title: Inferring causal molecular networks: empirical assessment through a community-based effort.
abstract: It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense.
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA.|Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Heiser
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cokelaer
authors.affiliation: Automatic Control Laboratory, ETH Zurich, Zurich, Switzerland.|Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Unger
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Nicole K
authors.initials: NK
authors.lastname: Nesser
authors.affiliation: Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Carlin
authors.affiliation: Department of Computer Science, New Mexico State University, Las Cruces, New Mexico, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Artem
authors.initials: A
authors.lastname: Sokolov
authors.affiliation: Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Evan O
authors.initials: EO
authors.lastname: Paull
authors.affiliation: Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Chris K
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Kiley
authors.identifier: http://orcid.org/0000-0002-4569-8444
authors.initials: K
authors.lastname: Graim
authors.affiliation: Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bivol
authors.affiliation: Department of Computer Science, New Mexico State University, Las Cruces, New Mexico, USA.
authors.forename: Haizhou
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Bahman
authors.initials: B
authors.lastname: Afsari
authors.affiliation: Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.|Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Ludmila V
authors.identifier: http://orcid.org/0000-0003-2813-3094
authors.initials: LV
authors.lastname: Danilova
authors.affiliation: Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.|Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.|Laboratory of Bioinformatics, Research Institute of Genetics and Selection of Industrial Microorganisms, Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Favorov
authors.affiliation: Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Wai Shing
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Statistical and Applied Mathematical Sciences Institute, Research Triangle Park, North Carolina, USA.|Department of Mathematics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Dane
authors.identifier: http://orcid.org/0000-0003-1851-3309
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: Chenyue W
authors.initials: CW
authors.lastname: Hu
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: Byron L
authors.initials: BL
authors.lastname: Long
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Noren
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Bisberg
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA.|Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-4096-7078
authors.initials: M
authors.lastname: Kellen
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Thea
authors.initials: T
authors.lastname: Norman
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Stephen
authors.identifier: http://orcid.org/0000-0002-0830-7600
authors.initials: S
authors.lastname: Friend
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: Amina A
authors.initials: AA
authors.lastname: Qutub
authors.affiliation: Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Elana J
authors.initials: EJ
authors.lastname: Fertig
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.|Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Computer Science, New Mexico State University, Las Cruces, New Mexico, USA.
authors.forename: Mingzhou
authors.identifier: http://orcid.org/0000-0002-6883-6547
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.affiliation: Automatic Control Laboratory, ETH Zurich, Zurich, Switzerland.|Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
authors.forename: Heinz
authors.initials: H
authors.lastname: Koeppl
authors.affiliation: IBM Translational Systems Biology and Nanobiotechnology, Yorktown Heights, New York, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Stolovitzky
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK.|RWTH-Aachen University Hospital, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany.
authors.forename: Julio
authors.identifier: http://orcid.org/0000-0002-8552-8976
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.|School of Clinical Medicine, University of Cambridge, Cambridge, UK.|German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Sach
authors.initials: S
authors.lastname: Mukherjee
mesh_terms: D000465:Algorithms; D015984:Causality; D019295:Computational Biology; D003198:Computer Simulation; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics*; D025941:Protein Interaction Mapping / Q000379:methods*; D015398:Signal Transduction; D012984:Software; D049490:Systems Biology; D014407:Tumor Cells, Cultured