind this is the idea that there's some genetic information that's actually quite important, quite relevant. And if somebody had it in their possession, it might enhance their decision-making. It would enhance their ability to make autonomous decisions about their health and other life considerations. And also, I think what's embedded in this argument is an idea that returning results also recognizes and sort of repays a participant's contribution to research. There are a number of other arguments that are made in support of an obligation to return genetic research results. The principle of beneficence, the general idea of doing good, of doing something that's beneficial or sort of raising the prospect of benefit of participating in a study. The notion of reciprocity, the idea that is actually related to the point on the last slide about giving participants something back, recognizing their contribution and realizing it's fair to give something back if you can. The principle of justice, it's a little more of a nuanced point, but it has to do with the idea that some of our research participants are going to be in categories that are considered more vulnerable. They may have less access to health care resources. And if they're in a study where it may be their only access to certain kinds of services and certain kinds of information, that might heighten the obligation for us to disclose what we know because we can't reasonably expect them to be able to find out this information somewhere else. So a principle of fairness would say we might treat certain populations in a particular way and we might give them certain kinds of information as a result. The principle or issues around investigator integrity and professional responsibility, I think of these as having to do with what some medical geneticists have described to me as the feeling of wanting to be able to sleep at night. The idea that if they're engaged in this research and they know enough to know that what's sitting there on their computer is actually relevant to somebody's health care, they think it's a matter of professional responsibility to make this information available. These are often going to be investigators who are playing a dual role. There's a dual aspect to their profession and a research aspect, but the clinical aspects tug at them and would keep them up at night, and this is what drives their sense of obligation to return some findings. Okay. So on the flip side, some arguments against an obligation to return incidental findings. So there are some who dispute that these principles that I've just described, beneficence, respect for persons, atrocity and even justice, they dispute that these are violated by a failure to disclose or a lack of disclosure. They will emphasize that the core purpose of research is to generate generalizable knowledge. Research is different than clinical care and we shouldn't be in the business of recreating a clinical setting. And in fact, there's risks of doing so that conflating research and clinical care to do things like lead to therapeutic misconceptions where people start to expect more from the research environment than perhaps they should. We perhaps also don't want to overestimate the value of some of these results to individuals or we at least want to be really sure that they're of the sort that are clinically relevant, actionable and meet certain criteria and that many emerging results will not. A whole different set of arguments is made around practical considerations such as resource limitations. It is very resource intensive to do the sorts of analyses and disclosure that you've heard described here. It requires lots of technical expertise, lots of access to bioinformatics tools, access to counseling resources, the ability to pay for clear validation and we all know that we're operating in an environment without overflowingly abundant resources. We're living under resource constraints and so there might be some practical considerations that weigh against our obligation to disclose incidental findings that we have to take into account. At the very least, acknowledge that more resources are needed to be able to do this well across the board to be able to extrapolate from the ideal models that we're hearing described. So many have attempted to develop guidance and to sort of assimilate all of these competing values into a set of coherent principles that will help us figure out what do we actually do with all of these different commitments and obligations and as you can see there's actually quite a few guidelines out there. There's the NHLBI guidelines which are very commonly cited and were referred to earlier but there's a lot of other approaches out there as well. And when you look across all of these approaches they do have some common features. So they do come up with a generally consistent set of factors that should be applied to figure out which kind of results are the sort that generate an obligation for disclosure. So the characteristic of analytic validity, we want to make sure that this is an accurate, a real finding. Clinical relevance, it should be related to something that's actually important and relevant to one's health and healthcare. Actionability, the idea that there's something that can be done to alter the course of a negative outcome whether it's a therapeutic intervention, screening procedures, perhaps a different reproductive decision depending on what kind of a result you're talking about. And a fourth feature of almost all of these guidelines is that a result should be desired that individuals should be asked whether they want this information and that their decision about whether or not to receive it should be respected. But there's disagreements across the different guidelines as well. One area where there's some considerable disagreement is the level of clinical relevance that we should... What is the threshold? Where is the cutoff between clinically relevant and not? And there's different ways that this gets defined and debated in all of these guidelines. There's even disagreement about this question of desirability, whether we really want individual subjects to actively consent to receive all kinds of results. There may be, some people