The utility of imputation for molecular mismatch analysis in solid organ transplantation

HLA genotyping has undergone a rapid progression in resolution since the development of DNA-based typing methods. Despite the advent of high-resolution next-generation sequencing, the bulk of solid organ genotyping is performed at intermediate resolution, which provides multiple possible two-field results for each classical HLA loci. As a result, several methodologies have been developed to impute the most likely allele-level (two-field) HLA genotype for the purposes of donor-recipient compatibility analysis. The advent of molecular mismatch analysis, however, has placed a new emphasis on the accuracy of imputation. While seminal molecular mismatch studies have relied on the imputation of intermediate resolution genotyping, several recent studies have performed analysis showing that imputation generates inaccuracies in epitope identification. While the clinical impact of these errors is not clear, it is important that these concerns do not preclude future progress in understanding the utility of molecular mismatch analysis in transplantation. In the future, advances in genotyping methods will result in routine two-field resolution that will abrogate these concerns. In the meantime, however, studies are needed in order to address the role of molecular mismatch in diverse patient populations and to carefully address the potential of molecular mismatch analysis in the context of imputation.