The approaches that we outline here rely on initial use of achievable sample sizes that may be more likely to be more homogeneous. Initial samples can nominate sets of SNP markers, genomic regions and genes that can be studied in additional independent replicate samples. A requirement that genes display SNPs whose allelic frequencies distinguish disease from control individuals in multiple samples is one of the few assurances against false-positive results that is likely to pass ultimate statistical muster and also to yield feasible experimental designs. There is a downside to this approach: rates of false negative results are also unavoidably elevated by requirements for replication (see below).
