The analysis of 2.5 million SNPs across the genome poses an obvious multiple-testing problem. Before sharing results, working groups select a p-value threshold to identify a set of genotype-phenotype associations, almost all of which can be expected to replicate in similar populations. With 2.5 million tests, the use of a Bonferroni correction to control the Family-Wise Error rate (FWER) at 0.05 yields a threshold p-value of 2E-8. Another way to interpret this threshold is to estimate the expected number of false-positive (EFP) tests: if there are no true associations, each test contributes on average 2E-8 false positives and, across the genome, yields an expected total of 0.05 false-positive results. Similarly, a threshold of 1/2.5 million, which equals 4E-7, gives an expectation of one false-positive result for all tests. Unlike the FWER interpretation, the control of EFP is not “conservative” for correlated tests (24). The CHARGE Analysis Committee recommends pre-specifying a fixed p-value threshold as well as a number of tests, but the decision about the exact threshold to use is left up the working groups. The Analysis Committee has also provided power calculations for both continuous (Supplemental Figure 1) and binary phenotypes (Supplemental Figure 2).
