title: Comparison of HLA allelic imputation programs.
abstract: Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.
authors.affiliation: Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona, United States of America.
authors.forename: Jason H
authors.identifier: http://orcid.org/0000-0001-5001-3334
authors.initials: JH
authors.lastname: Karnes
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Shaffer
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bastarache
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|School of Anatomy, Physiology and Human Biology, University of Western Australia, Nedlands, Western Australia, Australia.|Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Glazer
authors.affiliation: Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona, United States of America.
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Steiner
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.|Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Phillips
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.|Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D001741:Black or African American; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People
chemical_list: D006680:HLA Antigens