Lucia Hindorff: Great, thank you Katrina, and thank you everybody
for your feedback.
Let me pull up my presentation here.
I will be giving a short overview, the last in this series of morning talks here; from
the NHGRI perspective, particularly to CSER.
So we have now heard high level NHGRI priorities as well as priorities from NHGRI’s division
of genomic medicine and the sequencing program from Eric, Terry, and Carolyn.
We have also heard about CSER from the perspective of the investigators from Katrina’s talk.
So, my talk today will focus on CSER from the program office perspective, the history
of the program and how we would like input from all of you today about thinking about
future opportunities in this area.
So, to understand CSER’s future, I think we first need to look at its past.
First in history then, CSER arose from two RFA’s, an initial one in 2010 and a re-issue
in 2012.
We refer to these, as Katrina mentioned, as the U Awards.
From the outset, the RFA’s were framed in the context of clinical care, so, recruiting
patients as they enter the clinical workflow.
We anticipated a number of challenges and opportunities to become evident in generating
genomic sequence data in the clinical workflow.
Interpreting the data for the physician and patient; and whether and how to communicate
results to patients, and in some cases, their family members.
And overarching to this entire RFA was a focus on the ethical legal and psychosocial implications.
So, built in the RFA was this required three-project structure.
Project one: focusing on the recruitment and the return of results in the context of a
clinical genomic study.
Project two: the sequencing analysis and interpretation of sequencing data and then project three:
the LC component that I mentioned to you before.
So each set was required to address these, and what we did was we wanted to build in
comprehensiveness of the clinical workflow, and of the pipeline, and emphasize within
the RFA the opportunities to generate, analyze and cross-pollinate DNA and ideas, both within
and across sites.
So you will note that along the spectrum that there are opportunities to involve multiple
perspective; first of all, the patients, second of all, the physicians and then third, a focus
on lab and clinics.
And so you will see that within these individual aspects, there are a number of scientific
questions to be address.
But just to take a step back, there are opportunities for research and implementation along these
interfaces; for example, the physician/patient interaction, the lab/physician interaction,
just to name a few.
And to take a step further back, because all of the U Awards are doing this -- I forgot
my animation -- all the awards are doing this, we can identify best practices and lessons
learned among the Consortium that we will -- we hope will be beneficial to the entire
field.
Because this broad focus mirrored that of the ClinSeq program in our intramural division,
we integrated and are fortunate to have the collaboration of our colleagues in the ClinSeq
program.
So, as you have heard, CSER also includes an R Award component.
In 2011, NHGRI funded a set of grants addressing LC issues, related to the return of results.
Although the RFA focused on returning research results, over time the investigators have
had a much broader impact in the discussion of LC issues related to clinical sequencing.
They have done this by generating empirical evidence, both qualitative and quantitative,
analyzing normative considerations, analyzing legal and regulatory issues; all with the
aim of ensuring that any recommendations made regarding clinical sequencing are evidence
based as well as legally and ethically sound.
And I want to note that the R awards began -- R award grantees began meeting with the
“Project 3” U award grantees from the very beginning.
The rational being that we would have more opportunities for collaboration and working
group papers.
In 2013, the existing R awards were formally merged with the CSER consortium, but because
they were initiated prior to this, as of today at least, the R award funding has ended.
So, with the basic RFA structure in mind, let’s take a look at where we are in the
program time line.
So the first set of U awards was made in December 2011, in 2013 we funded a CSER coordinating
center to help facilitate the cross consortium work.
The fully integrated CSER was actually established in June 2013, when the second set of U Awards
were funded.
The nine existing R Awards are integrated and the NHGRI ClinSeq study was integrated.
In 2014, we convened the CSER advisory panel.
Of course, we’re all here today in September because of this Strategic Planning and Program
Review Meeting.
Looking ahead in December, we’re expecting to extend the phase one U grants to further
CSER’s impact in key areas and sync the two U grant phases in a time limited way until
a decision about a renewal has been made.
If NHGRI decides to renew the CSER program, we would take a concept clearance to NHGRI
counsel in spring or summer 2016 and schedule the review and reward components to occur
and sync with the ending of the phase one and phase two U Awards entering 2017.
