Robert Nussbaum: So, first of all, as opposed to what Dick
Weinshilboum said, I actually did follow the academic model and got everything done much,
much too late and did not have an opportunity to have a prolonged discussion with a panel
at all.
I did respond or react to Hakon directly about some of his material.
There was primarily specific questions I wanted to ask.
And now that I have been listening to the session here, and thus participating today,
as well as listening to Hakon's [unintelligible], I'd like to just go through a couple particular
points, and then have the -- John and Jeff and Cynthia respond.
So, I wasn't quite sure what was meant by different paths for phenotyping, but I think
what I understand about that now is just that there's adult phenotypes and there are pediatric
phenotypes, and that these are being done in different places by people of expertise,
either in pediatric or adult phenotypes.
I really don't see this as an obstacle at all.
I think it's a strength.
In general, pediatric research has been underrepresented in genomics, and so I think it's perfectly
fine for there to be particular phenotypes that are enriched in pediatric patients and
are not seen in adults, and that special attention will be put to studying them.
I mean, this project, as I understand it from listening to Hakon, is that it is primarily
a discovery project, this is not an implementation project yet.
And so, discovering genotype and phenotype correlations in pediatric patients makes a
lot of sense to me.
I had a question about the informed consents, and I know we discussed that a little earlier
today.
I had a particular question which has to do with what happens to pediatric data once the
subjects become adults.
I know there are some recommendations and some thought that keeping this data without
re-consenting these individuals as adults is a problem.
I see that re-consent process of tens of thousands of people as being a huge problem.
And I'd like the panel and the people participating in this meeting to perhaps comment on that
issue.
I have some thoughts about it but I would like to hear what other people have to say.
The next issue is, okay, is the TPMT genotype imputation.
Has any of this been linked now to patient response?
What fraction of these tens of thousands of patients who have been genotyped have actually
been exposed to this drug?
And do we have follow-up data and do we know what happened to them?
I mean, you know, I think the impact of Mary Relling's work and other people's work on
TPMT genotyping to guide 6-Thioguanine or Azathioprine therapy is well- published and
understood, but I'm just wondering whether, in this particular project, we have any such
information.
I thought that the emphasis on the CNVs was also very welcome.
I think they have been they're obviously very important in clinical medicine.
It's great to have them more involved in this discovery project.
I just wanted to mention something I mentioned to Hakon, that the DGV is a valuable resource,
but there is ISCA, which is now become what we call the ICCG, the International Consortium
for Clinical Genomics, and there's a major attempt made through a grant that's been funded
by the NHGRI to try to get much more structural variant and copy number variant information
linked to phenotype into ClinVar, into the public domain.
And I think that having the eMERGE pediatric component work together with the ISCA or ICCG,
and to try to get as much information into the public domain as possible would be a great
benefit for everybody.
This is a small point about the concordance fray between sequencing and imputed haplotypes,
and it's not a big deal.
It has to do with whether they're common variants or not.
It's the rare variant that people are having more problems with imputing, and of course
that makes perfect sense, but for the more common SNPs, common variants, the imputation
is far higher concordance than this, and so I think that this is not really a major issue
at this point.
So, I think to summarize my reaction, is that I think some -- many of the things Hakon described
as being obstacles I actually think are strengths, and that's a good thing.
I would like some comment made about the removal of pediatric data once these individuals have
reached adulthood.
I'd like to hear more discussion about going beyond just simply how well you are doing
at imputing genotypes for TPMT, but instead, is it linked to the EMR, what do we know about
outcomes between the types, how many have been exposed to the drug.
And I'll stop right there and ask the other members of the panel to comment.
Male Speaker: Yeah, so, why don't we -- we'll pass the baton
to Jeff Botkin, who can, perhaps as well as his job as moderator, moderate the answers
to the questions that Bob has posed.