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Male Speaker: Okay, so now we thought we would take the
last part of our program this morning, as I mentioned earlier, to highlight a few of
the initiatives that NHGRI has supported that are in the implementation science space, and,
as we mentioned yesterday, a lot of our discussion was devoid of young kids, and even younger
kids. [laughs] So Anastasia is going to talk about the newborn sequencing program.
[laughter]
Anastasia Wise: Great. So, first off, I would like to thank
the organizers for having come down today to talk about this program, and I'm going
to talk to you about just a single NIH program that's a joint initiative between two institutes
at the NIH. So this is program that's been started recently between the Eunice Shriver
National Institute of Child Health and Development and NHGRI, the Human Genomics Institute. And
so what I'm going to do is talk to you, rather than focusing on the specific grants themselves,
but a little bit about the process of starting this genomic medicine project, and some to
the challenges that we faced while developing the initiative.
So, as many of you are aware, the cost of sequencing has been dropping very rapidly,
and this has allowed us to start considering using sequencing in a clinical context, as
the cost of sequencing is now starting to be very close or similar to the cost of doing
individualized genetic tests. In the United States, the newborn screening public health
program captures most of the population; over 99 percent of infants are tested and screened
as part of the newborn screening program in the United States. This is their first testing
that's done, and it's the most common genetic testing that is conducted in the United States.
However, most newborn screening testing is not done using DNA or any form of sequencing.
However, what we've learned from the community is that this might be one of the first groups
that would really be interested in applying sequencing in more of a clinical context,
and it could potentially reach a large number of the U.S. population.
So, to begin looking into this, we held a workshop back in December of 2010, this workshop
Newborn Screening in the Genomic Era: Setting a Research Agenda, and there's most information
that can be found online about this workshop that we held. And what we really heard at
this workshop was a call to do pilot studies, to look more into what sequencing could add
both to newborn screening as a public health program, as well as newborn screening more
in a genomic medicine context.
So the first thing that we really heard from the members who were present during this conference
was that we needed to look at the public health context, and could sequencing provide the
same type of data that these biochemical tests that are currently being done provide? As
well if we did sequencing in newborns, could this information be used throughout their
lifetime for genomic medicine and care throughout their life.
There were a number of questions that were raised about needing to explore the ethical,
legal, and social implications of this type of research, especially since we were talking
about newborns and providing their sequencing information, and potentially using it for
their care throughout their lifetime, where they wouldn't necessarily be the ones who
were then consenting at birth for the sequencing to occur. There was also a lot of questions
about the clinical validity and utility of this data, and that we needed to focus at
least at first on some higher-risk individuals, such as infants that were in the neo-natal
intensive care unit, or NICU, and incorporate the longitudinal data, so follow some of these
individuals over time and see how the information could be used in their care.
We took this information and started putting together some ideas for what this initiative
could look like between our two institutes, and presented this to our councils at both
NICHD and NHGRI. These councils serve as advisory boards for us to be able to present information
and to be able to provide feedback and recommendations for new initiatives that were developing.
And some of the concerns that we heard from both of our councils was that they had some
real ELSI concerns about the ethical, legal, and social implications of this research.
They wanted to really think about the populations that we were selecting, whether these were
going to be healthy or sick newborns, and the study designs, they thought, should really
be based upon what that population was.
There was also some concern about public perception and public relations, because at this point
in time, there had been some highly-publicized articles that had come out about newborn blood
spots being used in research, and the need to be able to consent parents when those blood
spots were taken for doing newborns screening for research use, if they were going to be
used in that context later on. So we really heard from our advisors that if we were going
to develop this type of initiative, we either needed to collect samples that were different
from the newborn screening sample and have them be specifically consented prospectively
for this sequencing study, or that the samples that were being used that were from the newborn
screening program needed to be specifically consented for research use.
