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Background gene expression networks significantly enhance drug response prediction by transcriptional profiling.

ABSTRACT: A central goal of gene expression studies coupled with drug response screens is to identify predictive profiles that can be exploited to stratify patients. Numerous methods have been proposed towards this end, most of them focusing on novel statistical methods and model selection techniques that attempt to uncover groups of genes, whose expression profiles are directly and robustly correlated with drug response. However, biological systems process information through the crosstalk of multiple signaling networks, whose ultimate phenotypic consequences may only be determined by the combined input of relevant interacting systems. By restricting predictive signatures to direct gene-drug correlations, biologically meaningful interactions that may serve as superior predictors are ignored. Here we demonstrate that predictive signatures, which incorporate the interaction between background gene expression patterns and individual predictive probes, can provide superior models than those that directly relate gene expression levels to pharmacological response, and thus should be more widely utilized in pharmacogenetic studies.

SUBMITTER: Torkamani A

PROVIDER: S-EPMC4846279 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Background gene expression networks significantly enhance drug response prediction by transcriptional profiling.

Torkamani A A Schork N J NJ

The pharmacogenomics journal 20110809 5

A central goal of gene expression studies coupled with drug response screens is to identify predictive profiles that can be exploited to stratify patients. Numerous methods have been proposed towards this end, most of them focusing on novel statistical methods and model selection techniques that attempt to uncover groups of genes, whose expression profiles are directly and robustly correlated with drug response. However, biological systems process information through the crosstalk of multiple si ...[more]

PMID: 21826086

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Project description:In recent years, drug sensitivity prediction has garnered a great deal of attention due to the growing interest in precision medicine. Several computational methods have been developed for drug sensitivity prediction and the identification of related markers. However, most previous studies have ignored genetic interaction, although complex diseases (e.g., cancer) involve many genes intricately connected in a molecular network rather than the abnormality of a single gene. To effectively predict drug sensitivity and understand its mechanism, we propose a novel strategy for explainable drug sensitivity prediction based on sample-specific gene regulatory networks, designated Xprediction. Our strategy first estimates sample-specific gene regulatory networks that enable us to identify the molecular interplay underlying varying clinical characteristics of cell lines. We then, predict drug sensitivity based on the estimated sample-specific gene regulatory networks. The predictive models are based on machine learning approaches, i.e., random forest, kernel support vector machine, and deep neural network. Although the machine learning models provide remarkable results for prediction and classification, we cannot understand how the models reach their decisions. In other words, the methods suffer from the black box problem and thus, we cannot identify crucial molecular interactions that involve drug sensitivity-related mechanisms. To address this issue, we propose a method that describes the importance of each molecular interaction for the drug sensitivity prediction result. The proposed method enables us to identify crucial gene-gene interactions and thereby, interpret the prediction results based on the identified markers. To evaluate our strategy, we applied Xprediction to EGFR-TKIs prediction based on drug sensitivity specific gene regulatory networks and identified important molecular interactions for EGFR-TKIs prediction. Our strategy effectively performed drug sensitivity prediction compared with prediction based on the expression levels of genes. We also verified through literature, the EGFR-TKIs-related mechanisms of a majority of the identified markers. We expect our strategy to be a useful tool for predicting tasks and uncovering complex mechanisms related to pharmacological profiles, such as mechanisms of acquired drug resistance or sensitivity of cancer cells.

Dataset Information

Background gene expression networks significantly enhance drug response prediction by transcriptional profiling.

Publications

Background gene expression networks significantly enhance drug response prediction by transcriptional profiling.

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