Jeff Botkin:So, I’m going to make a few comments
in the beginning here, and then I’ll turn to each of the panelists and see what additional
comments and questions they want to have. And I think, as you’ll see, that I and a couple
of the other panelists, at least, haven’t been immersed in the eMERGE system. So, a
lot of what I’m going to present here will be in the form of questions to prompt further
discussion, rather than presenting an alternative view of how things might be done.
So, next slide, please. So, just a couple of background comments about
what makes children different and why we may want to take particular interest on this group
of people, and, obviously, health conditions impacting children are different in many respects
from adults. Not entirely different: both suffer from asthma and atopic dermatitis,
et cetera, although the diseases may be somewhat different between children and adults. So,
obviously, the need to focus on kids and the healthcare conditions that affect kids. Now
in addition, obviously, many adult conditions may be secondary both to genotype and exposure
during childhood years, so there’s a need, potentially, to focus on kids in order to
better understand adult onset conditions. A big issue, of course, is that serious health
conditions in children are uncommon, and this will get, I hope, to a little bit of discussion
about recruitment goals for kids within the system and what would be adequate to study
conditions that are less common than things like can asthma or ADHD.
Kids can be found to be at risk for diseases early [spelled phonetically] years or decades
in the future, presenting, of course, some ethical issues about return of results. And
obviously children can’t consent to participation in research themselves. Older children can
assent. Interesting process in and of itself, but obviously, the need to engage parents
and children in the educational process, as well as the return of results process. So,
giving results to me is different than giving results to me about my child, and certain
parents and parent-child relationship, of course, is considered to be a vulnerable population
and a vulnerable relationship to psychosocial impacts, so we want to be particularly careful
about how we manage this type of information. Next slide, please.
So, here’s a couple of questions, and really just keying off Hakon’s presentation under
the general category of obstacles to current research. And he and I have an incongruity
between adult and pediatric datasets. Perhaps a need to clarify how pediatric and adult
conditions are selected for analysis, so within the network, but basic question, and I took
both comments to suggest that perhaps there’s not a need to have overlap here or any increased
synthesis of phenotypes, that it’s perfectly appropriate to focus exclusively on kids’
conditions and perhaps on adult conditions and overlaps where may be appropriate.
This last point, really, is a broader question, and I think the pediatric component is a newer
component, and Susan’s folks have been enormously productive with this. But perhaps a larger
background question is, given the rare nature of many pediatric conditions, given the need
to have a diversity of participants in the network, is the current network large enough
with respect to pediatric participants, and what are the thoughts about expansion, if
it’s not, over time. Next slide please.
Hakon emphasized new approaches to existing data. Copy number variants are good analytic
tools available, and really just reiterating Hakon’s presentation here in order to prompt
further discussion. New impacting better data on, as he stated, frequency and boundaries
of CNVs, and database of genomic variation. And can eMERGE contribute to data on pathogenicity?
Is the eMERGE network uniquely placed to fill in a significant gap about our better understanding
of CNVs? Next slide.
And prospective directions. Again, it came up in Hakon’s presentation, where he presented
the concept of a custom chip with [unintelligible] and clinically relevant variants and CNVs,
and there was a question about, is the field ripe for a tool of this sort? How would this
impact the nature of testing and return of results and informed consent, and the other
types of issues that the network has been battling with?
Next slide. So, a couple of additional questions raised
by panelists in some of our interchanges. So this first bullet point really is a reiteration
of that question about phenotyping. Now, second bullet: Should the eMERGE consortium
consider more gene environmental interaction data and collection for children? Seems to
me to be a particularly important and potentially rich area for this network to explore. Now
what are the opportunities and barriers to collecting those sorts of data for network
analysis? Questions about potentially unique issues
with pediatric participants. We’ve had a couple of panels on informed consent and return of
results. I think some, obviously specific focus, to the extent that these issues are
somewhat different within families and within the pediatric patients, adolescent patients,
et cetera. Return of results for dual-onset conditions, results of uncertain clinical
significance, external findings, we’ve got quite a bit about. And this issue of when
parents are analyzed or sequenced in order to better clarify a child’s results. What
are the issues that arise when the analysis extends to family members in this way? I think
my last slide. So other general questions that came up, and
I think there was a reference to this a little bit earlier today, so a real opportunity for
eMERGE potentially to work together with the new newborn screening sequencing projects
and be mutually supportive there. And so I’d be interested in a little more information
about what’s anticipated in that regard. And then either target conditions for genomic
analysis that may have early clinical utility in health care for children. There was a question
that came up, and I think part of this — part of the implication is that we’re perhaps still
looking for an additional proof of principle example. Where’s the lower hanging fruit in
the delaying of health care for children that might be a significant focus here to demonstrate
the utility of the approach being used within the network.
