title: Identification of high-risk amino-acid substitutions in hematopoietic cell transplantation: a challenging task.
abstract: Allogeneic hematopoietic cell transplantation (HCT) offers the potential to cure hematologic malignancies. In the absence of an HLA-matched donor, HLA mismatched unrelated donors may be used, although risks of GvHD and treatment-related mortality (TRM) are higher. Identification and avoidance of amino-acid substitution and position types (AASPT) conferring higher risks of TRM and GvHD would potentially improve the success of transplantation from single HLA mismatched unrelated donors. Using random forest and logistic regression analyses, we identified 19 AASPT associated with greater risks for at least one adverse transplant outcome: grade III-IV acute GvHD, TRM, lower disease-free survival or worse overall survival relative to HLA-matched unrelated donors and to other AASPT. When tested in an independent validation cohort of 3530 patients, none of the AASPT from the training set were validated as high risk, however. Review of the literature shows that failure to validate original observations is the rule and not the exception in immunobiology and emphasizes the importance of independent validation before clinical application. Our current data do not support avoiding any specific class I AASPT for unrelated donors. Additional studies should be performed to fully understand the role of AASPT in HCT outcomes.
authors.affiliation: Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Marino
authors.affiliation: Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Center for Structural Genomics of Infectious Diseases and Midwest Center for Structural Genomics, Argonne National Laboratory, Argonne, IL, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Binkowski
authors.affiliation: Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.|Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Haagenson
authors.affiliation: Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.|Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.
authors.forename: H-L
authors.initials: HL
authors.lastname: Wang
authors.affiliation: National Marrow Donor Program, Minneapolis, MN, USA.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-0198-2064
authors.initials: M
authors.lastname: Maiers
authors.affiliation: National Marrow Donor Program, Minneapolis, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Spellman
authors.affiliation: Division of Hematology, Weill-Cornell Medical College, New York, NY, USA.
authors.forename: K
authors.identifier: http://orcid.org/0000-0002-8164-6211
authors.initials: K
authors.lastname: van Besien
authors.affiliation: Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.|Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Karrison
authors.affiliation: Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Artz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006648:Histocompatibility / Q000235:genetics; D006801:Humans; D007223:Infant; D016015:Logistic Models; D008875:Middle Aged; D018570:Risk Assessment; D016896:Treatment Outcome; D061349:Unrelated Donors; D000069558:Unsupervised Machine Learning; D055815:Young Adult