It may also be worth considering a related study design in which very little error inflation was seen, which was considered by Howie et al. (2009). In their setting, a central control group in the WTCCC was genotyped on both Affy and Illumina, while different case groups from different disease studies were genotyped on just one of these platforms. The authors were interested in whether imputing SNPs missing in cases using both the HapMap and the central control group as a reference panel led to inflated Type I error. To assess this, they compared the central control group with another control group genotyped on Affy alone. They imputed SNPs missing in this new control group and then performed association tests. They found very few significant results, which demonstrated minimal inflation of Type I error in this setting. Their methods differ slightly from ours; however, we believe that the most important difference was the nested structure of their design – that is, that their central control group had SNPs from both Affy and Illumina chips, rather than Illumina alone. A comparison