So I’m going to stop there, and then what I’m going to do is run through our list of
panelists, and see whether they have additional comments or questions. So I’ll start with
John Harley. John Harley:We collect assent of the age of
13, and at the age of 18, we send a notice to participants in research studies about
whether they would, now that they are considered adults, whether they would wish to continue
their participation or not. If we don’t get an answer from them, we leave it the way it
is. If we get an answer from them, we respond, to the extent that we can, to follow their
wishes. And so that seems to be a fairly — the institution as a whole seems to be pretty
comfortable with this approach, and I think that it’s fairly standard across the pediatric
research institution to do it this way. The — Hakon has presented a lot of interesting
discoveries, which impresses me there’s gold to be mined left in all the work that’s gone
into doing the GWASes and that we should not ignore that. And there’s a wonderful opportunity
there. And it is an incredible database that will yield for years to come. The pediatric
group has one of the best opportunities for finding the outliers that you were talking
about before in the outlier — in doing outlier analyses, especially for sequencing. The severe
phenotypes of children presenting with adult diseases early in life generally has a much
higher genetic load, and would expect to be a very high yield small group, large odds
ratio kind of ascertainment group with which to work. And that seems to be a great opportunity
for us. There are lots of issues with integrating
the pediatric latecomers to the adult world of eMERGE, and I personally had resisted the
idea of having a pediatric work group that was separate because it would force us to
integrate better, and, as a consequence, I’m now chair of the pediatric work group — [laughter]
— and — but we have but this tendency to reproduce everything that the adult side does.
Every little issue that comes up is considered from the perspective of pediatrics, and then
we end up duplicating the work without forcing ourselves on the adult side in a way that
also encourages the adult side to come our direction some. So that’s an issue that will
probably continue, but we will continue to remind the adults that we’re here, and that
it’s an important piece of how we go forward. And the pediatric groups offer some incredible
opportunities. I mean childhood obesity is rampant; it’s almost a public health crisis.
Asthma is increasing in frequency and involves millions and millions of children and people
at this point. Bad allergies are a huge problem in the pediatric population. We have a different
concentration of illnesses, but many of them linger into the adult world pretty easily,
and so we will — we’ll find phenotypes that cut across and take maximum advantage, and
we’ll also do phenotypes that are pediatric oriented. There was talk earlier about the trouble with
using opiates. And there’s a huge problem with this fetal syndrome from children with
mothers who are addicts of opiates. And so those children cost — or live in our intensive
care units and cost billions, and understanding how they respond and can recover from these
things is really important. On the other hand, there’s never been a GWAS of any kind done
with appendicitis, which has a, what, 50 percent mortality rate and is only cured by modern
surgery. Female Speaker:If left untreated.
John Harley:If left untreated, the natural history of this problem.
[laughter] It’s 100 years ago, if you couldn’t do an
appendectomy in 30 seconds, you know, you were — let’s say [spelled phonetically].
And so there’s lots of interesting ways to interact and forward — and I appreciate the
Hakon going to the trouble of putting all that together from our perspective.
Jeff Botkin:John, this is Jeff. Let me clarify with you what you had mentioned about the
— when you send a notice out to families, now adults, of kids who have been enrolled
and you don’t get a response, how does — what is the network doing there?
John Harley:We leave it alone. We’ve tried to reach them, we made a good effort, and
they stay in the system. We continue using their information and data into their adulthood.
Male Speaker:And do you consider them consented or just not opted out? And what are the implications
for the use of the data there? John Harley:So we consider them still usable,
whatever you want to call that, in terms of the language you’d like to use; they’re not
thrown out. No active step was taken to eliminate them. And so —
Male Speaker:You wouldn’t — you might not recontact them as a consented participant.