So, as we start putting together this initiative, this is the general purpose that we came up,
which is to explore, in a limited but deliberate manner, which really captures that pilot project
idea, the opportunities to use genomic information for broadening our understanding of diseases
identified in the newborn period. This is intentionally a very broad mandate and purpose,
and that was intended to be able to cover both the public heath setting as well as the
more genomic medicine context, so that the researchers would really be able to look at
questions that related to both of these issues.
We also laid out for the researchers three questions that the grants had to address.
They had to at least one of these three questions in their research proposal. The first of these
questions was to look at disorders that are currently screened for in the newborn screening
program and determine whether or not genomic sequencing could replicate or augment those
results and be used in the newborn screening context. The second of these questions was
to look at what knowledge we could gain for conditions that are not currently screened
for in the United States as part of the newborn screening program, and see what genomic sequencing
could add to other conditions that might be relevant to the newborn period. And then the
third question was what general additional clinical information could be learned from
doing genomic sequencing in the newborn period that could be applied to clinical care?
We also require that each of the applicants perform three different components to their
research studies. The first of these was they had to have the sequencing component. The
second was they need to perform some sort of clinical research addressing one of those
three questions. And then we really wanted the ELSI -- ethical, legal, and social implications
-- research to be integrated as a part of these projects, and so each of the research
projects also has to have an ELSI component that's related to the clinical research that
they're doing, and really looking at the social and ethical implications of this research
work.
Since there had been some concern as well about how this was going to be received by
the public, when we put out the announcement for the four awards that we made in September
of 2013, we also did a tele-briefing and press release in order to be able to bring a group
of press officers together and really explain to them what our thoughts were behind the
program, what it was we were trying to address, and little bit of information about each of
the four grantees that we were awarding. And this really did help with the press that came
out from the announcement. As you can see, a number of these headlines, it came out very
positive. "NIH studies explore promise of sequencing babies' genomes," "Researchers
study the value of DNA analysis in screening newborns," and some of them still came bound
to that question of, "Is this good medicine or too much information? What happens if you
screen all of a baby's genes?"
So we think that we were able to then capture a lot of what the program was intended to
study, which is really how can sequence information add to the care of newborns, both in this
more public health and genomic medicine context.
As we move forward with the program, now that we've made these awards, there have been additional
other challenges that have come up. We found that we've received some questions from the
FDA, and we are looking into the need for investigational device exemptions for these
research projects because they are using sequencers that were -- have only so far been approved
for use in a research context, and potentially using that information for clinical care.
The FDA has looked at this from the perspective that even if we are doing the sequencing in
a CLIA of CAP-certified facility, that that's really certifying the process, and they're
very interested in whether or not the actual device itself, and that includes the entire
pipeline, from processing the initial samples through the sequencing on the machine to the
analysis pipeline itself, whether or not that has been approved by the FDA as a diagnostic
test. And they've had some concern over both the sequence data being returned for clinical
use, as well as the data being placed in electronic medical records for future care; so, not just,
have the results been Sanger validated for being used immediately for these newborns,
but how is this data going to be used in the future?
So we are working currently with our grantees, as well as the FDA, to be able to address
these questions, but I think this really show how even as we start looking into these areas
and putting forwards these new initiatives, it's a changing regulatory landscape, and
we're hoping that what we learn from these first initial forays into newborn sequencing
can teach us something about genomic medicine initiatives for the future.
And with that, I would like to thank all of our supporters, both at NHGRI and NICHD, especially
Tiina Urv, who is the program director at NICHD, my counterpart there, and ask if you
have any questions. Thanks.
[applause]
Male Speaker: Questions? Mark.
Mark Abramowicz: Mark Abramowicz in Brussels. Thank you very
much. This opens fantastic perspectives, but I also have a few concerns about if you take,
for example, those disorders for which we already screen using the phenotype, that means
knowing what is happening in the baby, if you shift to the genotyping, what are you
going to do with all the variants of unknown clinical significance? Are we ready to handle
this?
