PMID- 36426357
OWN - NLM
STAT- MEDLINE
DCOM- 20221128
LR  - 20231101
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - Benchmarking freely available HLA typing algorithms across varying genes, 
      coverages and typing resolutions.
PG  - 987655
LID - 10.3389/fimmu.2022.987655 [doi]
LID - 987655
AB  - Identifying the specific human leukocyte antigen (HLA) allele combination of an 
      individual is crucial in organ donation, risk assessment of autoimmune and 
      infectious diseases and cancer immunotherapy. However, due to the high genetic 
      polymorphism in this region, HLA typing requires specialized methods. We 
      investigated the performance of five next-generation sequencing (NGS) based HLA 
      typing tools with a non-restricted license namely HLA*LA, Optitype, 
      HISAT-genotype, Kourami and STC-Seq. This evaluation was done for the five HLA 
      loci, HLA-A, -B, -C, -DRB1 and -DQB1 using whole-exome sequencing (WES) samples 
      from 829 individuals. The robustness of the tools to lower depth of coverage 
      (DOC) was evaluated by subsampling and HLA typing 230 WES samples at DOC ranging 
      from 1X to 100X. The HLA typing accuracy was measured across four typing 
      resolutions. Among these, we present two clinically-relevant typing resolutions 
      (P group and pseudo-sequence), which specifically focus on the peptide binding 
      region. On average, across the five HLA loci examined, HLA*LA was found to have 
      the highest typing accuracy. For the individual loci, HLA-A, -B and -C, 
      Optitype's typing accuracy was the highest and HLA*LA had the highest typing 
      accuracy for HLA-DRB1 and -DQB1. The tools' robustness to lower DOC data varied 
      widely and further depended on the specific HLA locus. For all Class I loci, 
      Optitype had a typing accuracy above 95% (according to the modification of the 
      amino acids in the functionally relevant portion of the HLA molecule) at 50X, but 
      increasing the DOC beyond even 100X could still improve the typing accuracy of 
      HISAT-genotype, Kourami, and STC-seq across all five HLA loci as well as HLA*LA's 
      typing accuracy for HLA-DQB1. HLA typing is also used in studies of ancient DNA 
      (aDNA), which is often based on sequencing data with lower quality and DOC. 
      Interestingly, we found that Optitype's typing accuracy is not notably impaired 
      by short read length or by DNA damage, which is typical of aDNA, as long as the 
      DOC is sufficiently high.
CI  - Copyright (c) 2022 Thuesen, Klausen, Gopalakrishnan, Trolle and Renaud.
FAU - Thuesen, Nikolas Hallberg
AU  - Thuesen NH
AD  - Evaxion Biotech, Copenhagen, Denmark.
AD  - Department of Health Technology, Section for Bioinformatics, Technical University 
      of Denmark, Lyngby, Denmark.
FAU - Klausen, Michael Schantz
AU  - Klausen MS
AD  - Evaxion Biotech, Copenhagen, Denmark.
FAU - Gopalakrishnan, Shyam
AU  - Gopalakrishnan S
AD  - Section for Hologenomics, Department of Biology, University of Copenhagen, 
      Copenhagen, Denmark.
FAU - Trolle, Thomas
AU  - Trolle T
AD  - Evaxion Biotech, Copenhagen, Denmark.
FAU - Renaud, Gabriel
AU  - Renaud G
AD  - Department of Health Technology, Section for Bioinformatics, Technical University 
      of Denmark, Lyngby, Denmark.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221108
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (HLA-A Antigens)
SB  - IM
MH  - Humans
MH  - Sequence Analysis, DNA/methods
MH  - Histocompatibility Testing/methods
MH  - *High-Throughput Nucleotide Sequencing/methods
MH  - *HLA-A Antigens/genetics
MH  - Algorithms
PMC - PMC9679531
OTO - NOTNLM
OT  - algorithm
OT  - benchmark
OT  - depth of coverage
OT  - human leukycote antigen
OT  - next-generation sequencing (NGS)
OT  - typing resolution
OT  - whole exome sequencing
COIS- NT, MK and TT are employed by Evaxion Biotech and have a financial stake in the 
      company. The remaining authors declare that the research was conducted in the 
      absence of any commercial or financial relationships that could be construed as a 
      potential conflict of interest.
EDAT- 2022/11/26 06:00
MHDA- 2022/11/29 06:00
PMCR- 2022/01/01
CRDT- 2022/11/25 03:03
PHST- 2022/07/06 00:00 [received]
PHST- 2022/10/10 00:00 [accepted]
PHST- 2022/11/25 03:03 [entrez]
PHST- 2022/11/26 06:00 [pubmed]
PHST- 2022/11/29 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.987655 [doi]
PST - epublish
SO  - Front Immunol. 2022 Nov 8;13:987655. doi: 10.3389/fimmu.2022.987655. eCollection 
      2022.