Gene expression associations with the growth inhibitory effects of small molecules on live cells: Specificity of effects and uniformity of mechanisms

The NCI60 human tumor cell line screen is a public resource for studying selective and nonselective growth inhibition of small molecules against cancer cells. By coupling growth inhibition screening data with biological characterizations of the different cell lines, it becomes possible to infer mechanisms of action underlying some of the observable patterns of selective activity. Using these data, mechanistic relationships have been identified including specific associations between single genes and small families of closely related compounds, and less specific relationships between biological processes involving several cooperating genes and broader families of compounds. Here, we aim to characterize the degree to which such specific and general relationships are present in these data. A related question is whether genes tend to act with a uniform mechanism for all associated compounds, or whether multiple mechanisms are commonly involved. We address these two issues in a statistical framework placing special emphasis on the effects of measurement error in the gene expression and chemical screening data. We find that as measurement accuracy increases, the pattern of apparent associations shifts from one dominated by isolated gene-compound pairs, to one in which families consisting of an average of 25 compounds are associated to the same gene. At the same time, the number of genes that appear to play a role in influencing compound activities decreases. For less than half of the genes, the presence of both positive and negative correlations indicates pleiotropic associations with molecules via different mechanisms of action. Copyright © 2009 Wiley Periodicals, Inc. Statistical Analysis and Data Mining 2: 175–185, 2009