Charting Improvements in US Registry HLA Typing Ambiguity Using a Typing Resolution Score

Abstract

Unrelated stem cell registries have been collecting HLA typing of volunteer bone marrow donors for over 25 years. Donor selection for hematopoietic stem cell transplantation is based primarily on matching the alleles of donors and patients at five polymorphic HLA loci. As HLA typing technologies have continually advanced since the beginnings of stem cell transplantation, registries have accrued typings of varied HLA typing ambiguity. We present a new typing resolution score, based on the likelihood of self-match, that allows the systematic comparison of HLA typings across different methods, data sets and populations. We apply the typing resolution score to chart improvement in HLA typing within the Be The Match Registry of the United States from the initiation of DNA-based HLA typing to the current state of high-resolution typing using next-generation sequencing technologies. In addition, we present a publicly available online tool for evaluation of any given HLA typing. This typing resolution score objectively evaluates HLA typing methods and can help define standards for acceptable recruitment HLA typing.

Performance of an allele‐level multi‐locus HLA genotype imputation tool in hematopoietic stem cell donors from Quebec

“…We used a typing resolution score (TRS) to quantify the uncertainty (i.e., ambiguity) associated with the genotype imputation process (Supplementary Material 1, equation 3). The TRS score is bounded by 0 and 1 with low scores indicating highly ambiguous imputation results and high scores indicating little residual ambiguity .…”

Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR

“…Impact of race/ethnicity in the selection process Many HLA alleles and haplotypes are distributed at different frequencies among different racial/ethnic groups. 25,92,93 HLA alleles at low frequency in the general population are more likely found on distinct haplotypes along with the remainder of the HLA alleles from an ancestral racial/ethnic group in common between patient and donor. NMDP's predictive matching algorithm, HapLogic, takes the race/ethnic group into account when predicting the likelihood of a high-resolution match, so centers should attempt to accurately obtain and enter these patient details for the search.…”

Common, intermediate and well‐documented HLA alleles in world populations: CIWD version 3.0.0

“…Variation in the ability to assign polymorphic residues to one haplotype vs the other has also varied with the reagents and methods used producing, in many cases, ambiguity in the specific genotype carried by an individual. The history of all of these changes in the known allele database and the typing methods is reflected in the wide variety of HLA assignments found in the millions of individuals listed in donor registries around the world …”

“…For example, a two‐field assignment, A*01:01 , is not clear as to what alleles are included (eg, A*01:103 because it is included in the A*01:01:01G group) or excluded ( A*01:87N because it is a nonexpressed allele and the assignment was provided without the “P” because of registry specifications). This variation has presented a major challenge for determining the frequency of individual alleles …”