A machine learning approach for somatic mutation discovery

Derrick E. Wood, James R. White, Andrew Georgiadis, Beth Van Emburgh, Sonya Parpart-Li, Jason Mitchell, Valsamo Anagnostou, Noushin Niknafs, Rachel Karchin, Eniko Papp, Christine McCord, Peter LoVerso, David Riley, Luis A. Diaz, Siân Jones, Mark Sausen, Victor E. Velculescu, Samuel V. Angiuoli

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Variability in the accuracy of somatic mutation detection may affect the discovery of alterations and the therapeutic management of cancer patients. To address this issue, we developed a somatic mutation discovery approach based on machine learning that outperformed existing methods in identifying experimentally validated tumor alterations (sensitivity of 97% versus 90 to 99%; positive predictive value of 98% versus 34 to 92%). Analysis of paired tumor-normal exome data from 1368 TCGA (The Cancer Genome Atlas) samples using this method revealed concordance for 74% of mutation calls but also identified likely false-positive and false-negative changes in TCGA data, including in clinically actionable genes. Determination of high-quality somatic mutation calls improved tumor mutation load-based predictions of clinical outcome for melanoma and lung cancer patients previously treated with immune checkpoint inhibitors. Integration of high-quality machine learning mutation detection in clinical next-generation sequencing (NGS) analyses increased the accuracy of test results compared to other clinical sequencing analyses. These analyses provide an approach for improved identification of tumor-specific mutations and have important implications for research and clinical management of cancer patients.

Original languageEnglish (US)
Article numberaar7939
JournalScience translational medicine
Issue number457
StatePublished - Sep 5 2018

ASJC Scopus subject areas

  • Medicine(all)


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