Substituting imputation of HLA antigens for high‐resolution HLA typing: Evaluation of a multiethnic population and implications for clinical decision making in transplantation

Molecular mismatch analysis for assessment of histocompatibility in transplantation requires high‐resolution HLA typing. Algorithms to “guesstimate” high‐resolution from low‐resolution typing exist, but their accuracy remains unknown. We converted high‐resolution, sequence‐based, HLA typing of 310 subjects from an ethnically heterogeneous population to low‐resolution equivalents and tested the ability of the NMDP HaploStats and HLA Matchmaker programs to impute/reproduce the measured high‐resolution HLA type, using the more common “winner‐takes‐all” approach. Only 35.6% of the HaploStats imputed HLA‐A, ‐B, ‐C, ‐DRB1, and ‐DQB1 haplotypes had no mistakes, and the accuracy was significantly lower for non‐Caucasians (29.1%) compared to Caucasians (45.2%) (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3‐0.8; P = .004). HLA Matchmaker was not able to provide high‐resolution haplotypes for 45.2% of Caucasian subjects and 63.5% of non‐Caucasian subjects (P = .002). Of those with an imputed result, only 10.3% of Caucasians and 4.8% of non‐Caucasians had accurate 10‐allele high‐resolution output. Eplet analysis revealed additional, inaccurate eplets in 37% of individuals, with 22.5% showing at least 2 additional, inaccurate eplets; incorrect eplets were more common among non‐Caucasians (OR, 1.8; 95% CI, 1.1‐2.9; P = .018). Given this high error rate, caution should be taken before using imputation tools for clinical or research purposes, especially for non‐Caucasian individuals. Compared to high‐resolution HLA typing, the output of two commonly used programs to impute HLA antigens performs poorly, particularly for non‐Caucasians.