Studies of populations that are genetically more distinct from those examined by the HapMap consortium will require more careful consideration in the design of strategies for genotype imputation. For example, we expect that when imputing missing genotypes in Middle Eastern samples, Native American samples or even samples from the Indian sub-continent, it will be advantageous to use a reference panel that includes all HapMap haplotypes, rather than just the CEU, just the YRI or just the CHB+JPT haplotypes. Fortunately, whenever the choice of reference panel is unclear it is possible to mask a subset of the available genotype data, run genotype imputation using each of the different reference panels being considered, and finally contrast imputed and masked genotypes to identify the strategy that provides the most accurate genotypes. Table 2 summarizes the results of a recent analysis (59) that sought to identify the most appropriate reference panel for a series of samples in the Human Genome Diversity Panel (19).