John Harley:Yeah, we can’t reach them. So recontacting them for consent for something
else is not — is not — Male Speaker:Not an issue?
John Harley:Not admissible [spelled phonetically] for us. Not an issue.
Male Speaker:But it might be — Hakon Hakonarson:So on the talk side, we recontact
everyone who turns 18; maybe a success rate there is about 30 percent. But the other 30,
35, the other 65 percent, basically, they can’t stay in the database, but nothing new
gets added. But it gets just the identifying states they’re in in the same way we had it
when they turned 18. Male Speaker:Okay.
Female Speaker:This is Mary, we have the — Male Speaker:
We may want to pick up on that conversation a little bit more. Female Speaker:We have the same thing at St.
Jude. If we can’t confirm that the patient wants to stay a subject after the age of majority,
then they have to be dropped from the study. Teri Manolio:Well, that sounds quite different
Jeff Botkin:So let me delay further conversation on that point, which I think is quite important.
Let’s finish up with our panelists here and then get back to that discussion. So, Tracy?
Male Speaker:Yes, thank you. First of all I want to thank the eMERGE group for asking
me to be part of this. It was a very interesting day. I understood some of what you had to
say and I enjoyed learning about it. Appreciated my fellow panel members’ efforts.
Bob, I think Jeff “emerged” my comments into his slides perfectly, so I won’t take up anymore
time, it’s the end of the day here. But I will say I feel like eMERGE, as an entity,
is uniquely positioned to lead this translation of genomic information into pediatrics. It
will be harder, we’ve talked about all the barriers that make it a little more difficult,
but I think — I’m excited about what I hear going on. I look forward to any or all clinical
decision support tools showing up on my PC at the office, and look forward to ordering
that custom eMERGE chip on the newborns. So I’m excited about where we’re going. I
think my comments have already been included and look forward to other peoples’ thoughts.
Jeff Botkin:Great. Thanks, Tracy. Cynthia. Cynthia Powell:Yes. Hi, can you hear me okay?
Hello? Male Speaker:Yup, yup, yes, got you.
Cynthia Powell:This is Cindy Powell from UNC. And I’m a clinical geneticist and a pediatrician.
And I’m also one of the PIs here on our newborn screening whole exome sequencing study. So
I certainly think that, to answer one of Jeff’s questions, that there is a great opportunity
for eMERGE and our U19 project to share information. I think that one of the things that probably
applies in some of the areas — the other areas discussed today regarding return of
results is the FDA oversight, and although I think we may be one of the sort of guinea
pigs for this, but the FDA is asking us to submit sort of a pre-application to determine
whether we need an investigational device exemption for our study. In preliminary discussions
with the FDA, we’re — it seems that it revolves around return of results that are obtained
through research, you know, whole genome sequencing, and you know, if they’re approved in a CLIA
lab, that likely will be okay. But I think, you know, that the jury is still out, and
we’re waiting to find out, you know, how this is going to work. So I think going forward
this certainly can add, you know, cost, time, to many of the research projects that are
going to use next-gen sequencing. In thinking about some of the areas of study,
I’ve heard a lot about, you know, what we think about the common disorders of childhood
with obesity and asthma, autism already mentioned, but also I’d like people to consider birth
defects, certainly as a group, you know, one of the primary conditions of childhood, and
whether there would be some way to use the eMERGE network to look and gather, you know,
more data, whether it’s GWAS or sequencing data, about birth defects. And, you know,
thinking about the National Birth Defects Project and the CDC, I think, you know, they’re
gathering DNA samples on patients that are being ascertained and getting a lot of great
clinical information, but, you know, would probably welcome more next-generation sequencing
studies of these patients and, you know, utilizing their registry.
