title: Evaluating the evaluation of cancer driver genes.
abstract: Sequencing has identified millions of somatic mutations in human cancers, but distinguishing cancer driver genes remains a major challenge. Numerous methods have been developed to identify driver genes, but evaluation of the performance of these methods is hindered by the lack of a gold standard, that is, bona fide driver gene mutations. Here, we establish an evaluation framework that can be applied to driver gene prediction methods. We used this framework to compare the performance of eight such methods. One of these methods, described here, incorporated a machine-learning-based ratiometric approach. We show that the driver genes predicted by each of the eight methods vary widely. Moreover, the P values reported by several of the methods were inconsistent with the uniform values expected, thus calling into question the assumptions that were used to generate them. Finally, we evaluated the potential effects of unexplained variability in mutation rates on false-positive driver gene predictions. Our analysis points to the strengths and weaknesses of each of the currently available methods and offers guidance for improving them in the future.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218.|Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218.
authors.forename: Collin J
authors.initials: CJ
authors.lastname: Tokheim
authors.affiliation: Ludwig Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231.|Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21231.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Ludwig Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231.|Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21231.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Ludwig Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231; bertvog@gmail.com karchin@jhu.edu.|Howard Hughes Medical Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21231.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218; bertvog@gmail.com karchin@jhu.edu.|Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218.|Cancer Biology Program, Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
mesh_terms: D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D006801:Humans; D000069550:Machine Learning; D008957:Models, Genetic; D009154:Mutation; D059645:Mutation Rate; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes; D012984:Software
keywords: DNA sequencing; cancer genomics; cancer mutations; computational method evaluation; driver genes