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David Ledbetter: So, I'm going to present a very simplified
perspective. It's been my observation at this meeting and a couple of others that there
are at least three -- three different main groups attending these meetings. There's the pharmacogenomics group,
what I'll call the GWAS [spelled phonetically] common disease group, and then the more traditional
medical genetics or rare disease group, and then the last is the one that I come from.
And talking about how you move things from research to clinical applications is part
of routine medical care and standard practice in genetics and genetic testing and has been
the case for 50 years since the introduction of the karyotype and biochemical genetics
testing, both in the early 1960s that evolved over time to become a more formalized process
where we have CLIA [spelled phonetically] certified genetic testing labs. These are
usually in a genetics environment or a pathology lab medicine environment. There's a critical
team of experts that are involved in performing the clinical genetic testing, including lab
directors that are either certified by the American Board of Medical Genetics and Genomics
-- I forgot its new name for that professional organization -- or by College of American
Pathologists in the subgroup of Association of Molecular Pathologists.
There's usually a medical director or medical consultant associated with the labs that may
cosign reports and is responsible in also advising and developing new tests, and there
may be other clinical expert specialists associated with the lab. And for most genetic testing,
genetic counselors, are involved directly with the laboratory in a role, expert role,
advising about new genetic test development as well as interpretation and reporting of
test results.
So, this is clinical practice. There is a process of how we move new technology and
new scientific information into clinical practice, and I've made a simple diagram here. 0.2 [spelled
phonetically]. Okay. On the left, it shows new technology, much of it coming from industry
sources, new information from scientific literature and meetings, et cetera. Many clinical labs
have an R&D component, either formally or informally of variable sizes, that's involved
in implementation of new technology and also new information and development of new tests.
Again, this team of experts associated with the clinical lab is the ones that advisory
about what is "ready for primetime" and can be applied clinically, and CLIA specifies
the clinical validation process for offering these new tests.
Now, when the first one or two or three labs start implementing new technology or new specific
genetic tests, they often report K [spelled phonetically] series in the literature, so
there's a feedback from the clinical labs who are participating in clinical research
that contributes to the literature. Either the laboratories and genetics experts or professional
societies may do a meta analysis. And then, depending on the nature of the magnitude of
the change, a new technology or a new clinical application, professional societies, usually
the same major ones in terms of laboratory guidelines, that would be the American College
of Medical Genetics and Genomics, or the College of American Pathologists, for practice guidelines.
The clinical specialty area would be the ones who would determine the appropriate clinical
application of new technology or new tests.
So, from my perspective what's happened now is we're moving into a major new technology
change and capability with whole genome sequencing. For me, it's not totally distinct from what
I started out doing with karyotype analysis, which is looking at the whole genome in a
single laboratory test, and when we first started doing karyotyping, there were variants
of uncertain clinical significance that required a large amount of empiric data and experience
to determine which were clinically important and which were benign population variants.
So, now, if we just move to genomic testing, I would make the argument that whole genome
sequencing for undiagnosed patients is no different than what genetics has adjusted
to and evolved around new technology with every major technology, increased the magnitude,
the frequency of variants of uncertain clinical significance or unclassifiable variants, is
much greater than in the past, and the opportunity to identify incidental findings that may or
may not be clinical relevant and appropriate to reveal is much higher, but not qualitatively
different than what we've dealt with in genetics for many, many years.
The question I would pose to the group, and I'm not sure of the answer, is does this model,
has existing methods of assessing new technology at the individual lab level, forming networks
or consortium, and then having professional societies review the data for readiness for
primetime, does that work for pharmacogenomics and for risk assessment and common disease
GWAS, or do certain elements of it work? Can it be expanded, or is -- are the common disease
risk assessment, pharmacogenomics, applications of genetic data, totally unique from what
we've been doing in medical genetics? And I won't presume to know the answer for that.
Now, I would say that what we've not done a good job in genetics and it's come up a
lot at this meeting and other meetings recently is the determination of clinical value. So,
we've done a good job of the early translation feasibility clinical validity step, but in
terms of the impact in healthcare, the impact on outcomes and value to healthcare system,
and quickly moving this into routine clinical practice in the broadest way, we've not addressed.
And so, I think adding significantly more efforts in the genetics community and related
areas in that area is important, and that's the last of my slide and the last of my comments.
Female Speaker: David [unintelligible].
[laughter]
Female Speaker: So, I think that one thing that strikes me
about this and, in terms of the straddlers [spelled phonetically] and I think is a huge
issue that wasn't addressed is the training of geneticists and bringing up geneticists
through the pipeline. And so, the number of physicians going into genetics, as we know,
dropped, and has been relatively stable recently, but did go down and has not immediately come
back up. And I think that the physician workforce that's going to be needed for this is really
lacking in a big way. I mean, there weren't enough to begin with, and there certainly
aren't that many people going into it, and I know this is something that the ACMG, and
we have certainly addressed at that level, but I really think that we need to think beyond
this. How are we going to bring trainees, how are we going to bring physicians, how
are we going to educate people who are really interested in translating this information,
educating both practitioners and physicians? I think that's a big issue. Those are the
straddlers, and it's also true of generally [spelled phonetically] physician scientists,
that there are fewer and fewer people becoming physician scientists. I just want to point
that out, because I think that's important.
