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The Cluster Elastic Net for High-Dimensional Regression With Unknown Variable Grouping.

ABSTRACT: In the high-dimensional regression setting, the elastic net produces a parsimonious model by shrinking all coefficients towards the origin. However, in certain settings, this behavior might not be desirable: if some features are highly correlated with each other and associated with the response, then we might wish to perform less shrinkage on the coefficients corresponding to that subset of features. We propose the cluster elastic net, which selectively shrinks the coefficients for such variables towards each other, rather than towards the origin. Instead of assuming that the clusters are known a priori, the cluster elastic net infers clusters of features from the data, on the basis of correlation among the variables as well as association with the response. These clusters are then used in order to more accurately perform regression. We demonstrate the theoretical advantages of our proposed approach, and explore its performance in a simulation study, and in an application to HIV drug resistance data. Supplementary Materials are available online.

SUBMITTER: Witten DM

PROVIDER: S-EPMC4011669 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The Cluster Elastic Net for High-Dimensional Regression With Unknown Variable Grouping.

Witten Daniela M DM Shojaie Ali A Zhang Fan F

Technometrics : a journal of statistics for the physical, chemical, and engineering sciences 20140201 1

In the high-dimensional regression setting, the elastic net produces a parsimonious model by shrinking all coefficients towards the origin. However, in certain settings, this behavior might not be desirable: if some features are highly correlated with each other and associated with the response, then we might wish to perform less shrinkage on the coefficients corresponding to that subset of features. We propose the <i>cluster elastic net</i>, which selectively shrinks the coefficients for such v ...[more]

PMID: 24817772

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Project description:BackgroundMany kinase inhibitors have been approved as cancer therapies. Recently, libraries of kinase inhibitors have been extensively profiled, thus providing a map of the strength of action of each compound on a large number of its targets. These profiled libraries define drug-kinase networks that can predict the effectiveness of untested drugs and elucidate the roles of specific kinases in different cellular systems. Predictions of drug effectiveness based on a comprehensive network model of cellular signalling are difficult, due to our partial knowledge of the complex biological processes downstream of the targeted kinases.ResultsWe have developed the Kinase Inhibitors Elastic Net (KIEN) method, which integrates information contained in drug-kinase networks with in vitro screening. The method uses the in vitro cell response of single drugs and drug pair combinations as a training set to build linear and nonlinear regression models. Besides predicting the effectiveness of untested drugs, the KIEN method identifies sets of kinases that are statistically associated to drug sensitivity in a given cell line. We compared different versions of the method, which is based on a regression technique known as elastic net. Data from two-drug combinations led to predictive models, and we found that predictivity can be improved by applying logarithmic transformation to the data. The method was applied to the A549 lung cancer cell line, and we identified specific kinases known to have an important role in this type of cancer (TGFBR2, EGFR, PHKG1 and CDK4). A pathway enrichment analysis of the set of kinases identified by the method showed that axon guidance, activation of Rac, and semaphorin interactions pathways are associated to a selective response to therapeutic intervention in this cell line.ConclusionsWe have proposed an integrated experimental and computational methodology, called KIEN, that identifies the role of specific kinases in the drug response of a given cell line. The method will facilitate the design of new kinase inhibitors and the development of therapeutic interventions with combinations of many inhibitors.

Dataset Information

The Cluster Elastic Net for High-Dimensional Regression With Unknown Variable Grouping.

Publications

The Cluster Elastic Net for High-Dimensional Regression With Unknown Variable Grouping.

Similar Datasets

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