Whole Genome Approaches to Complex Kidney Disease
February 11-12, 2012 Conference Videos

Consent Issues: What Do Subjects Need to Know and How Do We Tell Them?
Julie Sapp, NHGRI

Video Transcript

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SARA HULL: Welcome or welcome back. We’re continuing with our conference on the theme of the ethical, legal, and social implications of

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genomics research in this exciting and important context. It’s my pleasure to introduce the next session. We’re actually going to have three

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sessions on informed consent, on return of results and on community considerations, then we break and have the breakout sessions which

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Dr. Kopp will come up and tell us more about in terms of where we’re going and what the themes are. So, I want to go ahead and introduce our

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first speaker who is Julie Sapp. Julie is a certified genetic counselor and a protocol coordinator within the Genetic Disease Research Branch of

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the national human genome research institute and she’s been there since 2005. She’s also a faculty member for the joint Johns Hopkins and NHGRI

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Genetic Counseling Training Program. She’s involved with a number of NHGRI research protocols for individuals with rare genetic

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conditions that are taking the lead on employing whole exome and genome sequencing analyses. Her research focuses on issues such as

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ambivalence regarding genetic testing and best practices for the consent and counseling challenges that are generated by the availability

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of whole genome medical sequencing results. Julie is somebody who, for years now, has been doing the hands-on work of explaining

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sequencing to research participants and getting their consent. So, we have a great deal to learn from her on the topic of consent issues, what

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subjects need to know, and how we tell them.

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JULIE SAPP: Good morning. Thank you very much for the opportunity to speak with you this morning and I hope I can be entertaining as your

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coffee kicks in. As Sarah mentioned I’m a genetic counselor in the Genetic Diseases Research Branch at NHGRI and these are big questions,

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right? How do we let participants know all the ins and outs that we think are most important for them to understand about exome sequencing,

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and how exactly do we go about telling them? I think these are questions that people have been asking increasingly over the years and I think

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that’s part of the reason why one of the main questions that our group gets asked about our exome sequencing protocols is, “Can I see you

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consent form?” or “Can you share your consent form with me?” We’re really happy to share the form but I think what’s more useful maybe for an

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audience like this is for me to kind of shed some light on the rationale behind some of the decisions we made, how exactly we go about consenting

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out participants and the process that we use, so you can decide how closely this meets your same goals and how you can employ similar or

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very different approaches to taking consent from participants. So of course, conformed consent is not a new idea. People have been consenting

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participants to genetic research protocols for decades, and again, there is nothing really new about this. We talked to participants a little bit

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about what it is that we’re trying to accomplish. We ask them to do a number of things for us and how what we’re asking them to do contributes to

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accomplishing our research goals, and then we let them know how we’re going to share our findings with them and with the broader scientific

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community. I think that when we think about whole exome sequencing that these issues become a little bit more involved and that there’s

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some additional relationships that are to our advantage to consider, actually. So, thinking more about how our research design might influence

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our informed consent and how our ability to consent participants may actually impact our research design, and then of course this big

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question about returning results and whether or not we should build that into our protocols, and of course, how that influences our informed

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consent discussion. So, I think this is again one of the biggest questions that is facing all of us in this field, and of course Ben is going to spend a long

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time talking about that so I’m not going to get into it very much, but there are many ethically defensible positions here and I do think, though,

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that it is really one of the key features about exome sequencing protocols that maybe sets them apart from other human subjects genetic

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research that’s been done in the past. It’s a really big question and there are a lot of results that may be in the ballpark to return to people, so I

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think it’s a really important consideration to keep in mind. So, this morning I’d like to outline some general considerations that we thought about

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when we were designing our informed consent process, basically answering the question, “What is it that I, as a researcher, need to keep in mind

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as I approach perspective participants?” Then I’ll describe a specific approach to consent. I’ll try to go into some actual nuts and bolts detail; the how

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exactly do I go about getting people to agree to participate in these studies. I’ll talk about some challenging populations and situations that we

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faced and how we have managed those, so basically answering the question, “What about kids, what about people with intellectual

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impairment, etc.?” And then I’ll briefly touch on some of our thoughts and conversations about how we go about returning results to

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participants. So, I think some general considerations that we have thought about in our exome protocols is that it’s been really helpful for

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us to really think about informed consent for our participants as really much more of a process—an ongoing iterative process—and it’s an

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opportunity, really, for us to engage in a meaningful dialogue with our participants. We found it very helpful to be very upfront about our

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goals; what exactly it is that we are trying to accomplish why we are bringing this particular technology to bear, why we need this technology