David Ledbetter: Now, I think that's an important point, but
it's a daunting task, given the declining number of physician geneticists being trained
currently. I think the other opportunities, look at other current geneticists and revamping
their training. We had a discussion at dinner last night about genetic counselors being
trained with more bioinformatics [spelled phonetically] and genomics training and the
opportunity to greatly increase the training program sizes for genetic counselors that
might help in this area. And, again, my bias as a Ph.D. laboratory person, there are a
gazillion underemployed Ph.D.s in the U.S. that could be rebooted and trained in more
clinically oriented computationally oriented, genomics oriented way to serve a valuable
role.
Female Speaker: Right. So, I'm going to point this out, because
I just got three emails about this morning. Genetic counselors can't bill [spelled phonetically].
David Ledbetter: Well, but that's a problem that we should
be addressing, and not --
Female Speaker: Exactly. I'm not suggesting that we shouldn't
be addressing it. We should be addressing it, but that, you know, you can do, it's a
huge, huge issue for the genetics community right now, that our genetics counselors cannot
bill for their time.
David Ledbetter: But the genetic counselors associated with
most laboratory programs are well absorbed by the profit margins of the laboratory.
Male Speaker: Just a comment, David, to follow up, I like
your concept of the R&D unit for laboratories. I would extend it to include some very well-defined
clinical environments with, you know, the full complement of the workforce that is part
of this as opposed to just the laboratory. I think what we've been talking about here,
and where I think some of the resistance is, is to implement things on a system-wide basis
from the get-go. Why not think about having small centers of innovation and R&D within
health systems that implement, innovate, and either diffuse or kill something when there's
sufficient justification to do so? And so the concept, I think barred from the cancer
community, is the rapid learning healthcare environment, and I think it's not hard to
do on a small, in a well-circumscribed basis. If you try to do it system-wide, it probably
is doomed to failure.
David Ledbetter: And I forgot to comment. I also borrowed from
the cancer community the notion of a comprehensive genomics center or program that had all of
the key expertise in one place to participate in the R&D validation and then implementation
of new technology and new information.
Male Speaker: Going back to Kathy's point, there's also
a movement, from my understanding, on ACMG and ABG [spelled phonetically] to move geneticists
into the model of ophthalmology where they do one year of internship and then go straight
into genetics, and I think that's exactly the wrong way to go if you're talking about
genomics. In genomics, you need to be broad. You need to understand heart disease, and
you need to understand pediatrics, you need to understand pharmacogenetics, and trying
to get a group that's so specialized to genetics too early is only going to harm the field
in the long term.
David Ledbetter: Maybe Mike knows more about current trends
and the restructuring training.
Male Speaker: I'm Reed [spelled phonetically].
David Ledbetter: Reed, sorry.
Male Speaker: So, there are, the first issue is this is
as VCG, I mean, this one year thing is an ACG issue. It's not something that we have
a lot of latitude on [unintelligible] medical genetics case. It's way, it's the only practical
way that we can satisfy the ACGME [spelled phonetically] [unintelligible] training [unintelligible].
So, unfortunately, that was out of our hands.
With regard to Kate's point in this issue, not about geneticists [spelled phonetically]
so we, the board of directors of the APMG [spelled phonetically] has also had, in the
process of having discussions with the American Board of Internal Medicine or other similar
groups in trying to think of something like a one year certificate [spelled phonetically]
of qualification or those sorts of things for, let's say, you know, oncologists or,
you know, adult cardiologists, or these sorts of things to kind of potentially take up the
slack with regard to qualified certified clinical practitioners.
Female Speaker: Yeah. So, I can involve [spelled phonetically]
with the cancer point of that with Bruce, and, so, I'm not trying to be difficult. I'm
trying to bring this up as a really important point when we're thinking about how to translate
this, that I agree this is very important, and this is what we need to do, but I think
that if you're sort of in the trenches as a medical geneticist, you see what's happening,
and the fewer, there are fewer people, and there are all these issues. And I think that
if this group really wants to do --
Male Speaker: I have the M.D. clinical geneticists here.
Female Speaker: I know, but --
Male Speaker: I just put them after the lab --
Female Speaker: No, no, no, no, no. It wasn't that.
[laughter]
It's not that they're, it's just that, it's that we need more, and --
Male Speaker: Absolutely.
Female Speaker: -- we have to think as a community how we
get more people appropriately trained. That's all I'm bringing up.
Female Speaker: So, David, there are already CLIA labs for
next generation sequencing. Has the group here been working on standards in addition
to CLIA? I mean, so where are you guys on --
David Ledbetter: There's a group of CLIA labs that have informally
gotten together. I think the first meeting was at Harvard Partners, and Heidi Rim [spelled
phonetically] organized that meeting. I'm not sure what their plans for continuing to
meet, and I know that there's some working group discussion by the college about guidelines
around next-gen sequencing technology applied to diagnosis at the moment. I don't know how
much of that is gene panels versus exome sequencing, but, yes, that group of experts doing sequencing
diagnostics is meeting and discussing the same topics we're discussing.