OR44 Evaluation of HLA typing ambiguity in the us registry

As clinical matching definitions for transplantation evolve there is a need to quantify the degree of uncertainty in a typing result relative to a particular resolution target. We aimed to develop such a measure and then applied it to quantifying the improvement in typing resolution of the Be The Match® Registry since 1993. We describe and apply a new typing ambiguity score, based on the likelihood of self-match which allows for comparison of HLA typings across different methods, data sets and populations. In order to compute the typing ambiguity score, we perform HLA genotype imputation on 14 million donors using high-resolution haplotype frequencies generated from unrelated donors from the National Marrow Donor Program database for 5 population categories. For this experiment the resolution target was 5-locus ARS exons with equivalent amino acid sequence. The Registry has seen an increasing trend in the score over time for all populations and all HLA loci, with the overall scores for recruitment typing rising from 0.31 in 1993 to 0.96 in 2015. Many discontinuities in scores coincide with changes in recruitment typing policy, such as the transition of HLA-A and B typing from serology to DNA, the start of sequence based typing, the inclusion of HLA-C and DQB1 at recruitment, etc. We find evidence that oligo-based kits were tuned to reduce typing ambiguity primarily for majority race/ethnic groups as European American donors generally had the most rapid increase in scores, while African American donors have the lowest scores and a slower increase in scores. Finally, we show that new recruitment HLA typing performed for the US registry today has very little ambiguity under the current standard of matching at HLA-A, C, B, DRB1, and DQB1, using the current laboratory methods that employ next-generation sequencing or sequence-based typing with panels of group-specific sequencing primers. Our typing ambiguity score objectively measured the improvement in HLA typing within the US registry from 1993 to the current state of high-resolution typing. We next aim to assess ambiguity among global registries in BMDW. This method is general and can be applied to other loci (e.g. DPB1, DPA1, DQA1) other systems (KIR) and other definitions of allele (all-exons or full-gene).