Multistage Sampling for Genetic Studies^*

In the past, to study Mendelian diseases, segregating families have been carefully ascertained for segregation analysis, followed by collecting extended multiplex families for linkage analysis. This would then be followed by association studies, using independent case-control samples and/or additional family data. Recently, for complex diseases, the initial sampling has been for a genome-wide linkage analysis, often using independent sib-pairs or nuclear families, to identify candidate regions for follow-up with association studies, again using case-control samples and/or additional family data. We now have the ability to conduct genome-wide association studies using 100,000–500,000 diallelic genetic markers. For such studies we focus especially on efficient two-stage association sampling designs, which can retain nearly optimal statistical power at about half the genotyping cost. Similarly, beginning an association study by genotyping pooled samples may also be a viable option if the cost of accurately pooling DNA samples outweighs genotyping costs. Finally, we note that the sampling of family data for linkage analysis is not a practice that should be automatically discontinued.