So, as I mentioned, the R awards have already ended, but of course we will have further
discussion about the best way to ensure that adequate LC expertise is represented in any
future CSER program or clinical sequencing program.
Okay, so let me turn from the past, to looking forward; to thinking about CSER’s future
and share with you a number of high level issues that we have been thinking about.
So from the very beginning, CSER was organized around a consortium model, with integrated,
highly coordinated efforts; sort of represented by this beautiful, carefully plotted out garden
here.
Within CSER, we adopted this model in the U awards by requiring that this three project
structure emphasizing participation in CSER wide working groups and developing and collecting
standardized metrics, which Katrina and the other CSER PI’s have really focused a lot
on in the past 12-18 months or so.
However it’s also true that when CSER was initially envisioned, that “many flowers
bloom” approach was also fundamental.
Within the basic project structure, investigators had the flexibility to refine their sites
focus on clinical settings, the choice of research approaches and site-specific expertise
that could drive innovation in key areas.
So, we’re not talking about hypotheses free research necessarily, only that the hypotheses
were specified by the individual sites, and not necessarily across the whole consortium.
So we will continue to need a balance of both perspectives, so one critical piece of feedback
for today is, “What is the value added at -- of a consortium?”
And NHGRI’s experience with these coordinated, organized networks, there has been value in
being able to suggest best practices for the field, which can be challenging for the individual
investigators.
However, there may be a point at which it is appropriate and desirable to move forward
without such influence.
So I think one open question for today is, “Looking forward, where do we see the balance
falling between these two approaches?”
I also want to take a look at the deliberate use of the word “exploratory”, which is
the E in CSER.
So in 2010, NHGRI, as Eric mentioned, was just beginning to establish a foothold in
genomic medicine; and for this RFA, we were pleasantly surprised to find a robust response,
with the field being very right for research in this area.
So as we embarked on this exploratory phase, so if you’ll excuse me, the parallel with
the Lewis and Clark expedition here, we equipped ourselves with a well-rounded set of resources.
So, Katrina mentioned many of these resources from the investigator perspective, but I also
want to highlight the breath of CSER interactions across NHGRI to build on what Terry and Eric
have mentioned.
So this is the NHGRI organizational chart, with the extramural research program on the
right and the other divisions on the left.
The CSER program actually touches on the Division of Genome Sciences, the Division of Genomic
Medicine, the Division of Genomics in Society as well as our partners in the Division of
Intramural Research.
So it impacts quite a broad swath of NHGRI.
As Eric mentioned, CSER is part of the Genome Sequencing Program, all of which the other
programs have other trajectories.
As Terry mentioned, CSER has sister programs in the Division of Genomic Medicine.
And then our colleagues in the Division of Genomics in Society have been early partners
integrating the R Award sites that were existing at the time to really provide a rigorous LC
partnership that goes beyond just having the LC investigators as consultants for human
subjects.
So, across the NIH, we’re also very thankful for our partnership with NCI, and co-funding
three awards, and contributing scientific expertise.
Okay, so having committed to going on this expedition, we knew there would be challenges
and bottlenecks.
We didn’t know exactly where they were.
You’ll hear today that the past almost four years of CSER have brought some mature projects
to bear, as well as established a firm foothold from which to address unanswered questions.
As we look back on our explorations, I think one of the questions we want to answer today
is, “What have we learned from our explorations?”
I think this has come up already.
Where should we go next?
So, open questions include: “What is the value of continuing to pursue a sort of exploratory
emphasis versus a focus on defined hypotheses.
If the exploratory focus is still a value to us, what is in scope and what balance should
be placed on the exploration?”
And then finally, “What is the emphasis on building the infrastructure in the process
versus focusing on some defined end goal in the future?
How will we know what we have accomplished what we set out to do?”
Okay, so back to our task for today then.
The goal is to come up with recommendations for NHGRI to consider and assessing future
opportunities in clinical sequencing in the next 5-10 years.