I think, one thing, is that the return of results, I think, is different when one thinks
about the age group, and although, you know, there’s a lot of overlap with incidental findings
that would be, you know, considered for both an adult and a pediatric patient, I think
we need to think carefully about the pediatric age group and going forward with this. You
know, like Heidi described for the Boston group, you know, we have a group at UNC that’s
looking at return of results not only for our adult patient population or research subject
populations, but also in pediatrics, and there’s definitely a lot of differences. And I think,
you know, we need to think carefully about how we’re going to, you know, use the data,
but yet, you know, if there’s certain conditions, for example, conditions that we wouldn’t want
to return to parents of the child, let’s say, you know, if we’re talking about Alzheimer’s,
but in the future, should a treatment, you know, be found, that’s beneficial, that could
potentially could start at a young age, or at least an early adulthood, we’d want some
method to go back and, you know, obtain that information and try to return that information
to families. And the other thing that I just wanted to
comment on is, you know, in pediatrics, although we think of the child is the patient, we are
evolving to more family-centered care. And I think, you know, going forward, you know,
thinking about how does family-centered care in the genomic age can be utilized and considered,
and such as, you know, if there’s a condition that’s identified in a child, such as an autosomal
dominant condition, likely one of the parents has it, and whether putting those results
into the parent EHR would be, you know, beneficial, and how one would go about doing that. So,
that’s all I have. Thanks. Jeff Botkin:Excellent. Thank you. All right,
I wanted to, you know, I guess about seven minutes or so. I wanted to pick up on at least
two points and then open it for whatever else folks have to say.
I want to get back to this question of re-consenting kids once they reach the age of majority.
And I believe what OHRP has to say about that is that re-consent is appropriate if the sample
or data is still subject to ongoing research, but, if you can get a waiver of consent, if
the ongoing research is considered — meets the criteria for a waiver, or, of course,
you can de-identify the information. But my guess would be, in this context, de-identification,
since you’re linking this to an electronic medical record, would not be considered feasible.
Maybe that’s a question rather than a statement. Other thoughts on that issue?
Male Speaker:Yeah, we have an I2V2 system that — we have de-identified patient records
that are available for non-human subject research in our institution for any faculty member
that wants to explore those data. Now, in the narrative portion, there’s a — claiming
that part is a subject of ongoing concern, but we have enormous amounts of data, a million
records. I think Boston has almost 2 million —
Female Speaker:Yeah. Male Speaker:– records and I don’t — CHOP’s
situation which is similar. So we have lots of de-identified data we can link to genomic
data and have it all be de-identified. That’s what we actually — I mean, I — a little
a bit sort of naïve, as if de-identification was a static property and it’s [unintelligible]
— Male Speaker:[unintelligible] de-identification.
Male Speaker:Yeah, and what we know is that biologic data and genomic data is so inherently
rich in attributes, that even if it’s de-identified, re-identification risk never goes to zero,
so the residual risk needs to be controlled with policy. And obviously there’s a whole
large working group that pediatrics will grow to know and love as far as eMERGE that’s looking
at quantitative de-identification science. But I do think the notion of — informatics
community, that the idea that de-identification is a safe wall you can hide behind is gone
now, and you just have to deal with non-zero re-identification risks in any of these classes
of data. Male Speaker:So this is [unintelligible].
I’ll play devil’s advocate just a little bit. It seems to me that the entire focus of the
eMERGE is to use existing electronic medical records to make large-scale genomics possible.
And I agree strongly that the diseases of children are worth studying, and that, in
fact, that diseases — adult diseases which have their onset in childhood are more likely
genetic. But one of the attributes of the eMERGE system is that you can identify 18-
and 21-year-olds that had the disease when they were 10, and you can get their DNA now.
So why do you need to go and collect DNA of all of these 5-year-olds and 10-year-olds?
Now newborn screening I think is a very different thing, [unintelligible], and probably pharmacogenomics,
because little kids are not just small adults. And so if you want to get the biological correlates,
you need that. But for many of the diseases — severe atopic dermatitis, pediatric onset
psoriasis — why not just got out and find people that had it 10 years ago?
You know, and I am playing devil’s advocate, I do not fully think that — and obesity,
I mean, come on, you have records, you can go back 20 years and find kids who were obese
at 3 years old. Female Speaker:But phenotyping them as a child,
you don’t have the, you know, phenotyping records back.
