Murray Brilliant: So, I am in the unenviable position of being
the last speaker between you and dinner.
But, and talking about periodontal disease, and then I realized that I am friend of Marc's
dentist, so there you have it.
So, this is a -- I'll try to be very, very brief.
Periodontal Microbiome Working Group was formed at the last meeting, and this is really in
response to some of the missing data that we have in terms of predicting, you know,
the genetic risk or risk to complex diseases.
Clearly, there is going to be environmental factors, and among those factors, very important
is the microbiome.
And so, in working and looking at complex genetic disorders, characterizing the microbiome
could help us stratify some subgroups of these patients.
So, and I also have been asked to look at potential demonstration projects.
So, I'll talk about one of those, which would be in the dental context: response to dental
analgesics and also to anticoagulants, which, you know, some patients are on and then they
have to have oral surgery so they have go off of those, and so, you know, what's the
kind of half-life from a genetic point of view for things like Warfarin.
And clearly the microbiome and periodontal disease in particular has effects on complex
diseases, such as coronary artery disease potentially and certainly type 2 diabetes.
So, the goal of our working group was, we set to establish an oral systemic health research
network and our aim then would be to share and pool patients and data across this network
to advance translational medicine and dental care.
The process that we focused on was to institute standards and best practices in setting this
up.
So, we've had, in addition to the last meeting, we have had two teleconferences and we've
had representatives from various organizations shown here, and I won't go into -- and you
can see who that is.
And among our discussions were, you know, inclusion and exclusion criteria for this,
expected sample sizes in these different -- from our different centers.
How do we classify periodontitis?
The types of oral samples to be collected for microbiome analysis, and timing of collection,
et cetera.
And again, because we're running a little late, I won't go into it in great detail,
other than to say that we are close to settling on most of these.
So, for inclusion and exclusion at the Marshfield Clinic, these are some of our inclusion/exclusion
criteria.
And, importantly, we want to make sure these individuals have both the electronic health
record, electronic dental record so that they see our dentists and have a primary care provider
in our system and haven't had antibiotic treatments in the past three months.
And I must say that we've started recruitment, and that seems to be going pretty well, at
the Marshfield Clinic.
We're interested in recruiting about 2,000 such patients.
Our definition for periodontitis is from the American Academy of Periodontology case classification
system.
Okay, so there is controversy about coronary artery disease or more specifically atherosclerotic
vascular disease and periodontal disease.
There is certainly an association between these two diseases, but a very recent review
article sponsored by the American Heart Association did not -- looking at net analysis, did find
a strong association, but not a causal relationship.
However, it didn't take into account microbiome variation and it did note short-term periodontal
disease treatment decreases systemic inflammation and endothelial dysfunction.
There is an error on this slide.
This one is about a recent study in diabetes and periodontal disease.
Present studies that do support an association -- and that should read "with type 2 diabetes";
there was unfortunately a duplication.
We should -- and it supports a bi-causal relationship between periodontal disease and type 2 diabetes.
And so in our system, we have nearly 2,000 diabetics who've had a dental visit within
the last year and about 900 of them have not had a dental visit within the past year.
So what we -- what this population can help us do is shown here.
This is one of the short-term demonstration-type projects that we have.
It's management of patients with both diabetes and periodontitis and it's -- our dentists
would refer patients who have periodontitis to the clinic for type 2 diabetes testing
and vice versa.
And we tell that, together with genetic and microbiome data, we could stratify these patients
and come up with more effective ways to treat both of these disorders.
Among other demonstration projects would be pharmacogenetics related the management of
dental patients, as I mentioned, in terms of pain management and coagulation management.
And so, we're working on a pharmacogenetics panel for, specific for dental patients, and
clinical decision support tools tailored to these medications relative to dental work
in an integrated electronic health record, integrated between our electronic health record
and our electronic dental record.
This is what our electronic dental record looks like, and it's probably difficult to
see, but in the bottom left panel there's an alert box that, you know, talks about medication
and such.
This is where the pharmacogenetics data would be and where referrals, say from our dentists
to our clinicians, would be in case of periodontal disease findings.
And many of these ideas have recently been published in the journal Oral Diseases.
One, we recently published talking about our personalized medicine model at the Marshfield
Clinic and one that was published a few months ago by Geoff Ginsburg's Group.
And they're shown here for your reference.
And recently NIDCR awarded about $67 million in a seven-year grant towards a national dental
practice-based research network; this is to University of Alabama at Birmingham School
of Dentistry.
We at Marshfield Clinic supported this application and will join this Midwest regional node of
this network, but we will also continue our efforts to form a national network of like-minded
institutions across the country to establish a large and diverse cohort of dental medical
patients with electronic health records, electronic dental records, and oral microbiome samples.
And if anyone is interested, there's contact information at the bottom shown in red.
So, and that's -- I tried to be very quick.
I'll stop here for any questions you that may have.
Questions?
Dan Roden: Murray is single-handedly driving this, and
you know it's going to happen.
Murray Brilliant: So, I do really think that, you know, by taking
into account the effects of the microbiome, we will be able to stratify a number of patients
that previously genetics alone doesn't gives us such significant data, so.
Dan Roden: Okay, if there's -- Geoff?
Geoff Ginsburg: Yeah, I was just going to ask you or maybe
Joanne and Naomi whether the dental environment, you feel is an environment that actually will
facilitate some of the genomics research in ways the medical environment cannot, particularly
from a payer point of view.
Joanne Armstrong: I would just say that, at least from an Aetna
research perspective, there's actually a lot of collaboration with Columbia Dental School
over this connection of oral health and cardiovascular disease, and I've been involved in the pre-term
birth connection of it.
