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Allografting

Identification by random forest method of HLA class I amino acid substitutions associated with lower survival at day 100 in unrelated donor hematopoietic cell transplantation

Bone Marrow Transplantation volume 47, pages 217–226 (2012)Cite this article

Abstract

The identification of important amino acid substitutions associated with low survival in hematopoietic cell transplantation (HCT) is hampered by the large number of observed substitutions compared with the small number of patients available for analysis. Random forest analysis is designed to address these limitations. We studied 2107 HCT recipients with good or intermediate risk hematological malignancies to identify HLA class I amino acid substitutions associated with reduced survival at day 100 post transplant. Random forest analysis and traditional univariate and multivariate analyses were used. Random forest analysis identified amino acid substitutions in 33 positions that were associated with reduced 100 day survival, including HLA-A 9, 43, 62, 63, 76, 77, 95, 97, 114, 116, 152, 156, 166 and 167; HLA-B 97, 109, 116 and 156; and HLA-C 6, 9, 11, 14, 21, 66, 77, 80, 95, 97, 99, 116, 156, 163 and 173. In all 13 had been previously reported by other investigators using classical biostatistical approaches. Using the same data set, traditional multivariate logistic regression identified only five amino acid substitutions associated with lower day 100 survival. Random forest analysis is a novel statistical methodology for analysis of HLA mismatching and outcome studies, capable of identifying important amino acid substitutions missed by other methods.

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Acknowledgements

We thank Theodore Karrison, PhD, for statistical support. This study was supported by the University of Chicago Cancer Research Center, Chicago, Illinois (Fund-6-33573 (SRM)). The Center for International Blood and Marrow Transplant Research is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc.; Baxter International Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma Inc.; Dynal Biotech, an Invitrogen Company; Eisai Inc.; Enzon Pharmaceuticals Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell Ltd.; GE Healthcare; Genentech Inc.; Genzyme Corporation; Histogenetics Inc.; HKS Medical Information Systems; Hospira Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co. Ltd.; The Leukemia and Lymphoma Society; Merck and Company; The Medical College of Wisconsin; MGI Pharma Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals Inc.; Miller Pharmacal Group; Milliman USA Inc.; Miltenyi Biotec Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc.; Otsuka America Pharmaceutical Inc.; Pall Life Sciences; PDL BioPharma Inc; Pfizer Inc; Pharmion Corporation; Saladax Biomedical Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; StemCyte Inc.; StemSoft Software Inc.; Sysmex America Inc.; Teva Pharmaceutical Industries; THERAKOS Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals Inc.; ViraCor Laboratories; ViroPharma Inc.; and Wellpoint Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government.

Author contributions: SRM conceptualized the study, interpreted the results and wrote the manuscript; SRM and SL designed the study; SL performed the univariate, multivariate, and random forest analyses; MM prepared amino acid database for analysis; MH prepared data for statistical analysis; SS and SJL contributed ideas and made significant contributions to the writing of the manuscript; JK performed multivariate analysis; TAB prepared the figure; KVB provided overall advice and guidance. All authors reviewed the manuscript.

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Authors and Affiliations

  1. Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA

    S R Marino

  2. Department of Health Studies, University of Chicago, Chicago, IL, USA

    S Lin

  3. National Marrow Donor Program, Minneapolis, MN, USA

    M Maiers & S Spellman

  4. Statistical Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA

    M Haagenson

  5. Medical College of Wisconsin, Milwaukee, WI, USA

    J P Klein

  6. Center for Structural Genomics of Infectious Diseases and Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne, IL, USA

    T A Binkowski

  7. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S J Lee

  8. Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA

    K van Besien

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  1. S R Marino
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Correspondence to S R Marino.

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Marino, S., Lin, S., Maiers, M. et al. Identification by random forest method of HLA class I amino acid substitutions associated with lower survival at day 100 in unrelated donor hematopoietic cell transplantation. Bone Marrow Transplant 47, 217–226 (2012). https://doi.org/10.1038/bmt.2011.56

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