argue, there may be a lot of results that are just so important that it wouldn't be reasonable for somebody to say they wouldn't want them. It's a life-altering result, an easy intervention that would change the course of their health outcomes. And we might override their right not to know or override their interest in making a decision and say, no, you have a duty to disclose that. And there's a lot of debate about that very question at the moment in the bioethics field. There's a lot of questions about analytic validity and what the standards are there. There are some people who question whether CLIA certification or clinical validation in a CLIA-certified lab is required. Now, it would be irresponsible of me to suggest that that's actually a valid question to ask here at the NIH. It is our policy, it is a policy out there that we follow here at the NIH that, yes, if you are planning to disclose to a research subject any kind of clinical result for that matter, it does have to be confirmed in a CLIA-validated lab first. But this is an area of debate that's out there and whether this is an appropriate or even good enough standard in some circles. Okay, so up until now, I've been talking about the ethical arguments and guidelines about the kinds of information, the kinds of genomic information that might generate an obligation for disclosure. But there are some additional layers that I want to throw out there and encourage you to think about that have to do with contextual factors, either about the study characteristics or population characteristics that might alter our obligations to disclose incidental findings. So some of these factors have to do with the nature of the study. Is a clinical trial a treatment intervention where somebody is coming with a hope and expectation for some kind of benefit? Is it a natural history study? Is it a basic science protocol? And do these purposes have some influence on expectations? Study resources. What resources are available? I've already hinted at this. Are there adequate resources for appropriate counseling and confirmation? What's investigator expertise to be able to do the right kinds of analyses? What are the aims of a protocol and what counts as incidental to those aims? And other practical considerations like how long has it been since we've been in touch with these subjects? And can we recontact them? Do we have current information if we want to follow up with them and give them results? And then some factors related to subject characteristics. And again, I've also mentioned many of these. Do they have alternative access? Are they on this particular study for care and for information? What degree of vulnerability does a particular population have? And another interesting question. What's the depth of the relationship between the subject and the investigator? Is this a long-term study where there's repeat follow-ups where they're going to have multiple opportunities to talk about some of these issues or is it a one-time interaction? Is this somebody known to them or somebody who's a stranger to them? Or is it a secondary and tertiary user of the data or samples as they've been drawn out of repositories? And how does that bear on the ability and obligations to disclose? So I want to go back to a question that I raised earlier, the question of what, if I'm using coded specimens that were given to me by an extramural collaborator? Okay. And I have a different case study that I developed around this. I identified a source of clinical samples from patients with a rare condition who are being seen at University X. And the samples were collected under University X's IRB. They were collected with informed consent that that IRB approved. They're planning to code the samples and effectively they'll be de-identified to you. You won't have access to patient information or any other patient names or other identifiers. And you want to proceed with whole exome sequencing and so you set up your planning meeting with NISC and Bashali over at NISC asks you, do you have appropriate institutional approvals from an NIH IRB or from OHSRP? Good question. So if you are using coded de-identified samples, it's true that you might not need IRB approval from an NIH IRB, from your own institution. And this is because under current regulatory guidance, current interpretations of the common rule, which is a set of rules that governs the conduct of human subjects in this country, if the use of data that's considered to be de-identified is not considered to be human subjects' research under certain circumstances. And because of that, it's not subject to IRB review and other oversight requirements. However, you don't get to make this determination as an investigator. This determination has to be made by the NIH Office of Human Subjects Research Protections. Some of you might be familiar with an acronym OHSR. In the same office, they recently added the P for protections to their names. So when you see these acronyms, they're interchangeable and they mean the same thing. And you submit a request for review to them through a form that they have available on their website, which I've made available here. And this connects to a second part of the NIH Intramural Policy that I mentioned earlier. It states that investigators requesting OHSRP review of whole exome sequencing research activities will be asked to answer a set of supplemental questions to allow for enhanced OHSRP review. So the idea is they were concerned that it would be inappropriate to quickly approve under current regulatory guidance the use of whole exome sequencing technology in protocols here without looking closely at some of the ethical considerations that I've been talking about, because there's still a whole lot of information that theoretically by somebody could be connected back to an original research subject, and so they wanted to be able to look at this a little more closely. So here's a sampling of some of the questions that OHSRP is interested in. They want to know whether an IRB or an ethics committee somewhere has looked at this proposal and has approved the conduct of whole exome sequencing research, for example, with a set of samples. So if another institution has done this and is okay