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to answer our research questions, and what our expectations are of our participants and then what their expectations are of us in terms of

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what results they can expect to receive and how long they can expect to interact with us. Then we go into a lot of detail about our plans and what

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their plans are for how they plan to use any information that we return to them. So, it really is…it’s been very helpful for us to think about this

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as a very two-way communication process where we’re learning what our participants are expecting of us and I’d really describe it as a

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partnership that we try to engage in with our participants. I think that one of the big things, which again I don’t think is really unique to exome

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sequencing but is most salient in human subjects research that employs exome or genome sequencing, is this idea of being really clear

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about our goals. So, the goals of our research really drive our informed consent process and our conversation with folks, and I’ll go into that a

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little bit more later. So of course, the big challenge here, when we’re thinking about interfacing with participants, are the data, right? So, as you heard

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yesterday and as you, I’m sure, know already, we generate an immense number of variants per participant whenever we engage in whole exome

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or whole genome sequencing, and the nature of these variants can lie on a continuum anywhere from completely novel in a particular family or in a

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particular individual to extremely well-characterized and well-understood, so everything in between. And of course then,

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when we think about categorizing these things in terms of their medical relevance to participants, they can range anywhere from completely benign

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to highly deleterious and something we would really want to think about returning to a patient. As well, there is this sense of iterative generation

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of these data in these protocols also, right? So, as the databases that we use to annotate our variants become more sophisticated and we can

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actually mine more data from those databases, we will probably reclassify variants as we go along. As our sequencing technologies advance

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it’ll be probably cheaper and better for us to resequence some samples because we’ll be able to get more data from them. So, these are all

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things that are being discussed and that we need to keep in mind so that these data are not static. There are downstream uses to the data that we

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generate from exome sequencing and there are downstream interrogation methods that we can use to get the most out of this really rich data

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source. And of course, there’s a lot of inherent uncertainty when we’re discussing the variant data that’s generated from exome sequencing.

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This is really a moving target, and fully conveying the scope and scale of the data that are generated from whole genome sequencing to

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participants I actually think is impossible. Unless they are very much in the know, they really don’t have a frame of reference with which to

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understand exactly what it is that we generate, particularly if we’re thinking about a cohort of a large number of participants, and the impact on

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participants will vary tremendously when we think about these data. Some people will be really not phased by anything that we could tell them

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and other people will be completely blown away by a lot of what we could tell them or what we could stand to learn, and of course as

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investigators, there’s a non-trivial impact of some of these data as well. So, we are faced with a very medically actionable result that we want to

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return to a participant. As clinicians, this is a non-trivial issue and something that we need to think about. So, I’m going to go ahead and outline a

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specific approach that we use with one of our research protocols; it’s this one, Exome Sequencing for Gene Discovery. It’s the one

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people want our consent form the most, I would say, and the protocol enrolls probands with rare disorders, so the goal really here is to determine

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the molecular etiology for well-characterized, primarily, rare conditions. We have really broad eligibility criteria, so we have a list of disorders

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that we’d really like to try to see folks on but essentially we’d like to employ this technology any time we think it has a chance of finding what

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is the genetic cause for a particular disorder. We often employ a trio approach. Usually these are singleton-affected probands in a family. It’s much

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more powerful for us to enroll their parents as well, so we often enroll a child and two biological relatives, but that’s not always possible and it’s

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not always necessary and it’s not always the best approach to try to understand what we’re looking for, and we do make comparisons across

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probands, again when possible, but we have enrolled a number of singleton kind of one-off cases, but it is again, much more helpful for us if

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we’re able to compare our results across probands with the same disorder. We do employ qualified results disclosure policy. So, this

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question here about whether or not to return results, I’ll just say off the bat, in the this protocol we do return results to participants and we

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return all kinds of results to participants, mostly because that’s an experimental manipulation. We’re really interested in the actual decisions

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participants make about their results and what their preferences are and what their expectations are and so we do offer a number of

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options to participants to return results, and I realize that that’s not something that everyone does and is maybe not relevant to a lot of what

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maybe you are considering doing but that’s something that we do. And so, again, I know that Ben is going to spend a long time talking about

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this extensive debate of the varied positions that folks can maintain about returning results, and like I said, many methods are extremely ethically

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defensible, but our approach or the way that we kind of conceptualize this is that these ancillary genotypes—and when we say ancillary, these

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genotypes that are really not related to what it is that we’re trying to find—they exist in the data. We can’t make them not exist and some of them

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are clinically relevant, some of them are medically actionable and there’s maybe a spectrum between those things and we’re interested in the

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fact that some of our participants opt to receive these results. I think that’s a key point in our informed consent conversation is that

