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While individual genetic variants have been implicated, the cumulative impact of genetic variation within relevant biological pathways remains unexplored. We evaluated single nucleotide polymorphisms across 18 pathways previously identified as relevant to mucositis in 278 pediatric patients with acute lymphoblastic leukemia from six academic health centers across Canada. Pathway enrichment was assessed using the Joint Association of Genetic variants tool, and a predictive model was developed using XGBoost, a supervised machine learning algorithm based on gradient\u2010boosted decision trees. Pathway enrichment identified significant associations in IL6 (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.04) and WNT\/\u03b2\u2010catenin (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.048) signaling pathways. The predictive model (area under the curve [AUC]\u2009=\u20090.76) highlighted single nucleotide polymorphisms associated with inflammation\u2010 and mucosa\u2010related genes, including\n                    <jats:italic>PRKCD<\/jats:italic>\n                    ,\n                    <jats:italic>IL17B<\/jats:italic>\n                    ,\n                    <jats:italic>MAST3<\/jats:italic>\n                    , and\n                    <jats:italic>CAPN9<\/jats:italic>\n                    , with both risk and protective effects. Model performance dropped by 0.15 in AUC (from 0.76 to 0.61) after removing single nucleotide polymorphism features, underscoring their predictive value. This pathway\u2010informed approach identifies genetic contributors to methotrexate\u2010induced mucositis and supports polygenic risk prediction. Our findings provide a foundation for individualized toxicity risk profiling and suggest potential therapeutic targets to mitigate treatment\u2010limiting mucositis in pediatric oncology.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70135","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T07:58:00Z","timestamp":1764575880000},"page":"447-456","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pathway\u2010Informed Machine Learning Identifies Genetic Predictors of High\u2010Dose Methotrexate\u2010Induced Mucositis in Pediatric Acute Lymphoblastic Leukemia"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3835-1924","authenticated-orcid":false,"given":"Xiao Yu Cindy","family":"Zhang","sequence":"first","affiliation":[{"name":"Bioinformatics Graduate Program University of British Columbia  Vancouver British Columbia Canada"},{"name":"British Columbia Children\u2019s Hospital Research Institute  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4660-7206","authenticated-orcid":false,"given":"Erika N.","family":"Scott","sequence":"additional","affiliation":[{"name":"British Columbia Children\u2019s Hospital Research Institute  Vancouver British Columbia Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4381-2696","authenticated-orcid":false,"given":"Hedy","family":"Maagdenberg","sequence":"additional","affiliation":[{"name":"British Columbia Children\u2019s Hospital Research Institute  Vancouver British Columbia Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Respiratory Medicine Amsterdam University Medical Center, University of Amsterdam  Amsterdam The Netherlands"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-1864","authenticated-orcid":false,"given":"Alice","family":"Man","sequence":"additional","affiliation":[{"name":"British Columbia Children\u2019s Hospital Research Institute  Vancouver British Columbia Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Medicine McMaster University  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy H.","family":"Li","sequence":"additional","affiliation":[{"name":"British Columbia Children\u2019s Hospital Research Institute  Vancouver British Columbia Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8005-2641","authenticated-orcid":false,"given":"S. Rod","family":"Rassekh","sequence":"additional","affiliation":[{"name":"British Columbia Children\u2019s Hospital Research Institute  Vancouver British Columbia Canada"},{"name":"Division of Oncology, Hematology and Bone Marrow Transplant, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4485-4054","authenticated-orcid":false,"given":"Bruce C.","family":"Carleton","sequence":"additional","affiliation":[{"name":"British Columbia Children\u2019s Hospital Research Institute  Vancouver British Columbia Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Medical Genetics, Faculty of Medicine University of British Columbia  Vancouver British Columbia Canada"},{"name":"Pharmaceutical Outcomes Programme British Columbia Children\u2019s Hospital  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1476-7037","authenticated-orcid":false,"given":"Colin J. 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