and has signed off on it, they will be reassured that somebody is paying attention to these questions. They also want to know whether it's possible that results from the proposed analyses will be returned back to subjects at that institution, and what this boils down to is they want to make sure that you and your collaborators have a clear plan in place for managing incidental findings. They also want to hear about any plans to deposit sequencing data into broad database sharing for data sharing purposes such as in DBGAP, the database for genotypes and phenotypes. They're also interested in knowing what kind of consent, if any, was ever given. And based on your answers to the questions on their checklist, they might ask you to go back to an institution and get some more information. They might approve it based on what you've submitted and say you don't need any further review here, or they might actually decide to send you on to an NIH IRB to have this looked at more closely than they're able to do. That provides a nice segue out of questions around incidental findings and into another topic that I'd like to cover, which is whether NIH data sharing policies apply to exome sequence data. The answer is possibly. And if I had more time to work on my slides, I think I would have revised this and said probably. So some of you might be familiar with the NIH GWAS, Genome Wide Association Study Data Sharing Policy. This is a data sharing requirement for all NIH-funded GWAS data that says there's an expectation that these data will be deposited in a repository like DBGAP or that investigators have to come up with some kind of alternative data sharing plan, either a different kind of a database or some other procedure for being able to collaborate with other investigators and share these publicly funded resources to help promote research. And we've heard, I think, in a lot of the talks earlier in the day, the value of this, how much of the information and comparison and reference data comes out of things that are available in databases like DBGAP. And so this is a very important principle. It promotes good ethical stewardship of resources and efforts to expand this policy to apply to broader genomic data types are underway. There's a committee looking at how this policy ought to be applied to broad data sharing. It hasn't yet been implemented. So there's not yet an across-the-board requirement that NIH-funded sequencing data has to be deposited into something like DBGAP. It is already happening and many programs have this as a requirement of their individual studies. Many investigators are starting to think through what a requirement like this would look like and how it would play out in their protocols. And I think this is a very good thing. I think we should be anticipating the probability that there will be some expanded data sharing requirements that will apply to whole exome and whole genome sequencing data. The way that this works at the IRB, when an investigator realizes that he or she is interested or required to deposit their GWAS data or exome and genome sequencing data into DBGAP, the IRB is asked to certify that the protocol and the consent form has taken several issues into account. They want the IRB to certify that the consent process covered the idea of broad data sharing and that research subjects are aware that this is happening and have given their approval. They also want the IRB and the institution to certify that appropriate confidentiality measures are being taken to de-identify the data that are being deposited, as well as that consideration has been given to minimizing risks in general to individuals, to families, and to communities as a whole. And I want to throw out there that there's another interesting and complicated question about how we think about the management of incidental findings that might be generated through secondary users of the data and whether there's an obligation to communicate back through the primary researcher these results so that they can sometimes, maybe in some very important cases, be disclosed to subjects. So I guess my advice or my encouragement is that, what I would say is that this process of certifying data for depositioning to DBGAP works best when investigators and IRBs have already anticipated that this is a possibility, when investigators have language already in their consent forms that addresses data sharing so that they don't have to re-contact subjects and get their re-consent around that issue and that the protocol has anticipated it that an appropriate level of engagement has taken place many steps beforehand to certain populations, certain communities will have strong opinions one way or another in favor of or against the idea of broad data sharing and figuring this out ahead of time is very useful and so I want to encourage investigators to start thinking about these questions in relation to whole exome sequencing to move on from the context of genome-wide association studies and it may be the case that there are some novel issues that come up. It might be harder, for example, to de-identify whole exome sequencing data. It might not, but I think it's very important that we're having this conversation at this point in time. Just a few comments about approaches to informed consent we're about to have a talk that I'm very much looking forward to from Julie Sapp, who is the expert, the in-the-trenches, has done this, knows how to do this expert on talking to subjects about these issues but I want to give a couple of framing comments about how IRBs at an earlier point in time have been thinking about informed consent. So there's a few elements of informed consent that I think can be highlighted as being specific to whole exome sequencing. So in general, just the broad scope of the analysis and the kind of results that are going to emerge and also the potential, the kinds of findings that might emerge, this is something that hasn't traditionally been covered in consent forms that may be relevant to an individual's decision making and might be something they would want to know as part of the consent process. More specifically, they are almost certainly interested in knowing whether results will be disclosed to them, whether