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participants need to want to receive these results, and so that’s one of the most important of that two-way dialogue components of our

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consent sessions. So in terms of the timeline, usually the participants…I’m going into a little bit of fine-grain detail here. So, the participants will

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figure out who they are and we’ll initiate some sort of contact with them, usually a phone call, and then on the phone I talk to them about the

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study and the purpose of doing that is to alert folks to some of the comprehensiveness of what we’re going to be asking them to do and I find that

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this is a really useful thing to do because it helps people decide, for whom they really wouldn’t be interested in doing this, decide not to do it. So for

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example, folks who maybe have some information about parentage that they would want to keep to themselves, that gives them the

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opportunity to kind of decide that maybe this kind of research isn’t for me. And then we send the consent form along with the one-page summary

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about the protocol and follow up with a phone call, and then folks come to NIH where we do extensive phenotyping and we do consent them

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in person on the NIH campus. So, kind of looking at the timeline here, there are a number of different key points in the protocol where we

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interface with participants. So, there’s the first time that we contact them, there’s the consent session and the phenotyping. I’ll just point out that

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we don’t ask participants to make hard and fast decisions about what kind of results they’d like to learn at the time of their consent; they actually

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can decide that at a point later and I’ll go into that in more detail later. And we do return clear results and the plan is to do that in person with folks at

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NIH, and then of course there’s this long period of periodic re-annotation, possibly resequencing, which would possibly entail some re-contact. So,

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while we’re doing all of that or while…so, while all of this is going on, of course hopefully we’ve determined the molecular etiology of the disorder

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that we’re interested in, we’ve annotated for secondary variants in some way, and we’ve maybe developed and implemented some

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additional research questions, and I think everything that’s above the arrow is really not visible to the participant at all, but we do alert

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them to the fact that this is what’s going on while we’re working with their data. And again, I think a key point here is that folks don’t make their

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decisions about what results they’d like to receive at the time of consent. Instead, we kind of alert them to what categories of information

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might be available and then they make their decision later after they’ve enrolled. So, when I talk to participants about this, I think when I attend

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these kinds of meetings and hear these kinds of talks, there’s a real tendency to talk about the data that are generated using water analogies,

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so a lot of people talk about trying to drink from a…it’s like drinking water out of a fire hose. I personally like the analogy of Niagara Falls, that

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when we sequence a genome of a family or an individual, we’re generating a torrent of data. We’re generating the equivalent of Niagara Falls

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worth of data. What we’re trying to do is find one very specific thing by going through all of those data, and so we talk to participants about how

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we’re going to generate this huge amount of data, but really what we’re after is one very specific nugget. So, we’re panning for gold in Niagara

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Falls and what we’re really after is this thing that we call the primary variant, and this is just our terminology, and it’s essentially the genetic cause

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of the disorder under investigation. Because these are generally families with children with rare disorders, they’re extremely motivated to

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understand this and they also think of this as a nugget of gold; it’s something really precious to them.

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But the problem is that this is us here, panning for gold in Niagara Falls, and we can find all kinds of other things as a result of doing that, and we

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think about everything else as the secondary variants. So, we talk to families about what it is that we would like to do with all of this other stuff

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that comes up as we’re panning for gold in Niagara Falls and we really define these things as very broadly. So, a secondary variant for us is

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anything that is not a primary variant, so anything that is completely unrelated to the molecular etiology of the disorder that we’re interested in.

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We also are very explicit with our participants that finding these things is not at all the goal of our study. The goal is to find that nugget, but

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inherent in our methodology, we come up with these other findings and we want to handle those findings as responsibly as possible and in

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a way that is as meaningful as possible to participants, and I find that they really do understand that component. So, then we go into

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some detail with our participants about what exactly are we talking about here. Some of those folks have heard of cystic fibrosis and

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Tay-Sachs disease; these are great examples of autosomal recessive disorders where we could find that folks are carriers for. And then we talk

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about some disease-causing variations or mutations, and the way that I usually frame this for participants is to talk about these things in

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three different ways, one in terms of time. So, whether or not this explains a health concern that they already have, so it provides a genetic

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explanation for something that they already know is going on with them or whether it’s going to predict some future disease state; whether or not

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there’s anything they can really do about this, if there’s treatment or prevention available for this particular disorder today; and whether or not

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they would find this surprising or expected based on their family history. So, a lot of people really will talk about their family history of heart disease

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or hypertension or things like that and they wouldn’t really be shocked to find that there was some genetic variation that contributes to that.

