Revisiting inconsistency in large pharmacogenomic studies
Authors: Safikhani Zhaleh , Freeman Mark , Smirnov Petr , El-Hachem Nehme , She Adrian , Quevedo Rene , Goldenberg Anna , Birkbak Nicolai Juul , Hatzis Christos , Shi Leming , Beck Andrew H , Aerts Hugo JWL , Quackenbush John , Haibe-Kains Benjamin 
Published: September 2015

Background:

In 2012, two large pharmacogenomic studies, the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE), were published, each reported gene expression data and measures of drug response for a large number of drugs and hundreds of cell lines. In 2013, we published a comparative analysis that reported gene expression profiles for the 471 cell lines profiled in both studies and dose response measurements for the 15 drugs characterized in the common cell lines by both studies. While we found good concordance in gene expression profiles, there was substantial inconsistency in the drug responses reported by the GDSC and CCLE projects. Our paper was widely discussed and we received extensive feedback on the comparisons that we performed. This feedback, along with the release of new data, prompted us to revisit our initial analysis. Here we present a new analysis using these expanded data in which we address the most significant suggestions for improvements on our published analysis: that drugs with different response characteristics should have been treated differently, that targeted therapies and broad cytotoxic drugs should have been treated differently in assessing consistency, that consistency of both molecular profiles and drug sensitivity measurements should both be compared across cell lines to accurately assess differences in the studies, that we missed some biomarkers that are consistent between studies, and that the software analysis tools we provided with our analysis should have been easier to run, particularly as the GDSC and CCLE released additional data.

Methods:

For each drug, we used published sensitivity data from the GDSC and CCLE to separately estimate drug dose-response curves. We then used two statistics, the area between drug dose-response curves (ABC) and the Matthews correlation coefficient (MCC), to robustly estimate the consistency of continuous and discrete drug sensitivity measures, respectively. We also used recently released RNA-seq data together with previously published gene expression microarray data to assess inter-platform reproducibility of cell line gene expression profiles.

Results:

This re-analysis supports our previous finding that gene expression data are significantly more consistent than drug sensitivity measurements. The use of new statistics to assess data consistency allowed us to identify two broad effect drugs — 17-AAG and PD-0332901 — and three targeted drugs — PLX4720, nilotinib and crizotinib — with moderate to good consistency in drug sensitivity data between GDSC and CCLE. Not enough sensitive cell lines were screened in both studies to robustly assess consistency for three other targeted drugs, PHA-665752, erlotinib, and sorafenib. Concurring with our published results, we found evidence of inconsistencies in pharmacological phenotypes for the remaining eight drugs. Further, to discover “consistency” between studies required the use of multiple statistics and the selection of specific measures on a case-by-case basis.

Conclusion:

Our results reaffirm our initial findings of an inconsistency in drug sensitivity measures for eight of fifteen drugs screened both in GDSC and CCLE, irrespective of which statistical metric was used to assess correlation. Taken together, our findings suggest that the phenotypic data on drug response in the GDSC and CCLE continue to present challenges for robust biomarker discovery. This re-analysis provides additional support for the argument that experimental standardization and validation of pharmacogenomic response will be necessary to advance the broad use of large pharmacogenomic screens.