they're related to the research question being studied or incidental to that question to the extent that that can be distinguished and whether or not they're going to be presented with choices and how to navigate those choices. This is a new element of informed consent that whole exome sequencing process to think about. And then the issue I was just talking about, plans for any data sharing of this sequence data and what the implications of that are to subjects. And there's some interesting questions about previously collected samples. So if somebody is enrolled here on a genetics protocol, they've been given some amount of information about genetic research and the attended risks and disclosure and so on. Is there a time and when is that time that they're going to need more information and give updated informed consent to anticipate in the expanded analysis? And a couple of things I'll say about that. I've been seeing a lot of reconcent going on. IRBs are asking investigators to get reconcent. And many investigators want to do this. They want an opportunity to talk to subjects again when their prior informed consent didn't anticipate these kind of issues. And I'll say that I think this is especially true when there are now more robust plans for the disclosure of incidental findings. But I would also say that this comes up even in protocols where there's a deliberate plan not to disclose findings. There's investigators and IRBs who still want subjects to know that the information is going to be there and maybe there are good reasons why they're not going to receive them. And then, again, choices about broad data sharing is another relatively new aspect of consent that many people are now anticipating is important in getting reconcent for. And what I've been seeing, I think that there's really three emerging models, three different kinds of protocols that are being approved here at the NIH. I can't speak as well to protocols that are outside of the intramural context. But there are some studies that have been approved where a very clear plan is articulated not to disclose incidental genomic findings to individual subjects. And the consent or a reconcent process actually covers this explicitly. Where I'm tending to see a cluster, the most studies that are being approved right now is something a little bit in the middle, a middle ground approach, where there's some limited commitment to providing incidental findings to subjects under very carefully specified, but relatively rare, certain stances. And then we're also familiar with approving proposals with very robust plans for the disclosure of findings. I apologize if some of that wasn't audible. The third kind of protocol that we're seeing, that we're comfortable with and that we've seen approved, features a very robust plan for the disclosure of findings and very detailed and often multiple time points associated with the informed consent process and a description of how subject preferences will be solicited over time. So as I was saying, what I'm seeing more of is a migration towards something in the middle, an emerging but limited obligation to, or a sense of obligation and plans surrounding this for the disclosure of incidental findings. And so I'm going to leave you with two main take home messages. If you've just tuned in now, the two most important things for you to know. In answer to the question, can I go ahead with whole exome sequencing based on protocols and consent forms that I already have in place? And the answer is no. The answer is not until you receive some level of institutional approval from either an IRB or OHSRP. But in addition to institutional approval, you should also be familiar with the many resources for consultation that you're able to draw on beyond this course, ethics consultation, the bioethics core, your colleagues who you've heard from who are all extremely generous about sharing what they know. It's useful to draw on the resources that we have around us as you put these plans together and submit them for approval. Okay, second take home message. What are the key things that an IRB or an entity like OHSRP is going to be looking for? And the answers are threefold, I think, that you and your collaborators have given thought to a plan for managing incidental findings that's coherent, internally consistent, takes into account things like your expertise that you have available to you, resources and subject expectations and contextual factors related to your study. And keep in mind that the IRB is open to hearing an account of what works in your particular circumstances and in working with you to figure out what the most ethically sound approach to your study is. A second thing that they're looking for is that you're starting to think about data sharing plans and what implications that has for your study. And third, we want to make sure that the informed consent process that either was in place or that needs to be in place reflects these various plans that you've developed in the context of a whole exome sequencing protocol. And the bottom line is this mostly has to do with expectation management. We want nobody to be surprised in any of this. We don't want an investigator who ends up with a result that they weren't expecting and is losing sleep over what on earth to do with it without having had the benefit of thinking this through ahead of time. We don't want subjects getting cold calls from researchers they've never heard of who are accessing their so-called de-identified data hearing about results that they weren't anticipating. We want everybody to go forward with as much advanced preparation and thought. And I guarantee you that there will be questions that come up along the way. That's why we have an ethics consultation service and we'll continue working with you on how to manage these questions. But we hope that we can help anticipate some of these problems and come up with ethically sound frameworks for doing whole exome sequencing research that starts to anticipate some of these challenges ahead of time. Thank you.


Nothing shall be given in future for the writ of inquisition by him who seeks an inquisition of life or limbs. Instead, it shall be granted free of charge and not refused.


