Causal integration of multi-omics data with prior knowledge to generate mechanistic hypotheses
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Multi-omics datasets can provide molecular insights beyond the sum of individual omics. Diverse tools have been recently developed to integrate such datasets, but there are limited strategies to systematically extract mechanistic hypotheses from them. Here, we present COSMOS (Causal Oriented Search of Multi-Omics Space), a method that integrates phosphoproteomics, transcriptomics, and metabolics datasets. COSMOS combines extensive prior knowledge of signaling, metabolic, and gene regulatory networks with computational methods to estimate activities of transcription factors and kinases as well as network-level causal reasoning. COSMOS provides mechanistic hypotheses for experimental observations across multi-omics datasets. We applied COSMOS to a dataset comprising transcriptomics, phosphoproteomics, and metabolomics data from healthy and cancerous tissue from nine renal cell carcinoma patients. We used COSMOS to generate novel hypotheses such as the impact of Androgen Receptor on nucleoside metabolism and the influence of the JAK-STAT pathway on propionyl coenzyme A production. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies. Abstract Figure
Authors 13
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Aurélien J. F. Dugourd Aachen Division of Nephrology and Clinical Immunology Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE)
Heidelberg University · University Hospital Heidelberg · RWTH Aachen University
Affiliation as printed
Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany
RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), 52074, Aachen, Germany
RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), 5074, Aachen, Germany
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Martin Luther University Halle-Wittenberg · RWTH Aachen University
Affiliation as printed
Department of Urology and Kidney Transplantation, Martin Luther University, Halle (Saale), Germany
Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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University of Cambridge · MRC Cancer Unit · Hutchison/MRC Research Centre
Affiliation as printed
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
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Enio Gjerga Aachen Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE)
Heidelberg University · University Hospital Heidelberg · RWTH Aachen University
Affiliation as printed
Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany
RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), 52074, Aachen, Germany
RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), 5074, Aachen, Germany
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University of Copenhagen · Novo Nordisk Foundation
Affiliation as printed
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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University of Copenhagen · Novo Nordisk Foundation
Affiliation as printed
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Sankt-Antonius-Hospital Eschweiler · Martin Luther University Halle-Wittenberg · RWTH Aachen University
Affiliation as printed
Department of Urology and Kidney Transplantation, Martin Luther University, Halle (Saale), Germany
Department of Urology and Pediatric Urology, St. Antonius Hospital Eschweiler, Academic Teaching Hospital of RWTH Aachen, Eschweiler, Germany
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Affiliation as printed
Department of Hematology, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA
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University of Copenhagen · Novo Nordisk Foundation
Affiliation as printed
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Christian Frezza corresponding
University of Cambridge · MRC Cancer Unit · Hutchison/MRC Research Centre
Affiliation as printed
MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
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Rafael Kramann corresponding Aachen Division of Nephrology and Clinical Immunology Faculty of Medicine
Erasmus MC · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Julio Sáez-Rodríguez corresponding Aachen Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE)
Heidelberg University · University Hospital Heidelberg · RWTH Aachen University
Affiliation as printed
Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany
RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), 52074, Aachen, Germany
RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), 5074, Aachen, Germany
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