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

00:22:55,166 --> 00:23:02,199
think there’s some familial implications that we generally review with our participants, which is namely, that not all family members may undergo

00:23:02,200 --> 00:23:07,766
the same level of genomic interrogation. Most people bring up some concerns about their extended family and how they will notify their

00:23:07,766 --> 00:23:21,532
extended family about anything that we could find, and we really emphasize that some of these approaches may require communication among

00:23:21,533 --> 00:23:31,133
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

00:23:31,133 --> 00:23:41,966
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

00:23:41,966 --> 00:23:50,499
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

00:23:50,500 --> 00:23:58,266
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

00:23:58,266 --> 00:24:04,566
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

00:24:04,566 --> 00:24:17,532
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,

00:24:17,533 --> 00:24:24,366
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

00:24:24,366 --> 00:24:31,132
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

00:24:31,133 --> 00:24:40,833
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

00:24:40,833 --> 00:24:48,166
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

00:24:48,166 --> 00:24:57,699
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

00:24:57,700 --> 00:25:04,166
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

00:25:04,166 --> 00:25:12,032
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

00:25:12,033 --> 00:25:18,833
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

00:25:18,833 --> 00:25:29,066
personalized medicine is to bring these techniques online in a more widely available fashion. And so, I think most participants really

00:25:29,066 --> 00:25:37,032
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

00:25:37,033 --> 00:25:47,433
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

00:25:47,433 --> 00:25:54,166
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,

00:25:54,166 --> 00:26:02,699
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

00:26:02,700 --> 00:26:13,633
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

00:26:13,633 --> 00:26:21,233
in general, anything that’s actionable in childhood or diagnostic we would certainly return. We’re also willing to return carrier status to folks

00:26:21,233 --> 00:26:28,766
because, again, these are parents who have young children and this could affect their reproductive risks and so we are okay with doing

00:26:28,766 --> 00:26:36,366
that if the family is interested in receiving that information, and most families are. Under very specific circumstances we would like to reserve

00:26:36,366 --> 00:26:44,999
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

00:26:45,000 --> 00:26:53,800
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

00:26:53,800 --> 00:27:03,133
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

00:27:03,133 --> 00:27:12,333
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

00:27:12,333 --> 00:27:21,033
age of majority so they can make their own decisions about what information they want to know. In the case of intellectual impairment this

00:27:21,033 --> 00:27:32,933
becomes a little bit more complicated. We have consulted our colleagues in ethics for these questions in the past. We do require proof of

00:27:32,933 --> 00:27:41,933
legal guardianship or surrogate decision-maker prior to consent, and when we think about intellectually impaired minors this is a very

00:27:41,933 --> 00:27:50,633
nuanced discussion that we have with folks that consent because the whole rationale behind reserving some results until a person reaches

00:27:50,633 --> 00:27:58,566
adulthood is that they can have autonomy and make their own decisions about what kind of result they’d like to receive. Oftentimes parents

00:27:58,566 --> 00:28:07,999
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

00:28:08,000 --> 00:28:17,833
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

00:28:17,833 --> 00:28:25,233
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

00:28:25,233 --> 00:28:33,499
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

00:28:33,500 --> 00:28:43,466
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

00:28:43,466 --> 00:28:50,599
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

00:28:50,600 --> 00:28:57,433
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

00:28:57,433 --> 00:29:08,099
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,

00:29:08,100 --> 00:29:16,466
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

00:29:16,466 --> 00:29:23,899
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

00:29:23,900 --> 00:29:31,100
that we previously identified. “When we talked a year or two ago you said that you were interested in learning things that were not

00:29:31,100 --> 00:29:38,000
surprising and treatable and preventable. What are your thoughts on that today? What kind of decision would you make today?” And so, once

00:29:38,000 --> 00:29:49,833
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

00:29:49,833 --> 00:30:00,033
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

00:30:00,033 --> 00:30:05,366
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

00:30:05,366 --> 00:30:13,432
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

00:30:13,433 --> 00:30:23,066
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

00:30:23,066 --> 00:30:29,766
have a similar theme but one participant said, “I think knowing is better than not knowing. I absolutely want to know whatever you find.”