Hey guys Today, let's make some eggs There's a couple in there I'll show you what we're going to do with them. Okay guys. We're going to boil all these eggs.  I learned a long time ago Wait when you're using like 12 eggs Get you a tablespoon of sugar and put it in there now what that's going to do is That's going to make the egg cells eggs of eggs shells softer so Lot of bubbles coming up off of them. So hopefully they're not already cracked But anyway, we're going to be making deviled eggs now over here. This is monkey supper I'm making some hot wings and they're huge, but this is about the eggs So we're going to let these boil and then I'll show you What else helps make the egg shells come off easier? So stay tuned. Let's let these boil Okay guys, I've got my eggs boiled Now I've strained them in this strainer. Now what I'm going to do is I'm going to put these Into an ice bath to cool Okay Now I'm going to let them fully cool Let them get all the way cool. So we'll give it a few minutes and Then we'll come back and we'll go ahead and peel them. So Stick around Okay guys, they have cooled down. It's been about 10 minutes. So let's see how well these These will peel for us That seems to be a lot of problem for a lot of people including me, of course, I'm not a chef but to have them peel and Without Getting them all messed up, you know, especially when you're doing something like this So like this one here is a little bit of a problem, but once you get past the membrane You're okay, but you can see they're kind of nicked it a little bit, but that's okay We're not We're not really in a culinary arts here. We're not going to try to show these off We're going to eat them now.  I hate that to be continued stuff Well, it's not really to be continued because that's a That's a totally different video in itself But you'll know why I made so many on this video. See I kind of ripped out one But monkeys in bed sick So she I've got to I've got to service the transmission tomorrow on the truck So I figured since she's probably not gonna be able to go to work tomorrow I'll go ahead and do that tomorrow and I'll do a video on that But yeah, I need service to slip it. I don't know if it's gonna help it any but I mean, you know See that one kind of got ate up a little bit, but Thing of it is is, you know If it don't help at least we tried, you know, we've got a 50-50 chance That would help and either way if we don't do anything.  So Anyway, these eggs are not peeling very well But sometimes you get eggs like that and then sometimes you get eggs that just Just fall fall right up right apart But anyway, when you put the sugar in it does help it. I mean I can tell a difference on it so And I'm sure you guys got hacks that you can do and that helps out for you guys and stuff. So Really, there's no right or wrong way. Just you got to peel them. So I'm gonna peel these up and Then we're going to cut them in half Okay, now I boiled these for 15 minutes As you can see they're coming out pretty good. See they're Sometimes they won't fall out like that, but that's a good thing.  I didn't eat my spoon. That was just in case I had to Dump them out there. Okay. Let's get on to making this stuff. Okay Now we're just gonna we're gonna smash this up We're just using a fork. What I do sometimes when I'm making this many I'll actually use the beater Or beater yet, but the mixer, you know Like the cake mixer thing just But I'm not gonna do that right now.  You don't want it too thick, right? Kind of like maybe a some coarse sand But that's up to you. How fine you want it and all that, but okay now our ingredients a Lot of people like to put a couple drops of hot sauce in which we're not going to do because we're having hot wings for supper tonight And some people will put a shenny you can do that. We're not gonna do that We're just making plain Jane and so what we're gonna needs we're gonna need mayonnaise I guess you can use your miracle whip if you want. We're going to use some mustard It's best if you use Dijon gives it more flavor, but that's okay if you don't have any I don't have any So we're just using the yellow mustard over I like to use apple cider vinegar But I don't know if I've got enough vinegar or not. So I'm going to use this with it just in case But now what I usually use Now these measurements aren't perfect, but say like about three tablespoons per six eggs We've got 18 eggs in here. Well, actually we have 20. I had to give two to monkey because I destroyed him But we've got 20 eggs in here. So let's call it 18 eggs so We're going to need nine Tablespoons of this and we have a tablespoon right here. So and like I said, don't have to be perfect Most of the time I won't measure it if you want to go buy like this this type of measurement and then and then go by go by taste That's fine, too. Now we've got teaspoon. I'm going to use three teaspoons of vinegar Which I would use one teaspoon per six eggs. So I'm going to use be. Oh, we may have enough. There's one. There's three. Okay, that's good enough Now we're going to use one tablespoon of mustard per six eggs to Like I say, usually you don't measure but this way it's just giving you an idea to go by You start with this you want a little more mayonnaise add a little more you want a little more mustard vinegar at it You know, it's