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Other things will be completely surprising because there’s no family history in the family. We also talk about how there are many variants

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that we generate that are of uncertain significance, and of course, many variants that we generate are part of normal variation. We

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don’t give participants the option to learn things that we can’t make sense of and the way I usually talk about that to patients is that if we

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can’t make meaning of it, we don’t want to leave it in their hands to make meaning of it because their probably less equipped to make meaning of it than

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we are, and we also don’t return anything that we think is of normal variation. So again, I think that when we talk about all of these specific

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variant results you really emphasize that it’s not our intention to generate these things and that it’s completely ancillary to what we’re trying to do,

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and I do fill participants in on this idea that, right now, annotation for these variants is extremely time-consuming. A lot of the databases that are

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available to help us make sense of these human genetic variations are works in progress and it takes a long time for us to make sense of these

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variants and that it’s also an iterative ongoing process, so that we could make a call today that in two years might change, and so it’s a bit

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flexible there, and that this represents a departure from traditional paradigms for many of these folks. So usually if you have a problem, you

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go to the doctor and you get a diagnosis; we’re turning that completely on its head, right? So, we could take someone who’s apparently healthy

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and then diagnose them with a problem based on just their genetic information rather than their symptoms. Participants readily identify that, for

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some people, this will really freak them out and other people think this is amazingly cool and they really, really want this information. And then of

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course, another thing that we mention to all of our participants is that we may not actually generate any of this information for any individual who

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participates because, if we enroll a trio, we may not actually sequence the parents. We may only look across probands or we may look across

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three probands and figure out what’s going on and then the fourth proband we enroll we might just use that person for confirmation. So even

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though they’ve enrolled and consented to undergo this testing, we may not do it for any person who’s enrolled, and I think that’s really an

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important thing to convey to people. So, I think that the main point that participants really seem to understand once we go through this kind of level

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of detail is that secondary variants or ancillary variants or really all of the variation that you can find when you sequence a genome, it really

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defies complete a priori delineation and categorization, so I cannot give participants a list and say, you know, this is the kind of stuff that

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we can find, because that would be many, many pages and they really wouldn’t be able to make sense of it. So, we really can’t completely and

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specifically predict what we’re going to find whenever we set out on this, and so it’s important to alert people to some examples of

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some possibilities. We really can’t go through and be more fine-grained than that. So, participants in this protocol can elect to receive results or not.

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So, they can decide that all they want to know is the primary variant and then they can learn about secondary variants by category. Each participant

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is an independent actor, so each parent that we enroll in a trio makes their own decisions and that makes for some interesting conversations when

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parents are not together or if they have extremely disparate views about what they’d like to learn, and we do explain this duty-to-warn exception in

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a little bit of detail because that’s one of the only incidences in which we would really not give participants a choice to know, and I know this

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was something that was discussed yesterday. So, we talk with participants about this idea that if we do generate a variant result that would make

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us really want to communicate that to them because it has immediate and serious health implications, we’d really like to be able to have the

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right to use our judgment to tell them that. And again, I think this resonates with most people, that they understand this. It’s important, I think, to

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emphasize that overall these variants are extremely rare and it’s not our intent, again, to discover these things and that we would

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discover them again in an ancillary fashion, that we’re finding them because we’re using this methodology to try to find a question that’s

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completely unrelated to what that phone call might look like, and most participants, I think, really identify with this intent that they would also

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prefer to be notified if there was something that we think could change their life in some way. My personal feeling is that our participants are

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particularly interested in this because they’re generally caring for children who have rare and complex medical disorders, and if we could give

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them any piece of information that could help them tailor their health care in a more specific way, they’re very, very open to that. So again, I

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think there’s some familial implications that we generally review with our participants, which is namely, that not all family members may undergo

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the same level of genomic interrogation. Most people bring up some concerns about their extended family and how they will notify their

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extended family about anything that we could find, and we really emphasize that some of these approaches may require communication among

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family members. And so, we may be enrolling cousins or other extended family members to try to answer our question. Of course, we do enroll

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minor probands and we will proceed with exome and genome sequencing. So, why so much detail, because it really is quite involving to go over all of

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this with folks? Again, we say that our goal is to return meaningful results to participants to allow them to make informed decisions about what they

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might do with the information and whether or not they want to receive it. I think the main reason that we spend so much time going over this is

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that once you choose to know something, it’s really impossible to return to a state of ignorance and that’s true for participants; it’s also true for

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us as investigators. And so, this is one of the research aims of our protocol is to see how people react to some of these conversations. So,

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we make it really clear that this is not like other genetic testing that they may have had. Again, these are families with children with rare

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disorders, so they’ve generally had at least a carrier-type or they’ve probably had a couple of single-genes sequenced to no avail, that this is

