Erynn Gordon: So for those of you who have not heard of
the Coriell Personalized Medicine Collaborative, this is a longitudinal research study that
started in 2007, and really the aim of the study is to understand the utility of receiving
personal genome information.
We are genotyping individuals, providing it back to, results back to participants and
doing a series of follow-up behavioral studies
to determine what they're doing with that information.
So, are they changing their diet or lifestyle based on that information?
Are they sharing the information with their health care provider and is their health care
provider making any recommendations or ordering any tests, changing their care or management
in any way?
In addition, we're looking to identify new genetic sites that are associated with common
medical conditions and drug response.
As I said, the study was launched in 2007, and at this point we have more than 6,000
participants that have enrolled.
Just briefly, how the study works.
Participants, the majority of our participants have been enrolled through group-informed
consent sessions.
Individuals actually come to the Coriell Institute or other group sessions that we've held at
the end of an informed consent presentation, they, if they choose, sign the consent form
and spit into a tube which is always nice in a group setting.
Everybody loves that.
[laughter]
After they have provided their sample, they then receive an online activation and the
remainder of the study is really conducted via the Internet.
People create a personalized account.
They fill out a series of required questionnaires including family history, medical history,
lifestyle, demographics.
And once they have completed those required questionnaires, they're put in the cue for
genotyping.
We do our genotyping using the Affymetrix 6.0 and DMetrix currently.
And then, once results are generated based on those genotyping platforms, we are ready
to release results.
But here's the caveat: an important component of the consent process is that participants
consent to only receiving results that are approved by our advisory group called the
Informed Cohort Oversight Board, and I'll go into greater detail.
So this is sort of a vetting process for how we will determine what results you report
to participants.
So that's going to be the crux of the talk and let me just finish sort of the general
outline of the study and then I'll go into greater detail about that.
So once that group approves what results will be reported, reports are prepared and they
are pushed out to participants through this secure web portal.
Participants get an email that say a new result is ready but none of their results are communicated
via email.
They're always pushed to go to, to log onto the secure portal to view their personal genomic
information.
After they view that information they can contact us to speak with a genetic counselor,
we also have a pharmacist coach network so that if they have questions about their pharmacogenomic
results they can speak with a pharmacist as well.
And we follow up with a series of online questionnaires, again asking them what they did with the information,
was it useful?
Did it prompt any anxiety?
Did they actually share the information with their health care provider, because the information
is going directly to a participant.
So, I just want to talk a little bit about, because the focus of this session is selecting
variants for the return, I want to talk a little bit about how we go through that process.
We, the Coriell staff, actually selects what variants we want to put forward to our advisory
group and there are a series of technical guidelines which I'll discuss that guide that
selection process.
We then prepare a report that goes to two different advisory groups, our ICOB Informed
Cohort Oversight Board and our pharmacogenomics advisory group.
Only those drug-gene pairs that would relate to drug metabolism would go to the pharmacogenomics
advisory group, everything does go to the ICOB.
The ICOB reviews and approves or disapproves, rejects, what we've put forward to them.
Obviously only those things that are approved move forward to report development and then
the deployment of the report to participants.
So we have two sets of technical guidelines, one for health conditions and one drug-gene
pairs.
And it's a fairly in-depth process.
This was published by one of our colleagues, Stack, Cathy Stack earlier this year.
So we go through a literature search for all of the, looking at published GWAS.
We will only select studies that, variants that have been replicated across multiple
studies, moderately sized studies and we do have minimum cutoffs for the number of participants
that need to be included.
And we're looking for variants that have been associated with common complex diseases, not
traits, so we had actually originally considered putting forward variants that had been associated
with things like height or eye color and have since rejected that idea.
Those types of variants are not included in the study.
Once we've identified disease-associated variants, we go through a process of selecting a single
variant per health condition currently.
And looking at variant selection hierarchy, we rate each variant that we've identified
as potentially worthy of inclusion based on whether or not it's been looked at through
a meta-analysis in multiple studies, replication in multiple independent studies or replication
in multiple cohorts in a single study.
We take all of that data, compile it into a nice report and summarize it for the Informed
Cohort Oversight Board and only, obviously, only those conditions with valid genetic associations
are passed through that process.
From the standpoint of pharmacogenomics, this is a slightly different process.
We're looking to identify and select drugs and key genes that are associated.
We do this by reviewing published literature as well as public databases including the
FDA table of drugs and biomarkers, PUBMED, PharmGKB, the CYP450 Drug Interaction Table,
national prescription data and also our own population and the reported medication use.
Obviously, we're not as interested in reporting on a drug-gene pair where there's one person
in our entire cohort that's on that particular medication.
That just wouldn't be of interest to the population and as a result, setting utility wouldn't
be all that, wouldn't be very interesting.
We also review published and public data, drug metabolism pathways, PUBMED again, PharmGKB
and the (CYP) Allele Nomenclature Database.
Based on all that, we try to define key alleles and haplotypes and identify a minimum set
of defining variants for those haplotypes and then select haplotypes for inclusion based
on evidence scoring.
So the evidence scoring is a detailed process: we rate different studies based on the greatest
two obviously, the lowest evidence based on whether or not there have been clinical outcome
studies conducted, the available pharmacokinetic and pharmacodynamic studies, molecular and
cellular functional studies and genetic variant screening studies.
So this goes into a complex scoring process that goes from one to 13.
Variants that have been only seen in one study, such as a case report, will not be included
if there is functional data that suggests that the particular variant or haplotype or
gene directly impacts the metabolism of the drug of interest, that is rated more highly
than if the drug is associated with -- I'm sorry, if the gene is associated with a drug
that is related but not the one that we're particularly interested in.
