High-dimensional randomization-based inference capitalizing on classical design and modern computing.

A common complication that can arise with analyses of high-dimensional data is the repeated use of hypothesis tests. A second complication, especially with small samples, is the reliance on asymptotic p-values. Our proposed approach for addressing both complications uses a scientifically motivated scalar summary statistic, and although not entirely novel, seems rarely used. The method is illustrated using a crossover study of seventeen participants examining the effect of exposure to ozone versus clean air on the DNA methylome, where the multivariate outcome involved 484,531 genomic locations. Our proposed test yields a single null randomization distribution, and thus a single Fisher-exact p-value that is statistically valid whatever the structure of the data. However, the relevance and power of the resultant test requires the careful a priori selection of a single test statistic. The common practice using asymptotic p-values or meaningless thresholds for "significance" is inapposite in general.