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We enrolled 60 patients with computed tomography (CT)-negative mTBI (World Health Organization [WHO] criteria; Glasgow Coma Scale [GCS] 13\u201315; age 18\u201359) within 24\u00a0h of injury, 17 orthopedic injury controls, and 24 healthy controls without mTBI in the prior 5\u00a0years. Fifty-nine serum biomarkers were quantified by Luminex\u00ae. The group comparisons used ANOVA or Kruskal\u2013Wallis tests with corrected post hoc contrasts. Random Forest models were trained under leakage-safe nested cross-validation (outer 5-fold; inner 3-fold) with biomarker-only and biomarker-plus-demographics feature sets. SHAP values were computed on held-out folds and stability was assessed across resamples. Twenty-three biomarkers differed across groups after Bonferroni correction for post hoc comparisons (BDNF, EGF, Fracktalkine, G-CSF, GRO, IL15, IL-1\u03b1, IL-1\u03b2, IL-2, IL-3, IL-4, IL-5, IL-9, LIGHT, MMP-9, MPO, NCAM, NRG1-\u03b21, S100B, TGF- \u03b1, VEGF A, sICAM-1). In nested cross-validation, three-class balanced accuracy ranged ~0.48\u20130.70, and mTBI one-vs-rest receiver operating characteristic area under the curve (ROC-AUC) frequently exceeded 0.85; Control vs mTBI classification achieved balanced accuracy ~0.70\u20130.90 with precision\u2013recall area under the curve (PR-AUC) consistently &gt;0.82. Sex and age added minimal incremental value. Stable SHAP contributors (top-5 in \u22654\/5 folds) were LIGHT, IL-5, sCD40L, MMP-9, EGF, and fractalkine. Acute mTBI is associated with a reproducible serum signature spanning inflammatory, vascular, and growth-factor pathways.<\/jats:p>","DOI":"10.1007\/s12035-026-06130-1","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:51:54Z","timestamp":1790358714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Determining Acute-Phase Biomarkers for Mild Traumatic Brain Injury Through Exploratory Data Analysis: A Preliminary Report"],"prefix":"10.1007","volume":"63","author":[{"given":"Jo\u00e3o Lu\u00eds Vieira Monteiro","family":"de Barros","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u00edra Gl\u00f3ria","family":"de Freitas Cardoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle Emely","family":"de Souza 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