Obviously this is a complex process that I won't go into in detail but I'm happy to talk
with anyone afterwards about the strength of evidence scoring system.
So those are the technical guidelines that guide the selection of variants and drugs
and health conditions that we put forward to the ICOB and the PAG.
But just want to briefly talk about that process itself.
So we have the Informed Cohort Oversight Board, this was an external advisory board.
There are no voting members from Coriell.
It's composed of scientists, medical professionals, ethicists and community members.
This is modeled after Kahana's [spelled phonetically] ICOB concept that was published in Science
in 2007 where an expert group would review drug-gene pairs and that would be used to
determine what information could be reported back to participants.
So Coriell's Informed Cohort Oversight Board consists of many notable scientists, some
of whom are in the room.
And actually this group just met this past Monday.
Their charge specifically is to determine whether each health condition or gene involved
in drug metabolism is at minimum potentially actionable.
And I know David just said he hates that term.
[laughs] it's hard to say what the cutoff should be.
How do you decide what gets included but because we want to look at the potential utility of
this information, we felt like some level of actionability was needed.
So we have provided the ICOB with some guidance with respect to that.
In addition, they're also charged with determining whether or not the genetic associations that
we're proposing are statistically valid.
The pharmacogenomics advisory group is a separate board and they are, were specifically chosen
based on their expertise in pharmacogenomics.
They provide recommendations to the ICOB, so their decision alone does not determine
what goes out to participants, and this group is composed of pharmacists, pharmacologists,
ethicists and clinicians.
Again, we have members of this group in the room and certainly appreciate their service.
Their charge is similar but a little bit different.
So it's to determine whether or not there is sufficient evidence to support the role
of each gene in the metabolism of the proposed drug.
Whether the impact of one or more haplotypes is clinically relevant with respect to the
proposed drug and whether the drug-gene pair is potentially actionable.
Again, the workflow of the ICOB and the PAG is that although both review these submissions,
the decisions of the PAG are then submitted to the ICOB for approval and there are cases
where the ICOB does overturn a recommendation or rejects a recommendation of the PAG.
Just a list of the currently approved diseases and drug metabolism pairs that have been approved
by the ICOB so far and acknowledgments of the staff and ICOB and PAG that participate
in this project.
Thank you.
[applause]
Male Speaker: So we have time for a couple of questions
or comments now and then this session is interrupted by lunch, but we have three speakers after
lunch and then a longer discussion session at the end of the session.
Howard.
Howard Levi: Just a quick point of clarification, you had
indicated that a single variant would be chosen per condition.
Do you mean that at a site where there are lots of different variants that are the same
haplotype block you're only selecting one SNP or do you mean for a common complex disease
you will choose one and only one variant?
So for example, in the case of diabetes this gives me some concern given the plethora of
potentially relevant variants that exist.
Erynn Gordon: So, thank you, that's -- it's an important
clarification.
So for common complex diseases, we are currently only reporting on a single variant and it
certainly is concerning given the multi-genic models that are coming out and the number
of different variants that are known to contribute to the risk of these common complex diseases.
At this point, we are working on coming up with a multi-genic algorithm that would be
approvable by the ICOB.
Not at this past ICOB meeting but at the previous one we had put forward some multi-genic models
and the problem that we ran into is that they're not replicated.
And so although we can, we all agree that there are multiple validated and replicated
variants associated with each of these common diseases, how do you put forward, you know,
are we going to give people 50 different variants and make them process that?
We'd prefer to give people multi-genic risks but none of those models have been validated.
Do you choose a model that has multiple validated variants within it?
And so we're still trying to think through that process.
In the meantime, we certainly see it as a limitation and we make it clear on our reports
that it's a limitation, we're only providing you a very small insight into the many genetic
risk factors that can contribute to this but at this point we feel like it's one approach.
I will say that for pharmacogenomics, we are using multiple variants and reporting using
the star nomenclature that's commonly accepted.
Male Speaker: Ken.
Kensaku Kawamoto: Comment on, so this is great work and it does
seem like it takes a lot of effort.
Could you comment on sort of the amount of effort it takes and how this could scale?
So for example, at different institutions that are tackling these same issues, you know,
typically can get together a committee but then it ends up, well, maybe we discuss one,
whatever's hot that particular, you know, month.
How can this scale one, for example do you make your knowledge available to others to
be able to use at other institutions?
And if not, how do you sort of see this scaling beyond this particular initiative?
Erynn Gordon: So that's a great question and is one that
is discussed routinely by our advisory groups.
The amount of preparation work that goes into each of the ICOB and PAG meetings is absolutely
enormous on the part of the staff at Coriell.
Because we really feel like, as an advisory group, they shouldn't need to go out and do
all of the leg work to try and determine this but we should present it to them and they
should be evaluating it with, you know, additional supplemental material if needed.
Currently we give them, on average, I would say four either health conditions or drug-gene
pairs to evaluate at each meeting.
We would need an army of staff in order to scale this up and so one possibility would
be, as ideas like this pick up momentum at different institutions, is having different
groups of people working and sharing their knowledge across different institutions.
I think we are happy to share our model, we have always said that we would make the decisions
of the PAG transparent and we can certainly discuss sharing the submission materials with
other institutions so that there's some collaboration and, you know, everyone isn't reinventing
the wheel.
Male Speaker: Okay, I think we're going to have to move
on to our next speaker.
Thank you, Erynn.