MOTIVATION: Differential network analysis is an important tool to investigate the rewiring of gene interactions under different conditions. Several computational methods have been developed to estimate differential networks from gene expression data, but most of them do not consider that gene network rewiring may be driven by the differential expression of individual genes. New differential network analysis methods that simultaneously take account of the changes in gene interactions and changes in expression levels are needed. RESULTS: : In this article, we propose a differential network analysis method that considers the differential expression of individual genes when identifying differential edges. First, two hypothesis test statistics are used to quantify changes in partial correlations between gene pairs and changes in expression levels for individual genes. Then, an optimization framework is proposed to combine the two test statistics so that the resulting differential network has a hierarchical property, where a differential edge can be considered only if at least one of the two involved genes is differentially expressed. Simulation results indicate that our method outperforms current state-of-the-art methods. We apply our method to identify the differential networks between the luminal A and basal-like subtypes of breast cancer and those between acute myeloid leukemia and normal samples. Hub nodes in the differential networks estimated by our method, including both differentially and nondifferentially expressed genes, have important biological functions. AVAILABILITY AND IMPLEMENTATION: All the datasets underlying this article are publicly available. Processed data and source code can be accessed through the Github repository at https://github.com/Zhangxf-ccnu/chNet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Reconstruction of cancer gene networks from gene expression data is important for understanding the mechanisms underlying human cancer. Due to heterogeneity, the tumor tissue samples for a single cancer type can be divided into multiple distinct subtypes (inter-tumor heterogeneity) and are composed of non-cancerous and cancerous cells (intra-tumor heterogeneity). If tumor heterogeneity is ignored when inferring gene networks, the edges specific to individual cancer subtypes and cell types cannot be characterized. However, most existing network reconstruction methods do not simultaneously take inter-tumor and intra-tumor heterogeneity into account. RESULTS: In this article, we propose a new Gaussian graphical model-based method for jointly estimating multiple cancer gene networks by simultaneously capturing inter-tumor and intra-tumor heterogeneity. Given gene expression data of heterogeneous samples for different cancer subtypes, a non-cancerous network shared across different cancer subtypes and multiple subtype-specific cancerous networks are estimated jointly. Tumor heterogeneity can be revealed by the difference in the estimated networks. The performance of our method is first evaluated using simulated data, and the results indicate that our method outperforms other state-of-the-art methods. We also apply our method to The Cancer Genome Atlas breast cancer data to reconstruct non-cancerous and subtype-specific cancerous gene networks. Hub nodes in the networks estimated by our method perform important biological functions associated with breast cancer development and subtype classification. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/Zhangxf-ccnu/NETI2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.