Howard Levy: So, Alan Shuldiner unfortunately couldn't
make it, so I was asked at the last minute to pinch-hit.
Many of you who have heard me speak know that I like to either quote classic rock or a movie
in every talk and I didn't have time to put in a slide, but it occurs to me that for those
of you who know the Princess Bride, Alan would be Wesley and I think that makes me Prince
Humperdinck, the alternative to suicide, and I think that makes Marc Princess Buttercup.
[laughter]
Yeah, that's me.
The other point I'll make is that yes, I did intentionally wear the same shirt as Les and
that's to highlight Rex's point about the difference between clinical and research being
very, very hard to truly tell.
[laughter]
Oh, let's see here.
I got my pointer.
So, two disclosures.
I am a paid consultant to Medco Health Solutions on their laboratory and therapeutics committee.
I don't think that makes any difference here today, but another important disclosure that
I'll factor into what I'm going to tell you is that I'm one of three co-editors in chief
and founders of a new resource called Gene Facts.
Gene Facts is intended to be the resource that is more generally useful for clinicians
at the point of care, not so detailed as the traditional genetics resources, but more useful
for the typical general medical use resources.
The other point I realize that I meant to make at the top is that for anyone who desperately
needs the bathroom or a cup of coffee, I'll tell you now the summary of what I'm going
to tell you.
As a clinician, tell me what I need to do, make it quick and easy to find, and preferably
make it accurate and reliable.
That's it.
If you need to go to the bathroom, you got my main point.
[laughter]
Back to Gene Facts, though, and the concept that Les pointed out about the perspective
versus a perspective, one of the principles that we've been using in trying to build Gene
Facts is rather than taking the thought that we as experts know what everyone else needs
to know, we've tried to go out to anticipated users and ask them, well, what do you want,
so that we can actually build something useful.
And with that in mind, what I tried to do is instead of stand up here and tell you what
I think is a useful resource, because I am a geneticist and like most of the rest of
you, if not all of you, we geneticists already know what's wrong with existing databases.
You don't need me to tell you that.
I think what we need to talk about is what do non-geneticist clinicians need to know.
So with that in mind I figured okay, let's collect some data.
So I did a survey and I have to air my dirty laundry.
My IRB approval was, it's last minute I'd like to get some data, so I'm not going to
go to the IRB.
[laughter]
Informed consent was minimal.
I sent out an email and I said, "I'm giving a talk tomorrow, can you answer a couple questions
for me?"
So they knew what they were getting in to.
They knew I was going to give a talk and present the data.
Subjects were by and large my colleagues at Johns Hopkins with a few exceptions, so this
is an academic, primary care selection of clinicians made up in part of clinician educators
who are actually taking care of patients, some of whom know some genetics, most of whom
don't consider themselves experts in genetics, some of whom are also clinician researchers
seeing patients half a day a week, but mostly doing research, and you might think that researchers
are going to think about things a little bit differently than clinicians, but again, the
line is blurred.
Researchers do see patients and clinicians do occasionally dabble in research, sometimes
with dangerous consequences.
So the recruitment period that I listed here was seven hours yesterday.
As of half an hour ago, though, I got two more responses, so we'll stretch it out to
about 16 to 18 hours of data collection.
So I asked two questions.
The first was, and these are actually the questions that were in the original email
to Alan, so I'm just kind of picking up and trying to give his talk.
What resource or resources do or would you turn to if you want more information about
the significance or management of a genetic variation?
I rephrased the question a little bit, but that's what I asked my survey respondents.
And the second one was well, what do you want?
What would the ideal resource provide for you?
So, the next point is that just like I can dress up in a suit and make myself look presentable,
that adds some authority to what I'm going to tell you.
I'm going to give you data from a highly-biased, small set of data that is completely unscientific,
but I've dressed it up really nicely in a pretty table.
[laughter]
And that makes it look much more relevant.
And while I'm intentionally trying to make you laugh, I think it's an important point
that when grading the value of the evidence and what to do if something is presented in
a neat, organized way and looks really slick, it carries a lot more authority than a guy
in a t-shirt and shorts saying, I think that would be a good idea.
So here's what I found.
There were 16 respondents as of last night and now there are 18.
And, not surprising to anyone who actually does clinical care, the first and most commonly
listed resource was UpToDate by half of respondents and in fact, there's one more who responded
this morning that also listed UpToDate equally distributed among the researchers and clinicians.
