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Friday, September 4, 2009

Risk Factors #2 and thanks to Dr. Steve.

Gotta love drive-by comments from Dr. Steve:

I don't have time to go into all of the many errors in this post, but for a start, the odds ratio associated with the celiac snp is about 5-10X *per allele* (about 50X for a homozygote). This HLA allele accounts for about 90% of celiac disease and its mode of action is well understood.

I understand this is just a blog and you are not supposed to be an expert, but you should do some basic reading on genetics before posting misinformation. Or better yet, leave this stuff to Daniel MacArthur.

While even the 6th grade bullies I knew could give Dr Steve a lesson in making friends, I may as well at least clarify my point.

To start with, Dr. Steve made one good point. I didn't know know what the risk factor for a single given Celiac SNP is - and thanks to Dr. Steve's incredibly educational message - I still don't. I simply made up a risk factor, which was probably the source of Dr. Steve's confusion. (I did say I made it up in the post, but apparently hypothetical situations aren't within Dr Steve's repertoire.)

But lets revisit how Risk factors work, as I understand it. If someone would like to tell me how I'm wrong, I'll accept that criticism. Telling me I'm wrong without saying why is useless, so don't bother.

A risk factor is a multiplicative factor that indicates your risk of expressing a given phenotype versus the general population. If you have a risk factor of 5, and the general population has a 10% phenotype penetration, that means you have a 50% chance of expressing the phenotype. (.10 x 5 = 0.5, which is 50%).

In more complex cases, say with two independent SNPs, each with an independent risk factor, you multiply the set of risk factors by the probability of the phenotype appearing in the general population. (You don't need me to do the math for you, do you?)

My rather long-winded point was that discussing risk factors without discussing the phenotypic background disease rate in the population is pointless, unless you know that the risk ratio leads you to a diagnostic test and predicts in a demonstrated statistically significant manner that the information is actionable.

Where I went out on a limb was in discussing other unknowns: error rates in the test, and possible other factors. Perhaps Dr. Steve knows he has a 0% error rate in his DTC SNP calls, or assumes as much - I am just not ready to make that assumption. Another place Dr. Steve may have objected to was my point about extraneous environmental factors, which may be included in the risk factor, although I just passed over it in my previous post without much discussion.

(I would love to hear how a SNP risk factor for something like Parkinson's disease would be modulated by Vitamin D levels depending on your latitude. It can't possibly be built into a DTC report. Oh, wait, this is hypothetical again - Sorry Dr. Steve!)

My main point from the previous post was that I have a difficult time accepting is that genomics consultants consider a "risk factor" as a useful piece of genomic information in the absence of an accompanying "expected background phenotypic risk." A risk factor is simply a modulator of the risk, and if you talk about a risk factor you absolutely need to know what the background risk is.

Ok, I'm done rehashing my point from the previous point, and that takes me to my point for today:

Dr. Steve, telling people who have an interest in DTC genomics to stay out of the conversation in favor of the experts is shooting yourself in the foot. Whether it's me or someone else, we're going to ask the questions, and telling us to shut up isn't going to get the questions answered. If I'm asking these questions, and contrary to your condescending comment I do have a genomics background, people without a genomics background will be asking them as well.

So I'd like to conclude with a piece of advice for you: Maybe you should leave the discussion to Daniel McArthur too - he's doing a much better job of spreading information than you are, and he does it without gratuitously insulting people.

And I thought Doctors were taught to have a good bedside manner.

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Blogger Luke said...

We give relative risks because they can be usefully combined, interpreted and tested for significance. However, absolute risks can be, and often are, calculated easily, and I am pretty sure that both 23andMe and deCODE give the absolute risk a person has, not just their relative risk. No-one is hiding or ignoring this information.

It seems to me that Dr Steve got annoyed that your hypothetical risk SNPs tend to be a little on the low side for what we often get, and thus made DTC tests seem less useful than they are. Most people will tend to have genes totaling a relative risk of around 2, and many will have a total relative risk of 3 or 4; this might not be massive, but it can be useful, especially for common diseases like diabetes or cancer - being told you have a 25% rather than a 10% chance of developing breast cancer is actionable, and would not be an unusual result.

Not that I am saying Dr Steve was not being unpleasant; he does, of course, lose the Internet game.

September 5, 2009 4:34:00 AM PDT  
Blogger Anthony Fejes said...

Hi Luke,

Thanks for the response.

I think my confusion comes because the majority of the "risk factor" talks I've seen have been in a research setting, where the absolute risk is not touched upon. Perhaps this just further underscores the difference between medicine and research.

In the research setting,I've also seen plenty of talks with the rates in the 4-10% rate.

Still, I didn't intend to say that all rates are that low - just that when they are, the information isn't particularly useful.

Once again, thanks for the reply - and thanks for enlightening me in a polite fashion. (-:


September 5, 2009 6:53:00 PM PDT  

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