title: Combining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection.
abstract: The detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/.
authors.affiliation: 1] Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, California, USA. [2] Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Ewing
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Houlahan
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, California, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Ellrott
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Cristian
authors.initials: C
authors.lastname: Caloian
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Takafumi N
authors.identifier: 0000000310823871
authors.initials: TN
authors.lastname: Yamaguchi
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: J Christopher
authors.identifier: 0000000310061491
authors.initials: JC
authors.lastname: Bare
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: P'ng
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Veronica Y
authors.initials: VY
authors.lastname: Sabelnykova
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Michael R
authors.identifier: 0000000240967078
authors.initials: MR
authors.lastname: Kellen
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Thea C
authors.initials: TC
authors.lastname: Norman
authors.affiliation: Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Haussler
authors.affiliation: Sage Bionetworks, Seattle, Washington, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Friend
authors.affiliation: IBM Computational Biology Center, T.J. Watson Research Center, Yorktown Heights, New York, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Stolovitzky
authors.affiliation: 1] Sage Bionetworks, Seattle, Washington, USA. [2] Computational Biology Program, Oregon Health &Science University, Portland, Oregon, USA. [3] Department of Biomedical Engineering, Oregon Health &Science University, Portland, Oregon, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Margolin
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: 1] Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Department of Pharmacology &Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Paul C
authors.identifier: 0000000305537520
authors.initials: PC
authors.lastname: Boutros
mesh_terms: D000465:Algorithms; D019985:Benchmarking; D063045:Crowdsourcing; D016678:Genome; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide