A fast lasso-based method for inferring higher-order interactions

Large-scale genotype-phenotype screens provide a wealth of data for identifying molecular alterations associated with a phenotype. Epistatic effects play an important role in such association studies. For example, siRNA perturbation screens can be used to identify combinatorial gene-silencing effects. In bacteria, epistasis has practical consequences in determining antimicrobial resistance as the genetic background of a strain plays an important role in determining resistance. Recently developed tools scale to human exome-wide screens for pairwise interactions, but none to date have included the possibility of three-way interactions. Expanding upon recent state-of-the-art methods, we make a number of improvements to the performance on large-scale data, making consideration of three-way interactions possible. We demonstrate our proposed method, Pint, on both simulated and real data sets, including antibiotic resistance testing and siRNA perturbation screens. Pint outperforms known methods in simulated data, and identifies a number of biologically plausible gene effects in both the antibiotic and siRNA models. For example, we have identified a combination of known tumour suppressor genes that is predicted (using Pint) to cause a significant increase in cell proliferation.Author summary: In recent years, large-scale genetic data sets have become available for analysis. These large data sets often stretch the limits of classic computational methods, requiring too much memory or simply taking a prohibitively long time to run. Due to the enormous number of potential interactions, each gene or variation in the data is often modelled on its own, without considering interactions between them. Recently, methods have been developed to solve regression problems that include these interacting effects. Even the fastest of these cannot include three-way interactions, however. We improve upon one such method, developing an approach that is significantly faster than the current state of the art. Moreover, our method scales to three-way interactions among thousands of genes, while avoiding a number of the limitations of previous approaches. We analyse large-scale simulated data, antibiotic resistance, and gene-silencing data sets to demonstrate the accuracy and performance of our approach.