QC criteria that are dependent on population allele frequencies can generally be adapted for application in diverse cohorts by either stratifying the cohort into major populations prior to filtering (the stratified meta-analysis approach) or by adjusting the QC measure to allow for varying allele frequencies (the joint mixed model approach; see Figure 2). For example, individuals are often removed based on excess autosomal heterozygosity, as a potential indication of sample contamination, but the standard heterozygosity statistic assumes each variant’s expected allele frequency is constant across individuals. In diverse cohorts, regressing this heterozygosity statistic on principal components prior to identifying outliers can avoid excessive exclusions of individuals from subgroups in the cohort. Step-by-step considerations for common QC criteria, including sample QC workflows for the stratified meta-analysis and joint mixed model approaches, are given in Supplemental Methods I (see also Supplemental Table S2, Supplemental Figure 1). In addition to these pre-imputation QC steps, post-imputation QC steps should also consider ancestry (see Imputation).
