It is somewhat surprising that pre-phasing remains competitive with other methods when imputing rare variants (MAF < 1%; Table 2). Such variants should require longer flanking haplotypes for successful imputation, and a single pre-phasing solution may include errors that break up long-range haplotypes. One possible explanation is that existing methods also struggle to infer very long haplotypes, so that pre-phasing still looks accurate by comparison. Conversely, it is important to realize that imputation accuracy is affected by phasing accuracy in the reference panel and by the GWAS SNPs used to drive imputation4,5. Imperfections in the reference haplotypes would limit imputation accuracy even with perfectly phased GWAS haplotypes, and it may be difficult to impute rare variants with any method when using sparse GWAS scaffolds. These factors may outweigh the differences between methods that use pre-phasing and those that integrate over phase uncertainty.
