Inaccuracies in epitope repertoire estimations when using multilocus allele‐level HLA genotype imputation tools

Limited availability of allele‐level HLA genotypes prompts their imputation from allele‐group genotypes to estimate epitope mismatches. We evaluated the accuracy of epitope load and repertoire assignment when imputing allele‐level HLA genotypes. Analyses were conducted on 175 hematopoietic stem cell (HSC) donors from the Héma‐Québec registry (HQR) and 57 HSC donor‐recipient pairs from McGill University Health Centre (MUHC), Québec, Canada, genotyped for HLA‐A, ‐B, ‐C, ‐DRB1, and ‐DQB1. Multilocus allele‐level imputation was performed using HaploStats. Disagreement in B‐ and T‐cell epitope assignment and epitope mismatches were ascertained for imputed vs measured allele‐level HLA genotypes in HSC donors and donor‐recipient pairs, respectively. Imputation resulted in no differences in overall eplet mismatches and Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE‐II) for HLA‐A, ‐B, and ‐C in 83.4% and 93.7% of HQR donors and 87.7% and 87.7% of MUHC donors, respectively. HLA‐DRB1‐ and ‐DQB1‐derived eplet mismatches and PIRCHE‐II were correctly assigned in 72.0% and 85.1% of HQR donors and 70.2% and 71.9% of MUHC donors, respectively. No discrepancies in eplet load or PIRCHE‐II were observed in 96.5% and 86.0% of HSC donor‐recipient pairs and in 70.2% and 70.1% of pairs for HLA‐A, ‐B, ‐C, ‐DRB1, and ‐DQB1, respectively. Kappa statistics of 0.9708 and 0.9725, 0.8724 and 0.8177, 0.9827 and 0.9022, 0.5644 and 0.4939, 0.5085 and 0.6361 were estimated when assessing agreement between eplet mismatches and PIRCHE‐II of imputed vs measured HLA‐A, ‐B, ‐C, ‐DRB1, and ‐DQB1 types, respectively. To avoid inaccuracies in epitope compatibility estimation, mainly for HLA class II, multilocus allele‐level genotype measurement is recommended.