Thursday, July 29, 2010

GWAS advertising legerdemain

There's a recent GWAS review by Teri Manolio in the New England Journal of Medicine that demands a response, even in just our little blog. Dr Manolio reviews the success and (some of) the less positive issues attending to the genetic approach to disease.

This article lays out the nature, and the positive findings, of genomewide association studies. Manolio says things like:
Genomewide association studies — in which hundreds of thousands of single-nucleotide polymorphisms (SNPs) are tested for association with a disease in hundreds or thousands of persons — have revolutionized the search for genetic influences on complex traits.
Genomewide association studies have proved successful in identifying genetic associations with complex traits.
But she demurs from citing a number of authors who have raised substantial points critical of the GWAS approach, though the supportive literature is of course well represented.

The problem is that Dr Manolio is a bureaucrat working for the NIH's Human Genome Research Institute. She is a skilled person, but her job is advocacy of a particular program agenda--the funding of genetic research--and hence she has a vested interest in promoting the work they've decided to fund and hence advertising it as a success. Perhaps that's in her 'job description'--to be an advocate for a policy she feels is a good one. But that shouldn't be confused with science.

If the NEJM were ethically responsible (there have been many issues about that in recent years, including their relationship to the evaluation of drug safety and drug trial data), it would not publish an article evaluating GWAS written by a person vested in advancing that type of study. Such a review must be viewed as essentially a conflict of interest. And given the same suspicion that drug trials sponsored by drug companies get and have richly deserved.

It is not that GWAS are all bad or a total waste of resources. But they are far from as good as the article says. We've made many posts about GWAS and need not repeat them here (interested readers can find them by searching the blog). But a cheer-leading article in a prominent journal like the NEJM can and probably will be seen as evidence for the success of the effort to turn complex traits into genetic traits.

One legitimate issue, of course, is that investment in one place diverts funds from other avenues of research. There are areas in which the same investment might have much greater, and more immediate returns in terms of actual health improvement, even if such measures aren't as glamorous for the research industry.

And there's a further problem. Publishing this propaganda piece in the NEJM implies that GWAS have clinical relevance and are about 'medicine'. In a few rare cases (naturally, they're featured in the article) this is partly true, though the role of GWAS in their primary discovery is less clear. But generally we are so far from being able to apply GWAS in clinical practice that a review of GWAS results should not appear in a medical journal.

There are some new approaches being taken in association mapping, including those that go beyond considering just the most statistically 'significant' genome regions found for a given disease. They try to digest the information about risk from all or at least many more of the tested markers along the genome. These approaches are briefly mentioned in the article, but Dr Monolio does not say that by and large GWAS lead only to general statements of risk that have very little specific genetic value since most of the implicated regions contribute trivially to risk on their own.

And the article is naive about (and/or intentionally fails to cite) other problems, aspects related to evolution, and is downright misleading about the history of 'theory' in this area, which is much more a history of advocacy than of science.

The article provides a good summary about what GWAS are, with nice figures to show this. But it must be read as lobbying. It's too bad we have to live in an era when this is the way things are done. Science could make better progress, and contribute more directly to taxpayers who support it, if decisions about it were more centered in science itself.


James Goetz said...

Ken, did you notice that Manolio claims "No potential conflict of interest relevant to this article was reported." And here is the supposed disclose form filled out by Manolio:

Ken Weiss said...

It's a fine line, since everyone who writes a Commentary is presumably knowledgeable in his/her field, almost necessarily because they've worked in it. And I don't think there is any issue of personal honesty or questionable ethics here.

Still, I think there is a problem relative to the presentation of the science.