Male Speaker:Yeah. Female Speaker:It’s harder to —
Male Speaker:Electronic medical records — Female Speaker:It’s still, I think, it’s —
Male Speaker:And? Female Speaker:
[unintelligible] pediatric system than an adult system. Female Speaker:Yeah, so that is the other
piece of it. Is that we’re all at pediatric hospitals, so — and then they go on to someplace
else, but coming back to, you know, the [unintelligible] children enter the Brigham, so I have somebody
at the Brigham identify — how do I go to Children’s and get their medical records.
Do you see what I’m saying? If people are in the system that’s longitudinal like Geisinger
— Male Speaker:Geisinger is a good example.
Isn’t the idea of the consortium to use electronic medical records for your phenotyping, and
not go out and weigh a child and — Female Speaker:But what I’m saying is that
they suggest those to go to different institutions to get the medical records, and I think that
that’s probably a big piece of the problem. Male Speaker:Imagine you’re at the VA. Imagine
the VA with 85-year-olds trying to get, in 50 years, electronic medical records from
their childhood. Male Speaker:Yeah. Well, we’re trying from
the DoD, and that’s been going on for — [laughter]
Male Speaker:Or perhaps the more provocative notion, in the era of telomere shortening,
that you’re — that the common wisdom of a static genomic compliment that you keep from
a childhood is, in fact, completely wrong, and it’s really quite dynamic.
So samples require — Female Speaker: [unintelligible] you’re enriched,
for a lot of children who have a lot of diseases, and picking those out of all of the adults
is much harder to do. I think there are practical issues for picking them.
Male Speaker:So you’re imagining that all those children stay fat, you know, and there’s
a lot of change between the age of three, when you have early childhood obesity, and
the age of 21. A lot of those kids will get skinny.
Female Speaker:But Larry, the point is you have the —
Male Speaker: — if you’re ascertaining on being fat.
Male Speaker:But no, you’re ascertaining them on being fat at age 3.
Male Speaker:Oh. How do you do that as an adult?
Female Speaker:Where are you going to get that information? People don’t remember. People
— Male Speaker:You go and you walk up to [unintelligible]
— I’m talking about electronic medical records. Female Speaker:You use date stamps on the
records at the time of service funding, measure them. That’s how you determine it.
Male Speaker:But I think the point is that records go way, way back. But — and we can
identify some individuals who are, for example, in our biobank at MRC that were obese children.
Right? But our average age is something like 52 or something like that now. So even if
we go back 30 years, we’re not covering that. Male Speaker:So you’re saying you can’t do
it because you don’t have the sample funds. Male Speaker:We learned that adult records
are not electronic. Male Speaker:If your adult EHR [unintelligible],
you were a fat 3-year-old. [laughter]
Female Speaker:Well, maybe we need to — thank you for your provocative question. We have
about two more minutes for this panel, so are there other issues that we want to address?
Female Speaker:I think if you’re going to think about research studies, then that might
be the case that you can, you know, ascertain adults who were fat when they were younger.
But if you’re going to talk about clinical utility of any of this, the pediatric age
population of the time that you want to intervene. Male Speaker:I have an off-the-subject issue.
That we have the opportunity to bring to the clinic new technologies that haven’t been
— that haven’t really made it to clinical utility in the way that we imagine that they
will in the future, like methylation. The methylation pattern that you talk about at
childhood are going to be substantially different in adults, and those methylation patterns
are partially inheritable — are partially heritable. You can tell that your grandmother
smoked from your own methylation pattern in small population basis. And so I think there
are genomic technologies that we haven’t applied yet in eMERGE that will obviously be — that
look — so every promise, I should say, so every promise of becoming clinically important,
and we should prepare ourselves for being able to apply those when the research shows
that they are clinically relevant, like methylation patterns.
Male Speaker:Is that where eMERGE should be going?
Male Speaker:I think it’s one of the — one of the places where we should prepare ourselves
to take advantage of that for specific clinical issues when the research supports the methylation
patterns being important. Methylation patterns interacting with the genes we have is an obvious
way of leveraging the GWAS studies that we’ve already done.
Teri Manolio:Okay. So, we’re now at the stage — I just want to be sure. Jeff Botkin, did
you have anything else that you wanted to comment on in the pediatric panel?
Jeff Botkin:Nope, all finished, thanks very much.
Teri Manolio:Great, thank you.