Anastasia Wise: And that's one of the questions that these
grants are really looking to address. So, for example, one of the projects is specifically
looking at, like, sensitivity and specificity of the genomic sequencing results, and trying
to see can we get results that are equivalent to what was being done with more of those
biochemical, phenotypic tests that are currently being used for newborn screening, and can
we replicate that same kind of information? Is it really producing the same type of information,
or is this more of an additional type of information that could be useful in some contexts but
not necessarily in others?
Mark Abramowicz: If I may have a second question? About the
same issues of neo-natal testing for those conditions that you can act upon, what are
the really new ethical, legal, and social issues? You might argue that testing for MSUD
using biochemical testing has exactly the same questions. What do you see as new questions
in that range, the A column that you mentioned on your slide?
Anastasia Wise: So you're asking what are the new issues with
testing newborns beyond what was already concerned with doing the newborn screening testing?
So, part one of the ethical issues that came up with this initiative was the fact that
we were looking not only at testing sick infants, but also healthy infants, and whereas screening
is looked at as being part of the public health paradigm where these are conditions that you
really know how you're going to act on them, and because of that, doing that screening
can be justified. If you moved to doing sequencing, then we don't necessarily know how to act
on all of that information, so there was some concern about the ethics, then, of returning
that information to the parents if we aren't necessarily as certain of the information
from the sequencing as we are for the standards that a screening test would have to meet.
And so that's another question that some of these studies are looking at.
Male Speaker: So if you discovered one of these cancer-causing
genes in these newborns, what would you do?
Anastasia Wise: So the studies are looking at that in different
ways. We did not lay out for the grantees what results they needed to return or how
to handle return of results, and that's actually a question that they are looking into. So,
for example, one of the studies is looking at returning medically-actionable results
that are medically actionable in the newborn period, and then asking the parents about
whether or not they would like to receive other types of information in different bins
or categories of information, trying to study what is it that people really want to see,
and is that useful both to the parents as well as the clinicians.
Male Speaker: But you have guidelines, at the moment, published
guidelines, that you should inform the --
Male Speaker: In the clinical setting, not in the research
setting.
Anastasia Wise: Yes, that's in a clinical setting. Yeah.
Male Speaker: Okay.
Marc Williams: Correct. Yeah, so, again, just to clarify
that point, the ACMG guidelines do not -- they do indicate return for children, if sequencing
is done in children, but they are only for clinical application of exome and genome sequencing,
and they are specifically excluded from research for the very purpose of trying to answer some
of the questions that are being raised by this.
I wanted to come back to the point that Mark Abramowicz raised, and even though the focus
of this medicine -- of this meeting is genomic medicine, I think it's really important to
not get tunnel vision relating to the fact that, ultimately, precision medicine will
take advantage of any and all information that bears on the problem. There is never
a situation, in my opinion, where you would sequence the phenylalanine hydroxylase gene
and impute the phenylalanine level based on the sequence. You will measure the phenylalanine
level. And so we have to understand the fact that there -- while we are focused on genomic
medicine, there's a whole range of other things that are going to be important in terms of
improving care, and in some cases, it's going to be the combination of these other things
with the genomic information that is going to give us the best results. And so it's -- I
think it's really important for us to have a focus on genomic medicine, but to understand
that it's not the be all and end all.
Anastasia Wise: Thanks, Marc. I think that's actually a very
important point, and that is something that we tried to make sure we were cognizant of
when we're laying out these questions and that we were talking about sequencing as augmenting
or adding information to what's currently learned when you do these types of newborn
screening programs, rather than necessarily replacing the existing tasks.
Male Speaker: I want to ask a clarifying question. So in
the projects that are currently funded, are the traditional newborn screening data being
combined with the sequencing data, or, I mean, across the board?
Anastasia Wise: So, all of the newborns will receive traditional
standard newborn screening testing, and then the way that the different studies are looking
at it, some of them are then doing sequencing on a subset of those individuals. Some of
them are looking at a NICU -- neonatal intensive care unit -- setting, some of them are looking
at healthy infants. Some of them are specifically looking at infants that tested positive on
some of those newborn screening tests. They're looking at a variety of different populations
from there.
