GIMLET: Identifying Biological Modulators in Context-Specific Gene Regulation Using Local Energy Statistics

The regulation of transcription factor activity dynamically changes across cellular conditions and disease subtypes. The identification of biological modulators contributing to context-specific gene regulation is one of the challenging tasks in systems biology, which is necessary to understand and control cellular responses across different genetic backgrounds and environmental conditions. Previous approaches for identifying biological modulators from gene expression data were restricted to the capturing of a particular type of a three-way dependency among a regulator, its target gene, and a modulator; these methods cannot describe the complex regulation structure, such as when multiple regulators, their target genes, and modulators are functionally related. Here, we propose a statistical method for identifying biological modulators by capturing multivariate local dependencies, based on energy statistics, which is a class of statistics based on distances. Subsequently, our method assigns a measure of statistical significance to each candidate modulator through a permutation test. We compared our approach with that of a leading competitor for identifying modulators, and illustrated its performance through both simulations and real data analysis. Our method, entitled genome-wide identification of modulators using local energy statistical test (GIMLET), is implemented with R (≥ 3.2.2) and is available from github ( https://github.com/tshimam/GIMLET ).