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much more comprehensive. It is clinically available and so that’s also a choice that people can pursue, and if they don’t like our timeline we

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would encourage them to do that—so that is an alternative—and that withdrawal from these protocols is not simple. I think this is actually one

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of the more nuanced and important points to bring up with patients, that even though they may call us and say that they want to withdraw, if their

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data’s already gone to be sequenced then it’s living somewhere on someone’s hard drive and so, what do they want us to do with that? Can

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we continue to use it? Can we de-identify it? It’s not simple; it could be a long process. And then I think the other thing that really resonates with

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people is that right now we’re making a lot of hay out of this and we’re making a really big deal out of it, but you know, the whole goal of

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personalized medicine is to bring these techniques online in a more widely available fashion. And so, I think most participants really

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find it interesting to think about how, you know, this might be very much in clinical practice in the future, it might be available in your primary care

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physician’s office, and that right now we’re making a big deal out of it because it’s new. So, in terms of some challenging populations and

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situations that we’ve encountered, like I said, I think that one of the biggest ones that we had to wrestle with was enrolling minor probands. So,

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we will allow one parent to consent on behalf of a child and we do have a specific consent form that reads “you are consenting for this on behalf

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of your child” and we talk about some results that we may return to children and the circumstances under which we would return those results. So

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in general, anything that’s actionable in childhood or diagnostic we would certainly return. We’re also willing to return carrier status to folks

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because, again, these are parents who have young children and this could affect their reproductive risks and so we are okay with doing

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that if the family is interested in receiving that information, and most families are. Under very specific circumstances we would like to reserve

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the right, again, to return variants that are actionable in adulthood. This would be an example of this—that again, I think is unlikely but

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you can never predict who you’re going to have this information on—is if we did have some sort of BRCA or HNPCC variant that came up in a child

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when we hadn’t sequenced the parent, so this variant had to come from somewhere and one of the parents could be at great risk and we’d want

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to find a way to return that information to the participants. But really, our preference is that they recontact us when the child reaches the

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age of majority so they can make their own decisions about what information they want to know. In the case of intellectual impairment this

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becomes a little bit more complicated. We have consulted our colleagues in ethics for these questions in the past. We do require proof of

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legal guardianship or surrogate decision-maker prior to consent, and when we think about intellectually impaired minors this is a very

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nuanced discussion that we have with folks that consent because the whole rationale behind reserving some results until a person reaches

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adulthood is that they can have autonomy and make their own decisions about what kind of result they’d like to receive. Oftentimes parents

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will self-identify or will ask, “My child has an intellectual impairment and I don’t know that we could ever expect for him or her to be making

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their own decisions, so can we get those results back?” and we think that that’s an okay way to go. And so, any results could be returned per the

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family’s preference in this kind of situation. So, I think globally this kind of research is not appropriate for everyone and we say this to all of

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our participants. We ask them to be willing to engage with us over a period of years. It’s really helpful if the family structure is conducive to this

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kind of research, and so again, because each parent is an independent actor it is advantageous for parents to be on the same page and for family

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members to be on the same page with respect to what kinds of results they’d like to receive. And then of course, there’s this whole idea about

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what resources do people have to bear when they’re thinking about what they’re going to do with any of the findings that we might come up

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with? So, just some brief mention of how we’ve gone through returning results. Again, there’s a huge variety of policies out there—none, all,

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some. We employ what we would think of as a limited or qualified disclosure policy. So at the time of consent, again, we alert people to what we

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could find and then we send them home and then when we do have results available we contact them and we review with them those categories

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that we previously identified. “When we talked a year or two ago you said that you were interested in learning things that were not

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surprising and treatable and preventable. What are your thoughts on that today? What kind of decision would you make today?” And so, once

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they tell us kind of what they’d like to learn then we will CLIA certify those results only and return those results only to them. So again, that’s…I’m

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going to skip over this a little bit because I’m running short on time, but this is our process and I think the key point here is that we are currently

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envisioning that this will happen in-person at a return NIH visit that may take place over a couple of days where we can kind of go through all of

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the different results that are available, and again, this may happen more than once as we re-annotate the data or as we have new findings to

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share with folks. So, this is completely anecdotal but I’ll just share a couple of quotes from our participants. I think the first one is really…they all

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have a similar theme but one participant said, “I think knowing is better than not knowing. I absolutely want to know whatever you find.”