The next most common source that people went to was a consultant.
Pick up the phone, walk down the hall and ask the expert.
And Elaine made the point of don't over-simplify, but as a clinician, the clinicians out there
want it simplified.
They don't want it over-simplified, but dumb it down.
Give it to me simple.
After that, after UpToDate, which is an Internet-based primary care subscription resource, all right?
So, at Hopkins our institution buys it.
We have it.
I'm not sure that the family doc in Idaho has access to all the same resources that
we in major academic institutions have.
After that, an expert.
After that is general Internet resources; Google and Wikipedia are the most common places
people go.
And frankly, I sometimes go there myself, not Wiki, but certainly Google.
After that you then get into true primary literature and note that only two of the clinician
educators mentioned going to PubMed or Google Scholar, although one of the responses this
morning also listed PubMed.
All the rest of the people who are going to primary literature and guidelines were people
who are self-designated as researchers more than primary clinicians.
And then the next group is specialty Internet sites, the NIH sites, OMIM, gene test, gene
reviews, and my own database, Gene Facts.
You'll see asterisks throughout here, those are on the next slide.
I'll explain in a moment.
And there was one no answer, but I'll add to that.
One of the responses this morning was a little bit more specific than no answer.
The answer from this other respondent this morning was, "I don't think there's a resource
out there that tells me what I need to know in a useful and accessible manner."
So the asterisks, footnotes, qualifiers, et cetera, one of the people who said Google
actually shows up in there twice and this was a slightly more sophisticated answer.
So that person actually goes to Google, but uses a fairly smart search, so says NIH and
the mutation that that person is looking for, so that's at least trying to put some scientific
value on what they're looking for.
The NIH answers.
One of them was that Google search that I just mentioned.
The other one was some NIH polymorphism database, which I assume the respondent meant dbSNP,
but I don't know for sure and the respondent didn't know the name of the database.
But at least there was a concept among one and that was a clinician, by the way, that
was over here, not a researcher.
Someone at least was aware that the NIH has some sort of a database.
Hadn't actually gone there, but thought that it might be a useful resource.
The people who said Gene Facts and Gene Reviews are, in fact, my other two co-editors in chief,
so another --
[laughter]
Another flaw in the study is that anonymity is clearly not preserved, because if you know
--
[laughter]
-- or can figure out who we are then I've just called out the other two people.
Among the people who listed OMIM, so there was one more vote for OMIM, so now we have
a total of four people who mentioned OMIM, three of those four said they would use it.
One specifically said, "I would definitely not go to OMIM, because it's way too dense
and I can't get what I need."
Of the people who mentioned OMIM, one is one of the co-editors in chief of Gene Facts and
the one who said that OMIM would not be used, in fact, is the other co-editor in chief of
Gene Facts.
And then the notes of H or HH or HHH, that was the number of times that someone commented,
"I might use that resource, but it's really hard to find what I want within that resource."
So, that's the results of my highly unscientific biased irrelevant study.
What does the literature say?
Pretty much the same thing.
Clinicians like to get their data from the Internet.
This is old data, so CD-ROM was listed.
I'm not sure that's as often a place that people will turn anymore.
Textbooks don't really exist anymore, but maybe you'll look it up on your Kindle.
Consultants and specialists remain highly desired sources of information.
Seminars, meetings, other things as well.
People in general, especially highly-active clinicians, don't like to go to lectures,
because it takes up time.
They don't go to the journals and primary literature, again, because it takes up time,
and generally don't actually go to specific guidelines, although as we'll talk about later,
they do by some osmosis filter in some of the advice from their governing bodies or
society statements.
Other resources that I use that didn't get called out in that database, I certainly go
to PharmGKB.
A few years ago I would tell people it's like OMIM, it's a dense encyclopedia, but not so
clinically useful.
That's gotten better in recent years and importantly, the CPIC, Clinical Pharmacogenetics Implementation
Consortium, which Alan would have told you a lot more about were he here, and other guidelines
on that site are actually making it much more user-friendly for the clinician.
I often will go to the website of a specialty lab or call up the specialty lab, so Elaine,
sorry, the pressure you're feeling is true.
Once you make a call, we're going to assume that you've made the correct call.
So, yeah, the clinical lab has to get it right, and likewise we'll go to the researchers sometimes.
So, the researchers have to get this right.
I still love the Flockhart tables and there's a website there for it for you.
That's slowly collecting some actual clinical variant data, but even without that there's
still useful lists of what genes are -- I'm sorry, what drugs are metabolized through
what P450 enzymes.
And then algorithms for decision support.
Warfarindosing.org I think most of you are familiar with, and hopefully there'll be more
of those coming online as we get more clinically relevant data.
I should point out the results of the needs analysis study we did several years ago to
show that we should build Gene Facts.
We didn't ask questions about can you look up a specific genetic variant, but we did
write what we thought were 20 reasonably relevant questions in clinical genetics and we interrogated
nine different databases to see if they could answer those questions completely and accurately,
and what we found was the genetics resources, especially gene resources, were good.
UpToDate was the best of the non-genetics resources and most of the others really weren't
good enough, and really distressingly, some of the resources had wrong answers.
My favorite, which most of you are probably familiar with, some of them explicitly stated
that you can only inherit hereditary breast ovarian cancer, BRCA mutations, through the
maternal lineage and you don't have to worry about the paternal side.
Black and white clear statement of fact.
Yikes.
Second question, what would the ideal resource provide?
I got 12 responses to this.
Characteristics of the resource.
First and foremost it has to be concise, easy to use, I've got to get in and get out fast,
and it also needs to be accurate.
Free is desirable.
Educational was listed as something desirable.
Someone just said, "Something like UpToDate," by which I presume they meant put the actual
genetic variant data in there and make it so that I can find it.
And one person wanted links to other resources, which we saw highlighted in one of the other
talks already.
As far as the content, give me management information.
Give me the clinical significance.
Tell me what it means.
That was four responses.
And I list it separately, because I think it's important to note, but that's really
part of management, one person actually specifically called out give me clinical data support -- clinical
decision support right within the EHR, so that's really part of management and implications.
But it's nice to see that at least one person is thinking about putting it right there in
the medical record.
Actionability, clinical utility is common.
Information about testing.
Tell me about the clinical validity.
Tell me who to test and when to test.
Tell me about the test method.
Tell me how to interpret the test.
Tell me the cost of the test, one person called out.
Other things for the content.
Tell me about the pathophysiology, the phenotype, the prognosis, the whole spectrum of clinical
manifestations.
What does this thing actually mean?
Tell me about the frequency of a variation and especially highlight the most common variants.
Two people wanted to know about inheritance patterns or the frequency of a de novo versus
inherited mutation.
I think it's important to point out that I sent out my little survey and while I mentioned
we're asking about genetic variants, most people probably just read what do you do when
you have a genetics question, so some of these answers might not be unique to our question
today.
Some of them might be tell me about a genetic disorder, but still, people want to know about
inheritance and inherited versus new mutation.
And two people asked for evidence-based information, only two of the now 18 respondents.
One of them was a clinician educator, one a clinician researcher, so only two out of
18.
What the literature says is clinicians want it to be accurate.
They want it to be accessible.
They want it to be clinically relevant and they won't spend more than two minutes looking
for answers.
And other papers have gone on to say that essentially what clinicians are looking for
is a trusted authoritative research that will go out and digest all the primary data and
present it to the clinician in a way that they can just use from there.
They generally don't want to go look at the evidence themselves.
So, is evidence-based important?
And here I'm reporting not only what I got from my colleagues and my own opinions, but
this comes in part from email communication with Alan, so this is part of what he was
going to tell you also.
There's a lot of variation in terms of how much evidence users actually will demand.
Some want very high standards, will only implement some action if there's a good randomized clinical
trial or better.
Others have somewhat less rigorous standards and will use variants when there's a preponderance
of evidence that suggests that they're valuable, and many people will follow their specialty
society guidelines and recommendations.
So when a society comes out and makes a statement, that actually carries weight.
That's good or bad.
So, for example, outside the realm of genetics, orthopedic societies will tell practitioners
that a patient with an artificial joint needs to take antibiotics before they get dental
work done.
And infectious disease societies say nonsense.
The bugs that cause joint infections in artificial joints are skin organisms, not oral organisms,
so this is stupid.
Don't give antibiotics before a dental procedure.
So do you want to follow the advice of your infectious disease expert or your orthopedics
expert?
Well, what's the evidence say?
Oh, I'm not sure.
All right.
That's all I got.
[applause]
Male Speaker: Okay, questions for Howard.
Male Speaker: Ken Kawamoto from University of Utah.