So I want to emphasize that we encourage you to actually give us recommendations, not just
interest in a particular area, and to filter a bit based on what you have heard for what
NHGRI’s unique priorities would be.
We will write up a workshop report, by the way, and include your feedback that we have
heard today.
Everyone has a role to play.
We have invited a broad range of people, both within CSER and external to CSER.
We have invited staff from NIH and across other federal agencies, so please participate
actively in the discussion.
We encourage moderators in particular to give everyone a chance to speak up.
One comment about I think how we should spend our time today, for this meeting it would
be very helpful for this group to focus on generating ideas and prioritizing recommendation
about what NHGRI’s role should be in this space going forward.
I think, as Eric mentioned, any program would likely go forth in sort of a resource-constrained
setting.
We obviously are dealing with budget scenarios at this very day, but you know, for today
I think a stance of curiosity and enthusiasm should outweigh any sort of resource or budget
worries.
So, I would encourage you to be generous with your ideas and not be too constrained about
the budget.
Looking ahead to the agenda, and to wrap up my talk, I want to point you ahead to the
agenda.
We have organized a meeting into six topic areas, each topic is comprised of two talks:
one from CSER and one from an external investigator.
Followed by a discussion, co-monitored by two individuals; one from CSER and one from
an NHGRI advisor.
The concluding recommendations that we have heard during that session will be given by
the NHGRI advisor.
And then finally at the end of the day, Carolyn and I will summarize the recommendations we
have heard and then Bob Nussbaum [spelled phonetically] and Lucila Odem-Muchata [spelled
phonetically] will conclude with one final moderated discussion.
So, we are really, really looking forward to getting your input.
So before I turn it over to the first session topic, I would like to acknowledge the contributions
of many people today.
The planning committee: Chanita, Debra, Mary and Dan, Alex and other folks from NHGRI and
Sandra Bramburg [spelled phonetically] at Capital Consulting for Logistics.
Our various NHGRI advisors from five different advisory groups have given us good wisdom
and advise over the years, the CSER staff team from NHGRI and NCI have helped with the
planning of this meeting and represent the program office, along with myself.
I would like to thank NHGRI senior leadership and team sequence past and present for deciding
that we needed to dedicate resources in this area.
And of course, thank the CSER investigators for their continued work in this area.
In particular, we did a lot of asking to get people to give us information for the talks,
background materials and background paper, so we actually hope that those will be of
use for today.
Okay, so now I would like to ask the first session participant to come up.
I believe that’s Heidi, Dan Roden and Dan Masys and Ian Krantz [spelled phonetically]
for the first topic session on building an evidence base for health care systems.
Okay.
So you guys are here.
Of course.
Sure, great.
Kathy Wicklund: I just -- for purposes of today, one of the
gaps that I see is a population, the pre-natal setting in sequencing and you know there are
certain tests that are coming on the pipe for exome sequencing in a pre-natal setting,
is that something that should be part of our discussion or something that CSER would be
-- it would be appropriate for this group to look at, or is that something we should
stay away from?
Lucia Hindorff: So I’m going to give you a somewhat indirect
answer, which is that the NCITE program that Terry mentioned very briefly is focused on
clinical sequencing at least in the pre-natal and newborn setting, so that --
Female Speaker: Is it pre-natal or more newborn?
Lucia Hindorff: Well -- I -- you know, I think I would say
it’s focused on pre-natal and isn’t it early --
Female Speaker: I though it’s pretty much newborn.
It’s not pre-natal.
Lucia Hindorff: Yeah, okay.
So, you know I think that’s a good question to flag.
I might suggest we raise it in maybe the clinical utility session.
We will have a chance to look at different dimensions.
Anastasia, do you have a really quick comment?
Sorry.
Female Speaker: Yeah, I can just say that NSITE’s focused
on the newborn period, so it’s NICU healthy and sick infants.
Lucia Hindorff: Okay.
Female Speaker: So it’s both of those settings, but it’s
all newborns, not pre-natal.
Lucia Hindorff: Okay, sorry.
Thanks for clarifying.
And I’m ready to turn it over to Heidi now.
[end of transcript]