Hetairos is a histology-based artificial intelligence model for predicting central nervous system tumor methylation subtypes
Nature Cancer, vol. 7, pp. 884–898
Abstract
Abstract DNA methylation analysis has become an essential diagnostic assay for classifying tumours of the central nervous system (CNS). However, this test requires additional resources and time compared to conventional histopathological diagnosis using haematoxylin and eosin (H&E) stained tissue sections, which are available globally. Here, we propose to reduce time and resource requirements using Hetairos, an artificial intelligence (AI) algorithm that predicts 102 methylation-based CNS tumour subtypes from digital images of H&E slides. Hetairos is built and assessed using over 11,000 slides from 10 centres across four continents. Hetairos produces well-calibrated probabilities for each subtype. Across cohorts, Hetairos identifies 50-70% of cases, which it classifies with high confidence and an accuracy of 0.87 for its highest-rated predictions. Hetairos achieved higher accuracy than four board-certified neuropathologists in a direct comparison using only histology images (0.68 vs 0.28). A prospective evaluation within a routine diagnostic setting confirmed Hetairos’ performance and highlighted its 2-day turnaround time compared to an average of 12 days for molecular testing. Hetairos can assist diagnostic decision-making by limiting the number of likely diagnoses, informing efficient further testing, and by highlighting tissue areas indicative of specific diagnoses. These capabilities suggest Hetairos is a valuable tool assisting in the diagnosis of the full spectrum of paediatric and adult CNS tumours.
Authors 59
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German Cancer Research Center · Beihang University
Affiliation as printed
Division of AI in Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Image Processing Center, Beihang University, Beijing, China
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German Cancer Research Center · Heidelberg University
Affiliation as printed
Division of AI in Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
Division of AI in Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
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German Cancer Research Center · Heidelberg University
Affiliation as printed
Division of AI in Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Faculty of Mathematics and Computer Science, Heidelberg University, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Leiden University Medical Center · Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Pathology, Brain Tumor Center, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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German Cancer Research Center · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · Heidelberg University · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
Faculty of Mathematics and Computer Science, Heidelberg University, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Affiliation as printed
Division of AI in Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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Justus-Liebig-Universität Gießen
Affiliation as printed
Institute of Neuropathology, Justus Liebig University Giessen, Giessen, Germany
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Justus-Liebig-Universität Gießen
Affiliation as printed
Institute of Neuropathology, Justus Liebig University Giessen, Giessen, Germany
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Munich Center for Machine Learning · Technical University of Munich
Affiliation as printed
AI for Image-Guided Diagnosis and Therapy, School of Medicine and Health, Technical University of Munich, Munich, Germany
Munich Center for Machine Learning (MCML), Munich, Germany
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Affiliation as printed
AC Camargo Cancer Center, São Paulo, Brazil
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Princess Máxima Center · Amsterdam University Medical Centers · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Pathology, Amsterdam University Medical Centers/VUmc, Amsterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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Innsbruck Medical University · Universität Innsbruck · Medical University of Vienna
Affiliation as printed
Division of Neuropathology and Neurochemistry, Department of Neurology, Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria
Institute of Neuropathology and Neuromolecular Pathology, Medical University of Innbruck, Innsbruck, Austria
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German Center for Neurodegenerative Diseases · Humboldt-Universität zu Berlin · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, Berlin, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Department of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
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Technical University of Munich
Affiliation as printed
Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
Division for Stereotactic Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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University Hospital Heidelberg
Affiliation as printed
Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Neurology Clinic, University Hospital Heidelberg, Heidelberg, Germany
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German Cancer Research Center · National Center for Tumor Diseases · Hopp Children's Cancer Center Heidelberg
Affiliation as printed
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
National Center for Tumor Diseases (NCT), Heidelberg, Germany
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German Cancer Research Center · University Hospital Heidelberg · National Center for Tumor Diseases · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
National Center for Tumor Diseases (NCT), Heidelberg, Germany
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Affiliation as printed
Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman, Jordan
Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
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Affiliation as printed
Center for Medical Epigenetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
Department of Pathology, Center for Molecular Medicine Testing, College of Basic Medicine, Chongqing Medical University, Chongqing, China
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Affiliation as printed
AC Camargo Cancer Center, São Paulo, Brazil
DASA Laboratories, São Paulo, Brazil
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Goethe University Frankfurt · German Cancer Research Center · Frankfurt Cancer Institute · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany
Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Affiliation as printed
Department of Medical Sciences, University of Turin, Turin, Italy
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Justus-Liebig-Universität Gießen
Affiliation as printed
Institute of Neuropathology, Justus Liebig University Giessen, Giessen, Germany
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Inserm · Centre Hospitalier Sainte-Anne · Institut de Psychiatrie et Neurosciences de Paris
Affiliation as printed
Department of Neuropathology, Sainte-Anne Hospital, Paris, France
Inserm, UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
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Inserm · Centre Hospitalier Sainte-Anne · Institut de Psychiatrie et Neurosciences de Paris
Affiliation as printed
Department of Neuropathology, Sainte-Anne Hospital, Paris, France
Inserm, UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
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University of Geneva · University Hospital of Geneva
Affiliation as printed
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
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University of Geneva · University Hospital of Geneva
Affiliation as printed
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland
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Justus-Liebig-Universität Gießen
Affiliation as printed
Institute of Neuropathology, Justus Liebig University Giessen, Giessen, Germany
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Pontificia Universidad Católica de Chile
Affiliation as printed
Pathology Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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Pontificia Universidad Católica de Chile
Affiliation as printed
Pathology Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
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Affiliation as printed
Image Processing Center, Beihang University, Beijing, China
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German Cancer Research Center · University Hospital Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
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Felix Sahm corresponding
German Cancer Research Center · Heidelberg University · University Hospital Heidelberg · Hopp Children's Cancer Center Heidelberg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de
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Moritz Gerstung corresponding
German Cancer Research Center · Heidelberg University
Affiliation as printed
Division of AI in Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. moritz.gerstung@dkfz.de
Faculty of Mathematics and Computer Science, Heidelberg University, Heidelberg, Germany. moritz.gerstung@dkfz.de
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