Another way of exploiting summary statistics for rare variant analysis involves comparing haplotype frequencies between, for example, case and control groups, as opposed to genotype or single variant carrier status frequencies.43–45 Haplotype analyses require phase information, which is not trivial to obtain for genotyped rare variants or variants derived from sequence data (Box 1). In addition, if enough rare variants are studied, each individual in a sample of cases and controls may have their own unique haplotypes, making summary statistic approaches impossible. A recently proposed two-stage approach to haplotype analysis of rare variants could alleviate this problem since it collapses haplotypes into groups and eliminates variants not likely to be relevant prior to contrasting haplotype frequencies.46