00:30:29,766 --> 00:30:39,066
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

00:30:39,066 --> 00:30:47,199
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

00:30:47,200 --> 00:30:53,866
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

00:30:53,866 --> 00:31:01,266
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

00:31:01,266 --> 00:31:08,499
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

00:31:08,500 --> 00:31:14,966
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

00:31:14,966 --> 00:31:23,799
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

00:31:23,800 --> 00:31:32,066
of information. So in conclusion, again, most participants really, after this long discussion, they appreciate why this is complicated but they really

00:31:32,066 --> 00:31:41,332
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

00:31:41,333 --> 00:31:52,466
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

00:31:52,466 --> 00:32:00,199
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

00:32:00,200 --> 00:32:13,733
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

00:32:13,733 --> 00:32:21,933
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

00:32:21,933 --> 00:32:30,366
some food for thought about why some of these relationships are important to consider and how they could influence your informed consent

00:32:30,366 --> 00:32:45,932
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.

00:32:45,933 --> 00:32:49,133
So, questions, right? MATT SAMPSON: Good morning. Matt Sampson,

00:32:49,133 --> 00:32:55,899
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

00:32:55,900 --> 00:33:05,733
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

00:33:05,733 --> 00:33:13,199
are posted, how do you talk to families about informed consent about privacy issues and posting there? It seems like, you know, people

00:33:13,200 --> 00:33:20,133
alluded to yesterday that there were terrifying passages in long informed consents explaining what theoretically could happen. How do you

00:33:20,133 --> 00:33:26,799
balance letting people know what they need to know, versus what they could understand and what’s reality versus somewhat fantasy?

00:33:26,800 --> 00:33:33,966
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

00:33:33,966 --> 00:33:40,732
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

00:33:40,733 --> 00:33:46,799
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

00:33:46,800 --> 00:33:55,066
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

00:33:55,066 --> 00:34:04,366
really concerned about privacy and I think that, in those instances, we can spend a tremendous amount of time talking about that. In my

00:34:04,366 --> 00:34:11,066
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

00:34:11,066 --> 00:34:17,232
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

00:34:17,233 --> 00:34:25,266
difference that I have a child with manifest disease which is already…the insurance company already knows about all of that? So, I

00:34:25,266 --> 00:34:36,866
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

00:34:36,866 --> 00:34:42,199
could learn about it. MATT SAMPSON: I just want to follow up. How

00:34:42,200 --> 00:34:49,300
has Gillette decided to approach the concept of describing the theoretical ability to identify someone from a publicly database versus the

00:34:49,300 --> 00:34:53,666
reality of whether that’s possible or not? JULIE SAPP: So again, it’s mentioned in the

00:34:53,666 --> 00:35:00,132
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

00:35:00,133 --> 00:35:10,033
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

00:35:10,033 --> 00:35:18,633
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

00:35:18,633 --> 00:35:25,699
working through as a society and I share that with participants and they, again, seem to understand that.

00:35:25,700 --> 00:35:30,233
MATT SAMPSON: Thank you. JOHN SEDOR: John Sedor, Cleveland. Thanks. It

00:35:30,233 --> 00:35:39,133
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

00:35:39,133 --> 00:35:46,233
environment. It sounds like a huge effort in terms of FTE. How does this translate into the provinces, your usual academic medical center

00:35:46,233 --> 00:35:51,299
with all of the financial pressures and not really having that sort of…?

00:35:51,300 --> 00:35:55,200
JULIE SAPP: Absolutely. JOHN SEDOR: Have you all thought about the

00:35:55,200 --> 00:36:01,466
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

00:36:01,466 --> 00:36:06,732
environment where we don’t have the luxury of all the resources you all have.

