BACKGROUND: Glioblastoma (GBM) is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification. METHODS: We developed a highly reproducible, personalized prognostication, and clinical subgrouping system using machine learning (ML) on routine clinical data, magnetic resonance imaging (MRI), and molecular measures from 2838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, and III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR]). RESULTS: The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95% CI: 1.43-1.84, P < .001) and 3.48 (95% CI: 2.94-4.11, P < .001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort. CONCLUSIONS: Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach to personalized patient management and clinical trial stratification in GBM.

B ARGO Group Institut Investigació Germans Trias i Pujol Catalonia Spain

Biostatistics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Brain and Tumor Neurosurgery Neurosurgical Oncology Piedmont Health Atlanta Georgia USA

Brain Tumor Center Severance Hospital Yonsei University Health System Seoul Republic of Korea

Center for Biomedical Informatics and Information Technology National Cancer Institute Bethesda Maryland USA

Center for Data Driven Discovery in Biomedicine Division of Neurosurgery Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Center for Data Science and AI for Integrated Diagnostics University of Pennsylvania Philadelphia Pennsylvania USA

Central Brain Tumor Registry of the United States Hinsdale Illinois USA

Clinical Imaging Research Centre Yong Loo Lin School of Medicine National University of Singapore Singapore

Department of Bioengineering School of Engineering Santa Clara University Santa Clara California USA

Department of Biomedical Engineering University of Wisconsin Madison Wisconsin USA

Department of Biostatistics Epidemiology and Informatics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Computer Science Luddy School of Informatics Computing and Engineering Indiana University Indianapolis Indiana USA

Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of Medicine Baltimore Maryland USA

Department of Diagnostic Radiology Yong Loo Lin School of Medicine National University of Singapore Singapore

Department of Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania USA

Department of Neurological Surgery Indiana University School of Medicine Indianapolis Indiana USA

Department of Neurological Surgery Okayama University Okayama Japan

Department of Neurological Surgery University of California San Francisco San Francisco California USA

Department of Neurology The University of Alabama at Birmingham Birmingham Alabama USA

Department of Neuropathology Royal Prince Alfred Hospital Camperdown Australia

Department of Neuroradiology Ruskin Wing King's College Hospital NHS Foundation Trust London UK

Department of Neuroradiology Technical University of Munich Munchen Germany

Department of Neurosurgery Chris O'Brien Lifehouse Camperdown Australia

Department of Neurosurgery Hamamatsu University School of Medicine Hamamatsu Shizuoka Japan

Department of Neurosurgery Hermelin Brain Tumor Center Henry Ford Cancer Institute Henry Ford Health Detroit Michigan USA

Department of Neurosurgery New York University Langone Health New York New York USA

Department of Neurosurgery Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Neurosurgery University Hospital Río Hortega Valladolid Spain

Department of Neurosurgery University of Maryland School of Medicine Baltimore Maryland USA

Department of Neurosurgery University of Texas Medical Branch Galveston Texas USA

Department of Neurosurgery Yonsei University College of Medicine Seoul Republic of Korea

Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis Indiana USA

Department of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Population and Quantitative Health Sciences Case Western Reserve University School of Medicine Cleveland Ohio USA

Department of Public Health Sciences Center for Bioinformatics Henry Ford Health System Detroit Michigan USA

Department of Radiation Oncology Christiana Care Health System Philadelphia Pennsylvania USA

Department of Radiation Oncology Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Radiation Oncology Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia Pennsylvania USA

Department of Radiation Oncology The James Cancer Hospital at the Ohio State University Wexner Medical Center Columbus Ohio USA

Department of Radiology and Biomedical Imaging University of California San Francisco San Francisco California USA

Department of Radiology and Imaging Sciences Indiana University School of Medicine Indianapolis Indiana USA

Department of Radiology Case Western Reserve University and University Hospitals of Cleveland Cleveland Ohio USA

Department of Radiology Duke University Durham North Carolina USA

Department of Radiology Henry Ford Health System Detroit Michigan USA

Department of Radiology Hospital Clínic and IDIBAPS Barcelona Spain

Department of Radiology Na Homolce Hospital Prague Czechia

Department of Radiology New York University Langone Health New York New York USA

Department of Radiology Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania USA

Department of Radiology Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia Pennsylvania USA

Department of Radiology University of California San Diego San Diego California USA

Department of Radiology University of Pittsburgh Pittsburgh Pennsylvania USA

Department of Radiology University of Wisconsin Madison Wisconsin USA

Department of Radiology Washington University School of Medicine St Louis Missouri USA

Department of Radiology Yonsei University College of Medicine Seoul Republic of Korea

Division of Neurosurgery Spedali Riuniti di Livorno Azienda USL Toscana Nord Ovest Livorno Italy

Faculty of Medicine and Health University of Sydney Camperdown Australia

GBM Translational Center of Excellence Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania USA

Hillman Cancer Center University of Pittsburgh Medical Center Pittsburgh Pennsylvania USA

MD Anderson Cancer Center University of Texas Houston Texas USA

Penn Statistics in Imaging and Visualization Center and Center for Clinical Epidemiology ce and AI for Integrated Diagnostics University of Pennsylvania Philadelphia Pennsylvania USA

Research Unit Image Diagnosis Institute Badalona Spain

School of Biomedical Engineering and Imaging Sciences King's College London London UK

Seidman Cancer Center and Case Comprehensive Cancer Center Case Western Reserve University Cleveland Ohio USA

Sidney Kimmel Medical College Thomas Jefferson University Philadelphia Pennsylvania USA

Tata Memorial Centre Homi Bhabha National Institute Mumbai India

The Clatterbridge Cancer Centre NHS Foundation Trust Liverpool UK

Trans Divisional Research Program National Cancer Institute Bethesda Maryland USA

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