it's your creation. This is just kind of just base You know just you know what I'm talking about All right, so there's that now We're just going to mix this up like I said some most of the time. I'll just shoot all I'll use a mixer for this But and you can add salt and pepper if you'd like This will go on afterwards This is paprika, but I'm going to use smoked paprika. Like I said, we're not going to this is not going to be a presentation Yes, this is just this these are eating eggs. They're not to look pretty and you'll see why In the next video We'll fill the eggs up with our with our stuff now what you can do is you can use a baking pipe thing You know a paper that you You can do that. You can also I'll show you what else you can do. You can take a baggie Now it's best to use like a Ziploc bag This is just a little sandwich bag and I'll show you You just want to fill this up fill your baggie Get a kind of fool. I know most of you guys probably already know this but for the people that don't or you know I do have a younger crowd that watches as well. Sorry that watches as well So maybe they're you know, they're just learning to cook or whatnot. Okay. Now you're gonna take that I Made mine a little messy Because I don't have the right baggie, but it's kind of go like that and you're gonna want to Just trim your end off Jesus Christ Just trim your corner piece off and just squirt it squirt it in there and messed up on that one Okay, it tastes about right Little sour, maybe Maybe I should have added some more Oh I might have maybe should have added some more Maneys to it, but but it's okay, and you just do that now. I'm gonna go ahead and fill these up Then we'll show you what they look like Okay guys, so in a nutshell, that's pretty much how you make it. It's like I tell you it's like anything else use You know use your imagination do use what you want to use and however much to the flavor that you like, you know Like I said, it's not for presentation. I usually make them look pretty If I'm taking them somewhere, but like I said, this is just for you. Whoa This is just for eating. So we're just gonna put a little paprika.  So it's so this if you want Like to a barbecue or something. That's that's the stuff you want to take the smoke the smoked paprika. Okay, so there you go Okay, guys, so there you go. That's Pretty much in a nutshell that's the easiest way to make Deviled eggs. That's the quickest way. Like I said, you can get creative. You can put whatever you want in it Like I said, you can you can you can use horseradish instead instead of the the mustard or you can mix a little bit of both Relish you can put a little hot sauce in even a tiny drop of barbecue sauce for a barbecue You know what I mean? Then use your smoked paprika. It's a good hit. I've done it many different ways But this is just you know standard way to want it and No, I'm not going to taste test it You got to watch the very next video following this one for me to taste test this and you'll see why When you watch that video, hopefully you'll watch it. So please come back. All right guys So there you go. Shea bearer the myth man legend. I am chef Shea bearer, but I'm not a chef Just a little play on words there. So All right guys. Thanks for watching appreciate it. There you go. You're deviled eggs. All right So y'all have a good one. Take care. We'll see you soon. Bye. Bye


Yeah, but I grew up in a facility in Tucson, Arizona. They ran some tests on me, they gave me sororities. Oh, that's fun. One day, I thought, well, childhood, just like reading my own book. And I just thought about it really hard and then ended up hearing right now. Oh, oh my God. Yeah, okay, okay, okay. It's so human, do you know what you're saying? Yes? No, no, no, no, no. Fire, the wired machine over there. What? Excellent, excellent. Oh, no. I'm chilling. Yeah, Joe. You're looking very handsome. Why are you hiding that from us for an entire month? Because... It's funny. It is funny. It is funny.  I'm doing the wasting time. Since you hadn't been coming out, apparently, you weren't able to expedite the process? I've been working on my redemption art and I actually think that it's quite good now and that could be the hero of the day, so it'll be fantastic. Everything's always about this art. Maybe think about the greater good and the others around you for one star. But do we really got a greater good? Yeah, greater good like punch and sharks. Yeah. Thank you. Thank you. There's greater things at stake here, man. There's got things to figure out. You've got to stop thinking about everything else when people have their own problems. People have their own concerns. But at what point does a single person's singular problems outweigh the entire humanity? But when does a singular person's problems possibly have the solution to everything we're trying to find? You know, if you stop thinking to me like a human and you thought of me more like a god, then I think that things would be a lot more difficult. Well, maybe if you had thought about us like a community rather than your independent contractors, we would have been able to help you out and get out of this place soon. Thank you for your feedback. Can we continue? Let's go.  