Do you get the sense talking to your colleagues that your clinician colleagues view genetic
information any differently than other information or do you get the sense that, you know, just
like any other test, any other factor considered in clinical medicine, they just want to be
given information on well, what should I do with this information?
Howard Levy: So, as Marc pointed out, we've all in this
room done a great job of building up genetic exceptionalism much to our own chagrin.
Most geneticists just want to treat -- geneticists, sorry.
Most clinicians just want to treat it like any other information with the caveat that
they're aware that there's some bug-a-boo about it and we need to be careful about something
and generally what that typically translates into is, gosh that's complicated, I'd better
just refer to a geneticist and not touch it, which is also not so helpful because there
aren't enough of us geneticists out there.
Male Speaker: I have a question.
So what do your non-genetics clinical colleagues make of the classification probably causal?
Howard Levy: What do they make of probably causal?
Male Speaker: How useful is that to them?
Howard Levy: I equate that to when we would look for pulmonary
embolism before we had good CTs and we'd send our patients down to radiology for a nuclear
medicine scan and the report would come back moderate probability, please correlate with
clinical suspicion, which basically meant, we don't know.
It might be.
It might not be.
And it was completely useless.
So, you put everybody on heparin and you waited to see if they really had a problem or not
and we probably caused a lot of bleeding problems in people who didn't really need to be heparinized,
because they didn't have a pulmonary embolism.
So, no, it's not so helpful to say uncertain significance, but it's better than saying
a benign variant is pathogenic and it's clearly better than saying a pathogenic variant is
benign.
So, while it's not great to say we have no clue what this means, I think it's better
than lying.
Male Speaker: It's probably about as useful as the entry
for earth in the "Hitchhiker's Guide," "mostly harmless."
[laughter]
Howard Levy: That was the update.
So, the encyclopedia originally said "harmless" and the update was to add "mostly," yeah.
[laughter]
Teri Manolio: Teri Manolio from Genome.
It's interesting the list of information that people wanted about their variant didn't include
cost of the test or where you can get it.
And I practice over at the Navy and, boy, trying to figure out how to even order these
things is really a challenge.
Howard Levy: It is.
Teri Manolio: Is that something that you think would be
useful, too?
Howard Levy: So, one person did ask for cost.
Teri Manolio: Sorry.
Howard Levy: Nobody specifically asked where to go to get
a test, but there was when and who to test and test method.
So I think people danced around it.
Remember, this was yesterday and I said spend no more than 30 to 60 seconds answering this
question, so again, it's not a very scientific study.
Teri Manolio: Right.
And I'm not criticizing your respondents or you.
Howard Levy: Yeah.
Teri Manolio: I'm just asking you for your opinion.
Do you find that your folks at Hopkins, you know, tertiary care referral center, that
where is not a problem, that they just do it at Hopkins, or is this really a challenge?
Howard Levy: So I guess a little bit more about the sample
size or sample population, I surveyed general internal medicine folks.
I didn't survey specialists.
Specialists get a relationship with one or two labs.
They know where to get their tests.
They do it.
It's automatic.
Generalists don't have a relationship and I think that is another barrier that even
if you have an idea of what test you want to get, it's so hard to figure out where to
get it and fill out all the paperwork that it probably doesn't happen.
And, in fact, when I'm seeing patients in my primary care office without a genetic counselor,
I have a much higher threshold to order a test than when I'm seeing someone in genetics
clinic with a counselor, because I have to fill out all the paperwork and figure out
where I'm going to send it off.
So, even someone who's informed it's a barrier.
Male Speaker: Just to add on to that, I think this is a
big issue, but as we develop these resources, I think there's a couple of other barriers,
one relating to cost where with the genetic testing registry that's coming online that
there was a lot of pushback from clinical laboratories about actually submitting their
test cost data to that resource.
Not all of them were really thrilled about the idea that that would be out there.
The other thing that Elaine didn't talk about, but I think is really critically important
in a discussion like this is that some people treat their test-specific information as proprietary
and use that as a competitive advantage, which I think in the long run is going to be extraordinarily
harmful to this type of effort.
So I think those are things that we -- as we think about what is going to be in the
resource, how do we incent people to really do this?
Male Speaker: If I could just add to that.
You know, I think this whole discussion highlights the need for us to be thinking about the day
when either the whole sequence is there or a variant table is there, because it completely
makes all those issues go away.
Male Speaker: Great.
So if we move on to our last speaker now before the general discussion.