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Most people fall in this category. I think my favorite is this one woman who asked if we had to look, so essentially she was asking whether or

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not we had to annotate her data, and what was really interesting was that she was asking from a place of, “Gosh, that sounds like a lot of trouble

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that you guys go through, are you sure you need to do that? It really sounds like a lot of work. I really don’t need to do that.” So, I thought that

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was kind of interesting. And then I think the last quote really summarizes a lot of the tension that people experience here, this idea that they really

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want to know, particularly for their children, so I think several parents have said to me, “I have ownership over my child’s information.” They’re

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uncomfortable with the idea that we might know something about their child that they do not and so they say, “I probably want to know. I have a

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great fear of knowing but I really want to know.” So, I think that this really exemplifies some of the tensions that people have about learning this kind

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of information. So in conclusion, again, most participants really, after this long discussion, they appreciate why this is complicated but they really

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don’t care. They really want to know anything that they could find out. They completely, I hope, understand why it is that we’re embarking on the

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research design that we’ve chosen and why this is the methodology that is available and why we hope it’ll work. I think that the complexities of this

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are able to be made understandable to participants if you frame it in terms of the study goal and that they align with that goal, and of

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course, their preferences do vary. Not everyone is as homogenous as I made it out to sound. In fact, I had one family who took nine months to

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decide whether or not they wanted to be in this study and they eventually decided that they did want to consent. So, I hope I have given you

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some food for thought about why some of these relationships are important to consider and how they could influence your informed consent

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process and forms and discussions with participants, and I’d like to thank folks in our lab and of course our participants as well. Thanks.

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So, questions, right? MATT SAMPSON: Good morning. Matt Sampson,

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University of Michigan. Thanks for that talk. I have a couple of questions. One is, with whole exome sequencing is there an expectation that results

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are posted to dbGaP or something like that? And in addition, even if it’s not but for studies you’ve been involved in with the expectation that they

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are posted, how do you talk to families about informed consent about privacy issues and posting there? It seems like, you know, people

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alluded to yesterday that there were terrifying passages in long informed consents explaining what theoretically could happen. How do you

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balance letting people know what they need to know, versus what they could understand and what’s reality versus somewhat fantasy?

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JULIE SAPP: Yeah, absolutely, and I really didn’t go into a lot of detail about that. It is in, I wouldn’t say excruciating detail, in our consent form but it

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is in our consent form, so these ideas that your results may be deposited to these publicly available databases, that’s something that most of

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our families are really on-board with because…and I think it’s the nature of our population, right? So, they are generally pro-research and

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pro-sharing data because they want to avoid a diagnostic odyssey for future families who may be in their situation. And then some folks are

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really concerned about privacy and I think that, in those instances, we can spend a tremendous amount of time talking about that. In my

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experience, it hasn’t been enough to sway people but that’s one of the main conversations that I have with folks over the phone. So, what

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does this mean for genetic discrimination? Tell me about this genome law and exactly what does it do and what doesn’t it do? Does it make a

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difference that I have a child with manifest disease which is already…the insurance company already knows about all of that? So, I

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think that, again, for some people it’s a really big deal. For most people, it resonates more with them that we could share their data and they

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could learn about it. MATT SAMPSON: I just want to follow up. How

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has Gillette decided to approach the concept of describing the theoretical ability to identify someone from a publicly database versus the

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reality of whether that’s possible or not? JULIE SAPP: So again, it’s mentioned in the

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consent form and we talk to people about that. The main way that I talk to folks about this is this idea that, you know, DNA is different from any

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other kind of biological material because it has this inherent potential. You know, the reality is that there is a level of expertise that’s required to

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be able to make that identification and that there are relatively few people who have that ability. But honestly, it’s something that we are still

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working through as a society and I share that with participants and they, again, seem to understand that.

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MATT SAMPSON: Thank you. JOHN SEDOR: John Sedor, Cleveland. Thanks. It

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was a great talk about important issues, but I’m curious. One of the things that struck me as I was listening is you are doing this within the NIH

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environment. It sounds like a huge effort in terms of FTE. How does this translate into the provinces, your usual academic medical center

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with all of the financial pressures and not really having that sort of…?

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JULIE SAPP: Absolutely. JOHN SEDOR: Have you all thought about the

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best way that, you know, as these things become more available and studies go on and do this in not a typical environment but an

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environment where we don’t have the luxury of all the resources you all have.

