Aim: High-resolution (Hi) two-field typing is essential for accurate eplet mismatch (EpMM) assessment in predicting the development of de novo DSA and rejection post-transplant. This study aimed to evaluate the accuracy of EpMM estimates using imputed HLA alleles compared to Hi D-R typing in a larger cohort than we previously studied and presented in ASHI 2023.
Methods: (1) Hi and intermediate (Int) typing were obtained from 48 hematopoietic stem cell transplant patients, each serving as a donor (D) to pair with all 48 recipients (R), forming 2304 D-R pairs. Both matched and unmatched D-R scenarios were simulated. (2) Int typing (A, B, C, DRB1, DQB1) was imputed to two-field using HaploStats based on the high haplotype frequency strategy in five NMDP race categories: African American, Asian/Pacific Islander, Caucasian, Hispanic and Native American (due to unavailable race data). (3) Imputed alleles were compared to Hi alleles per race. (4) HLAMatchmaker was used to determine verified antibody-reactive EpMM (#EpMM) across six groups. Imputed #EpMM was compared to Hi-based #EpMM. (5) Differences in #EpMM (delta #EpMM) between imputed and Hi typing were analyzed by Class I and II and race. (6) Statistical analyses included paired t-test, linear regression and Wilcoxon test.
Results: (1) Across all race groups, 53% of patients had at least one imputed allele differing from their Hi-resolution typing (mean 25±3 for Class I and 25±2 for Class II). (2) Strong correlations were observed between imputed and Hi-resolution #EpMM values for both Class I and II alleles (Fig. 1). No difference in #EpMM (delta = 0) was found in 81.4±3.0% of D-R pairs for Class I and 64.0±4.3% for Class II. Delta #EpMM ranged from 0–4 for Class I and 0–11 for Class II (Fig.2). The distribution of higher delta #EpMM values by HLA locus and race is shown in Table 1.
Conclusion: Despite frequent discrepancies in allele misassignments through imputation, most simulated D-R pairs showed minimal changes in #EpMM across racial groups. Large deviations in #EpMM values were rare, especially in three major race categories. These findings indicate that imputed HLA typing can provide acceptable accuracy for EpMM estimation in most clinical scenarios. However, those rare patients with high delta #EpMM could lead to an erroneous risk stratification or change clinical management. We need to be careful during imputation.
