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The FDA’s methods on 23andMe would not pass peer review

2014.07.02

 

fda-logo123andMe is one of several companies that offers direct-to-consumer genetic testing. They use your genotype to draw conclusions about both your ancestry and health-related risk factors. Last year, the FDA forced 23andMe to stop marketing itself as a provider of health-related genetic tests.

23_logotype-01They are afraid that people will be provided with incorrect information regarding their risks over disease. Overestimating risk can make people overly concerned and demand additional unnecessary procedures from their physicians. Underestimating risk can make people feel complacent and not take the appropriate precautions.

I bring this up now because the FDA recently wrote a blog post about their decision to stop 23andMe from providing such results. While I share their concerns and am glad the FDA has taken interest, the methods they describe and the justification is pretty shaky and would certainly not stand up to peer review. Here is their experiment and results:

In 2010, at the behest of Congress, investigators from the U.S. Government Accountability Office purchased direct-to-consumer (DTC) genetic tests from four different companies—including 23andMe—and submitted two samples of their DNA to each company to receive risk predictions for 15 common diseases. The results varied across the four companies. One investigator was told that he was at below-average, average, and above-average risk for prostate cancer and hypertension. In some cases, the risk predictions conflicted with an investigator’s actual medical condition.

The main problem here is that if you are interested in accuracy, comparing methods against each other is a terrible way to assess it. Even if they all agreed, they could all still be wrong. And there are tons of reasons why they might not agree.

Problem #1: There are two steps to ensuring accuracy here. One is making sure that the genotyping itself is accurate. The other is that the conclusions being drawn from the genotype results is accurate. 23andMe has provided pretty solid evidence that their genotyping methods are quite good (although here is an analysis of their multiple-testing problem plus a little bit of melodrama). They will make some mistakes, but they will be rare. I don’t know about the other companies tested, but let’s just assume they have very high quality and focus on the differences in interpretation.

Problem #2: Different companies sequence different parts of the genome. We aren’t yet at the point where everyone is sequencing their entire genome; each company uses a different way to genotype some subset of the genome. If the companies have different information, obviously their results should differ.

Problem #3: What we know about disease risk is constantly changing. These companies rely on papers published by scientists to help them interpret your genotypes. As new research emerges, these results can drastically change. But incorporating new results into their predictions is not automatic, so this is another easy way in which results could be different.

Problem #4: Two samples? Really? Is the FDA seriously making its decisions based on a study with a sample of size two? The irony of this is that the whole process of inferring disease risk from genotypes is a statistical one, yet to challenge it the FDA says “Statistics? Meh.”

Problem #5: They report how for some diseases the companies failed to provide the same risk analyses. They did not report the many other diseases tested in which the companies all did agree.  This is called cherry-picking results. You have to show that the number of discrepancies you observe is significantly different from a null expectation using a statistical test.

Problem #6: “In some cases, the risk predictions conflicted with an investigator’s actual medical condition.” This is just silly. 23andMe provides risk information, not diagnosis. If I tell you that your chance of rolling a die and getting a 1 is 1/6, and you indeed roll a 1, does this mean my prediction about your 1-risk was wrong? Nope. That’s just how probability works.

I’m glad the FDA has taken an interest in the issue of direct-to-consumer genetic testing. It is important both to protect consumers from false claims as well as ensure they have accurate medical information. But if I were a reviewer of this paper I would summarily reject it. Of course it’s not a paper, it’s a blog, but it is targeted at the general public and on the surface makes their case seem much more persuasive than it actually is.

 

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2 Comments leave one →
  1. 2014.07.02 09:10

    Excellent points about cherry picking, and sample size — basically, they took a very anecdotal approach to their “survey”.

    If I can play devil’s advocate (and at the same time withhold my cynicism that the decision is partly a job protection racket for doctors) — the FDA is concerned that most people just don’t have the ability to interpret basic probabilistic statements.

    Glad to see you writing again, Science Cowboy! Great post.

    • 2014.07.02 09:23

      Thanks Owen. I completely agree. The prospect of teaching patients (and physicians for that matter) to understand both genetics and probability is a daunting one.

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