PMID- 28440342 OWN - NLM STAT- MEDLINE DCOM- 20190111 LR - 20221207 IS - 1473-1150 (Electronic) IS - 1470-269X (Print) IS - 1470-269X (Linking) VI - 18 IP - 3 DP - 2018 May 22 TI - Significant variation between SNP-based HLA imputations in diverse populations: the last mile is the hardest. PG - 367-376 LID - 10.1038/tpj.2017.7 [doi] AB - Four single nucleotide polymorphism (SNP)-based human leukocyte antigen (HLA) imputation methods (e-HLA, HIBAG, HLA*IMP:02 and MAGPrediction) were trained using 1000 Genomes SNP and HLA genotypes and assessed for their ability to accurately impute molecular HLA-A, -B, -C and -DRB1 genotypes in the Human Genome Diversity Project cell panel. Imputation concordance was high (>89%) across all methods for both HLA-A and HLA-C, but HLA-B and HLA-DRB1 proved generally difficult to impute. Overall, <27.8% of subjects were correctly imputed for all HLA loci by any method. Concordance across all loci was not enhanced via the application of confidence thresholds; reliance on confidence scores across methods only led to noticeable improvement (+3.2%) for HLA-DRB1. As the HLA complex is highly relevant to the study of human health and disease, a standardized assessment of SNP-based HLA imputation methods is crucial for advancing genomic research. Considerable room remains for the improvement of HLA-B and especially HLA-DRB1 imputation methods, and no imputation method is as accurate as molecular genotyping. The application of large, ancestrally diverse HLA and SNP reference data sets and multiple imputation methods has the potential to make SNP-based HLA imputation methods a tractable option for determining HLA genotypes. FAU - Pappas, D J AU - Pappas DJ AD - Center for Genetics, Children's Hospital Research Institute, Oakland, CA, USA. FAU - Lizee, A AU - Lizee A AD - Department of Neurology, University of California, San Francisco, CA, USA. FAU - Paunic, V AU - Paunic V AD - Bioinformatics Research Department, National Marrow Donor Program, Minneapolis, MN, USA. FAU - Beutner, K R AU - Beutner KR AD - Department of Neurology, University of California, San Francisco, CA, USA. FAU - Motyer, A AU - Motyer A AD - Centre for Systems Genomics, Schools of Mathematics and Statistics, and BioSciences, The University of Melbourne, Melbourne, VIC, Australia. AD - Data Science, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Vukcevic, D AU - Vukcevic D AD - Centre for Systems Genomics, Schools of Mathematics and Statistics, and BioSciences, The University of Melbourne, Melbourne, VIC, Australia. AD - Data Science, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Leslie, S AU - Leslie S AD - Centre for Systems Genomics, Schools of Mathematics and Statistics, and BioSciences, The University of Melbourne, Melbourne, VIC, Australia. AD - Data Science, Murdoch Childrens Research Institute, Melbourne, VIC, Australia. FAU - Biesiada, J AU - Biesiada J AD - Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center & Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA. FAU - Meller, J AU - Meller J AD - Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center & Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA. FAU - Taylor, K D AU - Taylor KD AD - Los Angeles Biomedical Research Institute, Torrance, CA, USA. FAU - Zheng, X AU - Zheng X AD - Department of Biostatistics, University of Washington, Seattle, WA, USA. FAU - Zhao, L P AU - Zhao LP AD - Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - Gourraud, P-A AU - Gourraud PA AD - Department of Neurology, University of California, San Francisco, CA, USA. AD - ATIP-Avenir Team UMR Inserm, 1064, Nantes, France. AD - Nantes University Hospital Department of Public Health, Nantes, France. FAU - Hollenbach, J A AU - Hollenbach JA AD - Department of Neurology, University of California, San Francisco, CA, USA. FAU - Mack, S J AU - Mack SJ AD - Center for Genetics, Children's Hospital Research Institute, Oakland, CA, USA. FAU - Maiers, M AU - Maiers M AD - Bioinformatics Research Department, National Marrow Donor Program, Minneapolis, MN, USA. LA - eng GR - R01 NS049477/NS/NINDS NIH HHS/United States GR - P01 GM099568/GM/NIGMS NIH HHS/United States GR - P30 DK063491/DK/NIDDK NIH HHS/United States GR - R01 NS076492/NS/NINDS NIH HHS/United States GR - U01 AI067068/AI/NIAID NIH HHS/United States GR - UL1 TR001881/TR/NCATS NIH HHS/United States GR - R01 NS046297/NS/NINDS NIH HHS/United States GR - R01 GM109030/GM/NIGMS NIH HHS/United States GR - U19 AI067152/AI/NIAID NIH HHS/United States GR - R01 AI128775/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20170425 PL - United States TA - Pharmacogenomics J JT - The pharmacogenomics journal JID - 101083949 RN - 0 (HLA Antigens) RN - 0 (HLA-A Antigens) RN - 0 (HLA-B Antigens) RN - 0 (HLA-C Antigens) RN - 0 (HLA-DRB1 Chains) SB - IM MH - Alleles MH - Genetic Variation MH - Genome, Human/*genetics MH - Genome-Wide Association Study MH - Genotype MH - HLA Antigens/classification/*genetics MH - HLA-A Antigens/genetics MH - HLA-B Antigens/genetics MH - HLA-C Antigens/genetics MH - HLA-DRB1 Chains/genetics MH - *Haplotypes MH - Humans MH - Polymorphism, Single Nucleotide/*genetics MH - White People PMC - PMC5656547 MID - NIHMS879450 COIS- Conflict of Interest SL is a founder and partner in Peptide Groove LLP. All other authors of this manuscript declare no competing financial interests. EDAT- 2017/04/26 06:00 MHDA- 2019/01/12 06:00 PMCR- 2018/11/22 CRDT- 2017/04/26 06:00 PHST- 2016/06/16 00:00 [received] PHST- 2016/12/07 00:00 [revised] PHST- 2017/02/14 00:00 [accepted] PHST- 2017/04/26 06:00 [pubmed] PHST- 2019/01/12 06:00 [medline] PHST- 2017/04/26 06:00 [entrez] PHST- 2018/11/22 00:00 [pmc-release] AID - tpj20177 [pii] AID - 10.1038/tpj.2017.7 [doi] PST - ppublish SO - Pharmacogenomics J. 2018 May 22;18(3):367-376. doi: 10.1038/tpj.2017.7. Epub 2017 Apr 25.