Causal integration of multi‐omics data with prior knowledge to generate mechanistic hypotheses
Molecular Systems Biology, vol. 17, pp. e9730
Abstract
Multi-omics datasets can provide molecular insights beyond the sum of individual omics. Various 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 metabolomics 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 eleven clear cell renal cell carcinoma (ccRCC) patients. COSMOS was able to capture relevant crosstalks within and between multiple omics layers, such as known ccRCC drug targets. We expect that our freely available method will be broadly useful to extract mechanistic insights from multi-omics studies.
Authors 18
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Aurélien J. F. Dugourd Aachen Division of Nephrology and Clinical Immunology Faculty of Medicine Institute of Experimental Medicine and Systems Biology Joint Research Centre for Computational Biomedicine (JRC-COMBINE) Division of Nephrology and Clinical Immunology Faculty of Medicine Faculty of Medicine Institute of Experimental Medicine and Systems Biology 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
Faculty of Medicine, Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Aachen, Germany
Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany
Division of Nephrology and Clinical Immunology Faculty of Medicine RWTH Aachen University Aachen Germany
Faculty of Medicine Institute of Experimental Medicine and Systems Biology RWTH Aachen University Aachen Germany
Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE) RWTH Aachen University Aachen Germany
Faculty of Medicine, and Heidelberg University Hospital Institute for Computational Biomedicine Heidelberg University Heidelberg Germany
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Christoph Kuppe Aachen Division of Nephrology and Clinical Immunology Faculty of Medicine Institute of Experimental Medicine and Systems Biology Division of Nephrology and Clinical Immunology Faculty of Medicine Faculty of Medicine Institute of Experimental Medicine and Systems Biology
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
Faculty of Medicine, Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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
Faculty of Medicine Institute of Experimental Medicine and Systems Biology 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, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
MRC Cancer Unit Hutchison/MRC Research Centre University of Cambridge Cambridge UK
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Enio Gjerga Aachen Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE) Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE)
Heidelberg University · University Hospital Heidelberg · RWTH Aachen University
Affiliation as printed
Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Aachen, Germany
Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany
Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE) RWTH Aachen University Aachen Germany
Faculty of Medicine, and Heidelberg University Hospital Institute for Computational Biomedicine Heidelberg University Heidelberg Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany
Faculty of Medicine, and Heidelberg University Hospital Institute for Computational Biomedicine Heidelberg University Heidelberg Germany
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University of Copenhagen · Novo Nordisk Foundation
Affiliation as printed
Faculty of Health and Medical Sciences, Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Faculty of Health and Medical Sciences Proteomics Program Novo Nordisk Foundation Center for Protein Research University of Copenhagen Copenhagen Denmark
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Affiliation as printed
Centre of Biological Engineering, University of Minho - Campus de Gualtar, Braga, Portugal
Centre of Biological Engineering University of Minho - Campus de Gualtar Braga Portugal
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University of Copenhagen · Novo Nordisk Foundation
Affiliation as printed
Faculty of Health and Medical Sciences, Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Faculty of Health and Medical Sciences Proteomics Program Novo Nordisk Foundation Center for Protein Research University of Copenhagen Copenhagen Denmark
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Jennifer Kranz Aachen Department of Urology and Pediatric Urology Faculty of Medicine Institute of Experimental Medicine and Systems Biology Department of Urology and Pediatric Urology St. Antonius Hospital Eschweiler Academic Teaching Hospital Faculty of Medicine Institute of Experimental Medicine and Systems Biology
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
Faculty of Medicine, Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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
Faculty of Medicine Institute of Experimental Medicine and Systems Biology RWTH Aachen University Aachen Germany
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Affiliation as printed
Department of Hematology, Erasmus MC, Rotterdam, The Netherlands
Department of Hematology Erasmus MC Rotterdam The Netherlands
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University of Cambridge · MRC Cancer Unit · Hutchison/MRC Research Centre
Affiliation as printed
MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
MRC Cancer Unit Hutchison/MRC Research Centre University of Cambridge Cambridge UK
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European Bioinformatics Institute · i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto
Affiliation as printed
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
Institute for Research and Innovation in Health (i3s), Porto, Portugal
European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Hinxton UK
Institute for Research and Innovation in Health (i3s) Porto Portugal
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European Bioinformatics Institute
Affiliation as printed
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Hinxton UK
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Affiliation as printed
Centre of Biological Engineering, University of Minho - Campus de Gualtar, Braga, Portugal
Centre of Biological Engineering University of Minho - Campus de Gualtar Braga Portugal
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University of Copenhagen · Novo Nordisk Foundation
Affiliation as printed
Faculty of Health and Medical Sciences, Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Faculty of Health and Medical Sciences Proteomics Program Novo Nordisk Foundation Center for Protein Research 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, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
MRC Cancer Unit Hutchison/MRC Research Centre University of Cambridge Cambridge UK
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Rafael Kramann corresponding Aachen Division of Nephrology and Clinical Immunology Faculty of Medicine Institute of Experimental Medicine and Systems Biology Division of Nephrology and Clinical Immunology Faculty of Medicine Faculty of Medicine Institute of Experimental Medicine and Systems Biology
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
Faculty of Medicine, Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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
Faculty of Medicine Institute of Experimental Medicine and Systems Biology 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) Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE)
Heidelberg University · University Hospital Heidelberg · European Molecular Biology Laboratory · European Molecular Biology Laboratory · RWTH Aachen University
Affiliation as printed
Faculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Aachen, Germany
Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany
Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg University, Heidelberg, Germany
Faculty of Medicine Joint Research Centre for Computational Biomedicine (JRC-COMBINE) RWTH Aachen University Aachen Germany
Faculty of Medicine, and Heidelberg University Hospital Institute for Computational Biomedicine Heidelberg University Heidelberg Germany
Molecular Medicine Partnership Unit, European Molecular Biology Laboratory Heidelberg University Heidelberg Germany
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