So my questions were, you know, you could look at this in the prenatal care arena.
Murray Brilliant: Absolutely.
The --
Joanne Armstrong: [inaudible]
Murray Brilliant: In fact, the Marshfield Clinic opened up dental
clinics because we noted that our population, which is essentially indigent and rural, lacked
dental care.
We had patients coming in that hadn't been to the dentist in many, many years and were
having, you know -- we saw lots of type 2 diabetes, coronary artery disease, et cetera.
So the clinic invested in opening up now eight different rural dental clinics throughout
northern and central Wisconsin to serve people who otherwise weren't getting dental care
because of really poor reimbursement Medicare-type rates.
Teri Manolio: Murray, I am wondering if you could comment
maybe on what you're learning from the microbiome or is this, you haven't done it yet and you're
hoping to learn, but maybe give us a feel for how that will contribute.
Murray Brilliant: Right, so right now, we have not analyzed
anything yet.
We have probably about a dozen microbiome samples, a dozen individuals with microbiome
samples currently collected.
So I can't really comment on what we're finding yet, but that it won't be long, I suppose.
Male Speaker: Hey Murray --
Murray Brilliant: And also, I'd just like to mention that, among
the other interested people in this group, Mount Sinai is already collecting actually
significant numbers of patients with microbiome samples.
Debra Leonard: So do you imagine that testing the microbiome,
I mean, sequencing all the organisms will move into clinical care or will you do research
that identifies certain characteristic organisms that then would be just targeted testing?
Murray Brilliant: Well I think that -- my understanding is,
what's emerging are sort of microbiome communities and certain subtypes of communities, and some
of those are more associated with disease than others, periodontal disease being one
of those.
So --
Debra Leonard: But in clinical care, do you have to do the
whole microbiome or can you just look for characteristic organisms within that community
that predicts the disease risk?
Murray Brilliant: Right, it's -- what you look for is, it's
not a single microorganism, but sort of, you can classify it by the presence of several
types.
So my understanding of this is, there are three or four major microbiome types.
Debra Leonard: So you imagine that in clinical care, we will
need to sequence the microbiome and that's the only to do this testing in clinical care?
Murray Brilliant: Maybe Erwin has a -- you had a comment?
MaleSpeaker: No, no, I just wanted to signal to the chair
that I --
Male Speaker: I have a comment that speaks to your question.
I think that --
Male Speaker: Your mic on?
Male Speaker: Yeah, my mic's on.
I think that the -- there is a lot of interest amongst the microbiology community in the
possibility that sequencing is going to replace culture for the speciation of both the bacteria
and viruses in the microbiology lab.
The leader in this area is George Weinstock at the -- Wash U. He's actually dong whole
genome sequencing.
And in the pathology community I think there's a lot of interest, you probably know these
people, Lynn Bry at our place is the person that's most interested in it.
But so, I think that, you know, in my view, actually, next to cancer, this is one of the
areas where there is the potential for a huge impact of sequencing in terms of clinical
practice.
I think there's a lot of hurdles that are going to have to be overcome, in terms of
the time it takes to speciate and so on and so forth, and how do you store the data and
everything else.
I think on the research side, you know, my own particular interest -- I mean, I think
there's a lot of evidence to support this, that in autoimmune disease, particularly in
the development of asthma, which is the disease I am most interested in, how human beings
tolerize is the function of what the microbiome is at birth.
And for both obesity and for asthma, there is elevated risk that's associated with C-section.
that those of us that are studying this think is related to the fact that these infants
are not exposed to the microbiome as part of the birth process, and that this is a process
that's set relative early in life.
And so we're actually testing the hypothesis, that the fetal microbiome may be a risk factor
for the development of autoimmune diseases, specifically asthma.
So I think there is research implantations, but there are also clinical implantations.
Murray Brilliant: And the way we would be looking at this is
really sequencing 16S RNA, and that's one of the major techniques for determining the
species.
Yeah.
Male Speaker: Yeah, just to follow up very briefly with
a comment on Scott's statement.
I think that's exactly right, I think our group here at Mount Sinai is very involved
in the pathogen characterization using sequencing, and that's certainly something going to be
very big.
Murray, I was interested in the your current inconclusion criteria.
Is it diabetes only or are you also extending to pre-diabetes, which could be very, very
interesting from a research point of view and then adding microbiome as a predictor?
Murray Brilliant: Right.
So what we're doing in the recruitment process is, as these people come in, they -- we take
a fasting blood sample to look at, you know, at the time that they are recruited, what
their blood sugar is.
We also look at hemoglobin A1C status and such.
And then, because they're part of the Marshfield Clinic system, we can look back and we can
look forward for their diabetic status.
So it's not -- we don't know whether they have diabetes when they come into the clinic,
so that's not one of the recruitment criteria.
Male Speaker: Kariss [spelled phonetically].
Kariss.
Female Speaker: I also wanted to emphasize, that we're sequencing
our DNA and not the whole microbiome, and it's --
Murray Brilliant: Right.
Female Speaker: It's pretty quick, but again the 454 sequencing
versus the Sanger sequencing argument's coming up because what we have found, and we [unintelligible]
cancers, is that, in [unintelligible] cancers versus healthy people the [unintelligible]
microbiome is less diverse in disease, and that diversity is hidden with 454 sequencing
because with Sanger sequencing, you're going to actually subspeciate better.
And the consortium microbiome might actually change to [unintelligible] methylation of
certain genes, which is what we found [unintelligible] information is the immune system, and it also
changed the metabolome, and sometimes it's the metabolome that promotes whatever the
disease is.
Murray Brilliant: Yes.
Yes, well, thank you.
So, very -- thank you.
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