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JULIE SAPP: Yeah, absolutely, and I think that’s a really great point and something that’s come up a lot when we’ve had these kinds of conversations

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that, you know, on our staff we have a full-time genetic counselor who’s devoted specifically to this and again, our volume is tiny, right? So, we’re

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not really using this for every single patient who walks through the door and we also have the ability to pick and choose who we’re employing

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this on and things like that. You know, I think that at the end of the day the key characteristics that need to be present and I think that people can

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start to think very creatively about is how we communicate this to participants. I’m not convinced that a consent form is necessarily the

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best way to communicate some of this information. I think that so much of the conversations that I have with folks are actual

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conversations where there’s the ability to give and take and ask some questions. Having said that, I’m not sure that that couldn’t be done in a

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group setting or through some sort of multimedia presentation where there’s the opportunity to ask questions afterwards. I think what is really

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comforting to us is that we have this relationship with participants and I know that people have this relationship with their clinicians as well. So, so

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much of it is trust and understanding of what exactly you’ll be planning to use the data for and things like that. I don’t know that that needs to be

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something that isn’t obtained over a long period of time, like a relationship the clinicians have with folks or something that can’t be established in

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some other method, but I fully recognize that this is tremendously time-consuming and we have these fantastic resources where we can ask

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people to spend two hours talking with us about this. I realize that’s not tenable in the clinic but I think it’s one of the reasons why we’re so

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interested in what we’re doing is trying to distill this down to the key points.

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FEMALE: I have a very quick question. When I think about this issue of consenting on behalf of minors and then the promise to re-consent them

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when they reach the age of majority, two issues come up. One of course, is that it’s assumed that the research team remains intact and adequately

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funded 15 and 20 years later—that becomes important—and it’s a big problem on behalf of an individual investigator, which responsibility

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ultimately falls really to that investigator as well as to the academic institution, where oftentimes that relationship may not exist.

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JULIE SAPP: Right. FEMALE: So, that promise is difficult and I think

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we’re setting up the expectation if that occurs with that real forethought and understanding about how we’ll actually employ that and honor

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that promise, and it seems to me sometimes that it’s worse to actually make a promise and then really have no intention of keeping it.

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JULIE SAPP: Right. FEMALE: The second thing is to ask the question

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from a perspective of the original consent when you talk to families, talk to individuals and you expect that we’ll come back and re-visit the level

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of need-to-know or desire to know in the future. When we think about the engagement of young adults, children, adolescents to young adulthood,

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I can imagine because we’re still developing, cognitively we’re still developing at the age of 18. We also, again, assume that 18 is the age of

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majority and yet I can’t imagine that we will have a maturing desire to know or not know, and I wondered if you’ve engaged the families and

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asked them specifically—and young adults very specifically—and directly, you know, do you want to be asked? Do you want to be asked again?

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How should this process be conducted? Did you have that conversation?

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JULIE SAPP: Yes. We do leave it open-ended and I think that one of the…so, I completely agree with you, this idea of 18 is fiction, right? There are

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some incredibly mature and autonomous 13-year-olds and then I have a number of patients who are in their 20s and are more like they’re 13

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emotionally, so I think that it is a fictional age, and again, the way that we manage this with patients is we say, you know, “This is our preference:

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our preference is that you contact us if you move and that you keep in touch with us and that you call me once a year to see what’s available.” We

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also send them a newsletter once a year and we have a return address on that so that if their address or other information changes we have a

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way to assess that, and then I think we really do engage with them in a dialogue of “how exactly do you want us to go forward?” Here’s our plan:

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our plan is that we both have a responsibility to keep in touch with each other, particularly if you have a child who’s 11, 12, 10—that kind of age

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range—so that we can handle this at an appropriate time, and actually in our consent form, we don’t say 18, we say we will share

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results with your child at the appropriate time, because it’s a moving target for some of the reasons that we already discussed. So, I think

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your point is extremely well-taken. It’s complicated, is the answer. Parents realize that it’s complicated and then when I’ve talked to

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young adults about this, again, I think they are in a generation that is really more inclined to want to share this information, so I think they’ll post it on

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Facebook because that’s where they put this information. They don’t have the same kind of expectations of privacy and confidentiality and

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what’s inherently theirs that the rest of us do, so it’s a challenging situation.

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FEMALE: The challenge is they’ll post it on Facebook at the age of 17 or 18 and will have an overwhelming desire to remove it from Facebook

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when they’re 21 or 22, right? JULIE SAPP: Exactly.

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FEMALE: And you can’t scrub it. JULIE SAPP: Yeah, absolutely.

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JEFFREY KOPP: Jeffrey Kopp, NIDDK. Thank you, Julie. That was a wonderful talk. I have two questions about possible opt-outs on the

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consent, and the first I really should have asked Laura yesterday, but is it consistent with federal policy to have an opt-out for dbGaP data

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placement? JULIE SAPP: Oh gosh, that’s such a great

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question and I don’t actually know the answer to that.