00:36:06,733 --> 00:36:14,566
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

00:36:14,566 --> 00:36:22,732
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

00:36:22,733 --> 00:36:28,733
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

00:36:28,733 --> 00:36:35,899
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

00:36:35,900 --> 00:36:42,933
start to think very creatively about is how we communicate this to participants. I’m not convinced that a consent form is necessarily the

00:36:42,933 --> 00:36:51,199
best way to communicate some of this information. I think that so much of the conversations that I have with folks are actual

00:36:51,200 --> 00:37:00,200
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

00:37:00,200 --> 00:37:07,666
group setting or through some sort of multimedia presentation where there’s the opportunity to ask questions afterwards. I think what is really

00:37:07,666 --> 00:37:14,232
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

00:37:14,233 --> 00:37:22,966
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

00:37:22,966 --> 00:37:31,499
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

00:37:31,500 --> 00:37:40,533
some other method, but I fully recognize that this is tremendously time-consuming and we have these fantastic resources where we can ask

00:37:40,533 --> 00:37:48,199
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

00:37:48,200 --> 00:37:52,700
interested in what we’re doing is trying to distill this down to the key points.

00:37:52,700 --> 00:38:01,833
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

00:38:01,833 --> 00:38:09,033
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

00:38:09,033 --> 00:38:16,766
funded 15 and 20 years later—that becomes important—and it’s a big problem on behalf of an individual investigator, which responsibility

00:38:16,766 --> 00:38:23,466
ultimately falls really to that investigator as well as to the academic institution, where oftentimes that relationship may not exist.

00:38:23,466 --> 00:38:26,332
JULIE SAPP: Right. FEMALE: So, that promise is difficult and I think

00:38:26,333 --> 00:38:32,866
we’re setting up the expectation if that occurs with that real forethought and understanding about how we’ll actually employ that and honor

00:38:32,866 --> 00:38:39,499
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.

00:38:39,500 --> 00:38:42,566
JULIE SAPP: Right. FEMALE: The second thing is to ask the question

00:38:42,566 --> 00:38:51,866
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

00:38:51,866 --> 00:38:59,932
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,

00:38:59,933 --> 00:39:08,566
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

00:39:08,566 --> 00:39:18,899
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

00:39:18,900 --> 00:39:26,866
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?

00:39:26,866 --> 00:39:31,299
How should this process be conducted? Did you have that conversation?

00:39:31,300 --> 00:39:39,733
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

00:39:39,733 --> 00:39:47,666
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

00:39:47,666 --> 00:39:56,866
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:

00:39:56,866 --> 00:40:02,399
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

00:40:02,400 --> 00:40:08,866
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

00:40:08,866 --> 00:40:18,132
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:

00:40:18,133 --> 00:40:28,166
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

00:40:28,166 --> 00:40:34,266
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

00:40:34,266 --> 00:40:44,099
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

00:40:44,100 --> 00:40:52,333
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

00:40:52,333 --> 00:41:01,199
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

00:41:01,200 --> 00:41:08,466
Facebook because that’s where they put this information. They don’t have the same kind of expectations of privacy and confidentiality and

00:41:08,466 --> 00:41:14,866
what’s inherently theirs that the rest of us do, so it’s a challenging situation.

00:41:14,866 --> 00:41:20,466
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

00:41:20,466 --> 00:41:23,232
when they’re 21 or 22, right? JULIE SAPP: Exactly.

00:41:23,233 --> 00:41:26,166
FEMALE: And you can’t scrub it. JULIE SAPP: Yeah, absolutely.

00:41:26,166 --> 00:41:32,632
JEFFREY KOPP: Jeffrey Kopp, NIDDK. Thank you, Julie. That was a wonderful talk. I have two questions about possible opt-outs on the

00:41:32,633 --> 00:41:40,899
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

00:41:40,900 --> 00:41:43,800
placement? JULIE SAPP: Oh gosh, that’s such a great

00:41:43,800 --> 00:41:46,633
question and I don’t actually know the answer to that.