Male Speaker: What exactly is the FDA concerned about with
respect to data being associated with a record?
Anastasia Wise: So, the FDA was concerned that it posed potentially
a significant risk which would necessitate an investigational device exemption if we
were doing sequencing as part of a research project and then putting that information
into a medical record where it could be queried later for other conditions that might come
up during the child's lifetime. They were particularly concerned with if any of that
information went into a medical record that had been -- that had come off of a sequencer
that was not yet FDA approved; that you needed some sort of investigational device exemption
that would then look at the risk of that particular situation and address those concerns with
the device itself.
Male Speaker: So they're banning you storing the information?
Anastasia Wise: No, they weren't saying that they were banning
us storing the information. They were just saying that because these devices are not
approved for clinical use, that if you were doing the sequencing on a research machine,
even if you were doing --
Male Speaker: Yeah, okay.
Anastasia Wise: -- it in a CLIA setting, that you needed an
investigational device exemption in order to be able to put that data other places.
This is one of the first cases where they've come to us --
Male Speaker: This looks like overreach.
Anastasia Wise: -- to discuss this.
Female Speaker: So I -- you know, we have one of the grants,
and I think that the challenge they're concerned with is if we were to take a whole genome
sequence or exome and deposit all of the raw data or even the variant call file into the
medical record in anticipation of using it later without doing what we normally do in
a clinical lab which is saying or confirming, or, you know, making sure those results are
up to the reporting standards. They're okay if we put our clinically-interpreted report
with the variants we have identified and interpreted and validated into the medical record, and
we are going to be doing that as part of the study, but they don't want us to put the whole
variant call file in there so that later on, you know, it will be queried.
[laughter]
Male Speaker: That's an impossible standard to --
Male Speaker: We need to --
Teri Manolio: Yeah, I mean I think it's important to recognize
that the FDA should respond to these concerns, and we can't speak for them, so can we set
this aside? That's not the major aspect of this program. The major aspect of this program
is how do we go about using sequencing in the newborn period.
Male Speaker: Okay, the question is to understand why they
object, what the rationale for the objection is, and I understand that they are much more
powerful than all of us combined.
Teri Manolio: Well, not only that, but I don't think that
we can speak to that, so -- I honestly don't think we can speak to it, so let's move past
that and get into other scientific issues.
Geoffrey Ginsburg: Last question, please.
Gert Matthijs: I'm Gert Matthijs from Belgium. My question
is the least scientific you can get. It's good to hear that you brief the press, and
then apparently whatever you get in the press then makes sense. Now the thing is, our local
press took up whatever was published here on this one, and all of the sudden it says
like, "Americans are Ready to Sequence Neonates," and then we had to reply and say to the questions
of, "Are you ready as well?"
[laughter]
So it sounds like you can brief the press, but on secondary thing, we get in trouble,
so maybe this is not a point to do on, how do we communicate globally on these things?
It's just something that pops up, as you mentioned it.
Anastasia Wise: No, it's good to know.
Geoffrey Ginsburg: When we surveyed all of you, the response
on newborn sequencing was two-thirds not at all, and one-third of you were already doing
it in specialized center. I'd be just curious, could you raise your hands, who is actually
doing newborn or neonatal sequencing, or do we have exomes? Okay, so there's still -- there
are a few hands, they didn't want to raise them very high for some reason.
[laughter]
And we also decided to drop this topic as one of the breakout sessions for this afternoon,
based on some of the responses and prioritization we got from you, but it seems, just from hearing
the dynamics of this discussion, it should be a topic for some future discussion, or
the few people who have already gone down this path a little bit, to link up with Anastasia
and the team, and think about what could be done as a collective group. So, thanks a lot.
Anastasia Wise: Thank you.