So true, Bestie. Ah! Fantastic. Yes, we do. And like that, I need to find some humans here. I've got some. We've got to use some of them. I mean, we've all got some. I mean... Put a hair. A hair. Yeah. A hair. From who? I could take spit, but I feel like that's a no-no right now. Yeah. Yeah. All right, well, just do more. All right, good. Good, good, good. There you go. Can you grab that little magical machine? Yes, I do. Don't worry about it. I'm so sorry. I'm so sorry. Hello. Hello. Hello. Hello. Hey, man. Hello.  Oh hello. We don't need to enter on you. We don't need to enter it on you.  We will see you soon. Let's go. Okay, alright, we will see you soon. So the current proposed theory was that any anomalies created by the Ikea would be kind of a cover-up in and of itself. It would try to blend in but not have a perfect story and so we were trying to screen for stories that with inconsistencies or vague ideas. That was pretty much my investigation. Um so the big one I was assigned to do was find like some specific memory not just like I mean I try to get to know everyone but kind of find a specific memory from before or just before you got into the Ikea. Everyone's checked out. One person I don't want to point fingers but I think we should use the little camera on them. Who is it? Hi Ren. I don't think we talked a lot. Whoa whoa whoa. It's a good idea. Anyway, let's watch it. What? It's a grenade. What are you making over there? It's just a simple mason jar. Mason jars sir. How are you able to scan her? What am I searching for slow? Check for mason jar. We have one scan left. Bad feelings about mason jars. Yeah. I started them all at the time. Okay I'm trying. What do you think what I do? This is your fault. It's your fault. Mason jar glass container. Bingo. When you use the whole physical objects to place no unusual properties however the owning entity may store concepts or ideas into the jar through a poorly understood process. So there's an idea inside that jar. That's where intelligence went. It's like a toy. She wanted to play with it. There's nothing wrong with that. Don't think so for the last time. But because you had an anomalous object on you, I don't know if my read was thorough and I don't have any other tape to check again. So Ren, you're in the clear now. What up mate? We're going to find more tape. He said that he used the last of it. Did you not? I had one last sample. Yeah we had one last sample. Can we turn the underwear back into tape? Back to work. Come on. Have you stubbed your toe yet? Awesome. I've been on in here. You'll get an opportunity to eventually. Don't worry about it. Do you even have like memories? Like before you were born? Like were those fabricated? I think I was a comforter and then I became a staff member. And so you don't remember me at all? Yeah. I was having a relationship at all. I remember I had the sense that there was somebody who made all of us and I guess that's you so that it kind of makes you my dad, right? Interesting. What do we think about this logic? I think it does follow, but I think you'll want to put in your thoughts of how you think about this. Come on, Daddy. Okay, yeah. I have been a father before. And I at one point in my life really wanted that to happen for me. But that was 130 years ago. So you saying that you want me to be your father, your daddy, that's a lot to hear right now.  How old are you? I don't think that's true. It might be. You were just born out of the ether one day here in this Ikea. It's been around for 10 years. I'm responsible for that again. Yeah. He's just a little guy.   I guess. Yeah, I will. Let's do this. Let's do it. We're going to help you.  I get it. I didn't have a pair on myself. I would have liked that. You got it. There you go. So that means that I can give that to you maybe. Maybe that's worth something. Yeah, I don't know.  I said that I'd have a redemption arc and here we are.   Thank you. Whoa. Let's go. All right. Here's what I'm going to need you to do. Yes. This thing is going to connect us. I will be a conductor with it. And you will be turning the dial one little thing until it's at the end. You can go at your own pace with it, but we're going to do a countdown together. Three, two, one, go. And when you say go, you can start. All right. Yeah, just one at a time? Yeah, one at a time. And this is going to hurt a little bit, okay? Okay. Just a little stay. You can take it. You got my pain tolerance like your daddy. All right. Three, two, one. Come on. You got this. You've dealt with wars.  I feel different. Do you feel different? I'm just going to do it. I'm going to hide the kite there. Yeah, yeah. Ever since I was three, I've had this voice in my head that sort of says like, get people out of there again or who don't belong there. It's not there. I don't get it. Put it in my voice. We did it.  Should we talk to the other? Should we talk to the researchers? Yeah, talk to the researchers. Like, where should I put the device? I can see the case. Count. Look out for yourself. Don't get yourself hurt. Where was it? It was at Sloan's desk. It was at Sloan's desk. Yeah, go check in with them. Sloan's not there at the moment, so go sneak it back. Sloan specifically, she has some thoughts about him. I'm just a resident here. Sloan. Thank you for listening.  Please become a patron or visit our merch store at the link in our bio to support our work. Secure. Contain. Protect.