Controlling for Multiplicity in Science

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Submission Summary
A problem that is common to many sciences is that of having to deal with a multiplicity of statistical inferences. For instance, in GWAS (Genome Wide Association Studies), an experiment might consider 20 diseases and 100,000 genes, and conduct statistical tests of the 20x100,000=2,000,000 null hypotheses that a specific disease is associated with a specific gene. The issue is that selective reporting of only the ‘highly significant’ results could lead to many claimed disease/gene associations that turn out to be false, simply because of statistical randomness. In 2007, the seriousness of this problem was recognized in GWAS and extremely stringent standards were employed to resolve it. Indeed, it was recommended that tests for association should be conducted at an error probability of 5 x 10—7. Particle physicists similarly learned that a discovery would be reliably replicated only if the p-value of the relevant test was less than 5.7 x 10—7. This was because they had to account for a huge number of multiplicities in their analyses. Other sciences have continuing issues with multiplicity. In the Social Sciences, p-hacking and data dredging are common, which involve multiple analyses of data. Stopping rules in social sciences are often ignored, even though it has been known since 1933 that, if one keeps collecting data and computing the p-value, one is guaranteed to obtain a p-value less than 0.05 (or, indeed, any specified value), even if the null hypothesis is true. In medical studies that occur with strong oversight (e.g., by the FDA), control for multiplicity is mandated. There is also typically a large amount of replication, resulting in meta-analysis. But there are many situations where multiplicity is not handled well, such as subgroup analysis: one first tests for an overall treatment effect in the population; failing to find that, one tests for an effect among men or among women; failing to find that, one tests for an effect among old men or young men, or among old women or young women; …. I will argue that there is a single method that can address any such problems of multiplicity: Bayesian analysis, with the multiplicity being addressed through choice of prior probabilities of hypotheses. In GWAS, scientists assessed the chance of a disease/gene association to be 1/100,000, meaning that each null hypothesis of no association would be assigned a prior probability of 1-1/100,000. Only tests yielding p-values less than 5 x 10—7 would be able to overcome this strong initial belief in no association. In subgroup analysis, the set of possible subgroups under consideration can be expressed as a tree, with probabilities being assigned to differing branches of the tree to deal with the multiplicity. There are, of course, also frequentist error approaches (such as Bonferroni and FDR) for handling multiplicity of statistical inferences; indeed, these are much more familiar than the Bayesian approach. These are, however, targeted solutions for specific classes of problems and are not easily generalizable to new problems.
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Duke University

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