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JEFFREY KOPP: I’ll ask her. The other question is the duty-to-warn. I know you presented in the context of autosomal recessive disease in

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children. Again, do you have any thoughts about in an adult population? You find BRCA1 but your consent might have said—and here’s where I’m

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going—some patients say, “I don’t want to know anything.” Have you thought about an opt-out on the duty-to-warn?

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JULIE SAPP: Yeah. The way we actually manage that with participants is we say, “You probably shouldn’t sign up for this study if you never want

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to get a phone call, if there is a circumstance under which you would never ever want to hear from us,” because we’re less comfortable with

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that. I think if that actually happened we would probably engage our colleagues in ethics and try to make a decision about whether or not that’s

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okay. Honestly, I think that a lot of the angst for that is on us; that we just don’t want to be holding on to this information that could be life-changing

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and not have the opportunity to share it. By the same token, if a person makes a conscious and informed and autonomous decision about never

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ever wanting to hear that and they maintain that position over time, I think that is something that should be considered but we want to get some

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help on that. But the way I currently frame it is, you know, here are the circumstances under which I’d like to call you back. Do you agree? And

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they say “yes,” generally, and if they didn’t say “yes” then that would be an important thing for us to think about a lot.

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JEFFREY KOPP: Good. Thank you. MATTHIA KRETZLER: Matthias Kretzler,

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University of…oh. Marilyn, please go on. MARILYN HAILPERIN: Thank you. I’m from the

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NephCure Foundation. We’re a patient advocacy foundation that supports research. I want to know how we should be engaged in starting this

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education process prior to groups of individuals or an individual being enrolled in a protocol study. This is going to be something we can help with in

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terms of setting the stage for understanding how to engage in these conversations of informed consent. So, how would you suggest that we

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become engaged in this process from a patient education perspective?

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JULIE SAPP: I think it’s a great question. I think that one of the key components of patient education here is this idea that this is a powerful

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technology today and it’s the best technology that we have available and yet this is maybe not for everyone, that there are real concerns that some

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people may have that are brought up by the use of this technology and that people can think very carefully about whether or not they want to

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advance research in this way, because I think there will always be the need for controls and for folks where we would just validate information

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and that’s a way that they can participate without having to undergo the full-blown exome sequencing. Does that make sense?

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MARILYN HAILPERIN: It makes sense. I’m looking for the specificity of it. Is there a way to point to somewhere on a website, is there a

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recommendation for how much? And that’s a conversation we can have offline and I think what they’re really looking for and what we’re

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looking for is some specificity around how to have a good dialogue?

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JULIE SAPP: Yeah. Great. MATTHIAS KRETZLER: I think one important point

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because we were planning to actually address that with the speaker is…University of Michigan, Matthias Kretzler. What I have experienced in my

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practice twice now is that patients came and consulted me if they should start to look for living donor transplants because they were found in

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the 23andMe scan to have uromodulin, this genotype which increases the risk by an odds ratio of 1.04. So, what we are having here right

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now is a discussion inside the Ivory Tower. What’s happening in the real world is that there’s direct to consumer marketing of the genetic tests,

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a lot of 23-year-olds go to [---] parties and their DNA often [---] results back from 23andMe and they try to convey the information in a meaningful

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manner via websites but obviously always have the disclaimer, “Go to your primary care provider who, for sure, will be able to update them on

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what it is [---].” So, I think we actually invited 23andMe to come to our meeting and present their take on how they want to be involved or not

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in managing that information, and the fact that we never got a response, I think, is a very clear indication that [---]. So, I think what we are urged

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as a society and you mentioned that also, in your informed consent that two or three years down the road we probably will start to implement that

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in clinical working practice. So, I think the efforts in NIH are fantastic to learn which of these modalities are most implementable and practical,

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but even as [---] referred to in a setting where we have a multicenter study where we have all patients across North America, it becomes

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extremely challenging to ask questions like, if we have an actionable item, who actually pays for the trio lab?

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JULIE SAPP: That’s a big question. MATTHIAS KRETZLER: And there are other

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elements which I think are currently, to my knowledge, not resolved.

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JULIE SAPP: Right. No, I think they’re really big and really important questions. Do we have time for one more question?

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MALE: I just want to make a brief comment to Matthias that the NIDDK, the NHGRI, the NHLBI, and the NCI have cooperated in a U34 project

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regarding personalized medicine, patient education and physician education because they’re two-pronged, they have to be done

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together, and there is a grant application regarding setting up a large research project about this, which will predict [---] and we’ll let you

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know how that happens.

JULIE SAPP: Thanks again.




Date Last Updated: 9/18/2012

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