WDNE: an integrative graphical model for inferring differential networks from multi-platform gene expression data with missing values.

Abstract

The mechanisms controlling biological process, such as the development of disease or cell differentiation, can be investigated by examining changes in the networks of gene dependencies between states in the process. High-throughput experimental methods, like microarray and RNA sequencing, have been widely used to gather gene expression data, which paves the way to infer gene dependencies based on computational methods. However, most differential network analysis methods are designed to deal with fully observed data, but missing values, such as the dropout events in single-cell RNA-sequencing data, are frequent. New methods are needed to take account of these missing values. Moreover, since the changes of gene dependencies may be driven by certain perturbed genes, considering the changes in gene expression levels may promote the identification of gene network rewiring. In this study, a novel weighted differential network estimation (WDNE) model is proposed to handle multi-platform gene expression data with missing values and take account of changes in gene expression levels. Simulation studies demonstrate that WDNE outperforms state-of-the-art differential network estimation methods. When applied WDNE to infer differential gene networks associated with drug resistance in ovarian tumors, cell differentiation and breast tumor heterogeneity, the hub genes in the estimated differential gene networks can provide important insights into the underlying mechanisms. Furthermore, a Matlab toolbox, differential network analysis toolbox, was developed to implement the WDNE model and visualize the estimated differential networks.