Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration

James M. McFarland, Zandra V. Ho, Guillaume Kugener, Joshua M. Dempster, Phillip G. Montgomery, Jordan G. Bryan, John M. Krill-Burger, Thomas M. Green, Francisca Vazquez, Jesse S. Boehm, Todd R. Golub, William C. Hahn, David E. Root and Aviad Tsherniak ()
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James M. McFarland: Broad Institute of MIT and Harvard
Zandra V. Ho: Broad Institute of MIT and Harvard
Guillaume Kugener: Broad Institute of MIT and Harvard
Joshua M. Dempster: Broad Institute of MIT and Harvard
Phillip G. Montgomery: Broad Institute of MIT and Harvard
Jordan G. Bryan: Broad Institute of MIT and Harvard
John M. Krill-Burger: Broad Institute of MIT and Harvard
Thomas M. Green: Broad Institute of MIT and Harvard
Francisca Vazquez: Broad Institute of MIT and Harvard
Jesse S. Boehm: Broad Institute of MIT and Harvard
Todd R. Golub: Broad Institute of MIT and Harvard
William C. Hahn: Broad Institute of MIT and Harvard
David E. Root: Broad Institute of MIT and Harvard
Aviad Tsherniak: Broad Institute of MIT and Harvard

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The availability of multiple datasets comprising genome-scale RNAi viability screens in hundreds of diverse cancer cell lines presents new opportunities for understanding cancer vulnerabilities. Integrated analyses of these data to assess differential dependency across genes and cell lines are challenging due to confounding factors such as batch effects and variable screen quality, as well as difficulty assessing gene dependency on an absolute scale. To address these issues, we incorporated cell line screen-quality parameters and hierarchical Bayesian inference into DEMETER2, an analytical framework for analyzing RNAi screens ( https://depmap.org/R2-D2 ). This model substantially improves estimates of gene dependency across a range of performance measures, including identification of gold-standard essential genes and agreement with CRISPR/Cas9-based viability screens. It also allows us to integrate information across three large RNAi screening datasets, providing a unified resource representing the most extensive compilation of cancer cell line genetic dependencies to date.

Date: 2018
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DOI: 10.1038/s41467-018-06916-5

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