00:41:46,633 --> 00:41:53,199
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

00:41:53,200 --> 00:42:02,166
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

00:42:02,166 --> 00:42:08,499
going—some patients say, “I don’t want to know anything.” Have you thought about an opt-out on the duty-to-warn?

00:42:08,500 --> 00:42:15,600
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

00:42:15,600 --> 00:42:22,966
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

00:42:22,966 --> 00:42:29,566
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

00:42:29,566 --> 00:42:38,099
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

00:42:38,100 --> 00:42:46,033
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

00:42:46,033 --> 00:42:55,866
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

00:42:55,866 --> 00:43:02,799
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

00:43:02,800 --> 00:43:09,933
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.

00:43:09,933 --> 00:43:13,699
JEFFREY KOPP: Good. Thank you. MATTHIA KRETZLER: Matthias Kretzler,

00:43:13,700 --> 00:43:17,866
University of…oh. Marilyn, please go on. MARILYN HAILPERIN: Thank you. I’m from the

00:43:17,866 --> 00:43:23,932
NephCure Foundation. We’re a patient advocacy foundation that supports research. I want to know how we should be engaged in starting this

00:43:23,933 --> 00:43:35,333
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

00:43:35,333 --> 00:43:42,933
terms of setting the stage for understanding how to engage in these conversations of informed consent. So, how would you suggest that we

00:43:42,933 --> 00:43:47,066
become engaged in this process from a patient education perspective?

00:43:47,066 --> 00:43:53,132
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

00:43:53,133 --> 00:44:03,399
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

00:44:03,400 --> 00:44:12,100
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

00:44:12,100 --> 00:44:23,866
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

00:44:23,866 --> 00:44:31,499
and that’s a way that they can participate without having to undergo the full-blown exome sequencing. Does that make sense?

00:44:31,500 --> 00:44:38,966
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

00:44:38,966 --> 00:44:43,732
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

00:44:43,733 --> 00:44:47,399
looking for is some specificity around how to have a good dialogue?

00:44:47,400 --> 00:44:50,366
JULIE SAPP: Yeah. Great. MATTHIAS KRETZLER: I think one important point

00:44:50,366 --> 00:44:58,699
because we were planning to actually address that with the speaker is…University of Michigan, Matthias Kretzler. What I have experienced in my

00:44:58,700 --> 00:45:08,233
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

00:45:08,233 --> 00:45:20,266
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

00:45:20,266 --> 00:45:28,032
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,

00:45:28,033 --> 00:45:40,233
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

00:45:40,233 --> 00:45:48,899
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

00:45:48,900 --> 00:46:01,666
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

00:46:01,666 --> 00:46:11,066
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

00:46:11,066 --> 00:46:18,899
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

00:46:18,900 --> 00:46:30,766
in clinical working practice. So, I think the efforts in NIH are fantastic to learn which of these modalities are most implementable and practical,

00:46:30,766 --> 00:46:39,866
but even as [---] referred to in a setting where we have a multicenter study where we have all patients across North America, it becomes

00:46:39,866 --> 00:46:47,832
extremely challenging to ask questions like, if we have an actionable item, who actually pays for the trio lab?

00:46:47,833 --> 00:46:51,233
JULIE SAPP: That’s a big question. MATTHIAS KRETZLER: And there are other

00:46:51,233 --> 00:46:56,199
elements which I think are currently, to my knowledge, not resolved.

00:46:56,200 --> 00:47:01,400
JULIE SAPP: Right. No, I think they’re really big and really important questions. Do we have time for one more question?

00:47:01,400 --> 00:47:11,000
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

00:47:11,000 --> 00:47:18,700
regarding personalized medicine, patient education and physician education because they’re two-pronged, they have to be done

00:47:18,700 --> 00:47:27,800
together, and there is a grant application regarding setting up a large research project about this, which will predict [---] and we’ll let you

00:47:27,800 --> 00:47:36,566
know how that happens.

JULIE SAPP: Thanks again.

Date Last Updated: 9/18/2012

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