HetFCM: functional co-module discovery by heterogeneous network co-clustering.

Functional molecular module (i.e., gene-miRNA co-modules and gene-miRNA-lncRNA triple-layer modules) analysis can dissect complex regulations underlying etiology or phenotypes. However, current module detection methods lack an appropriate usage and effective model of multi-omics data and cross-layer regulations of heterogeneous molecules, causing the loss of critical genetic information and corrupting the detection performance. In this study, we propose a heterogeneous network co-clustering framework (HetFCM) to detect functional co-modules. HetFCM introduces an attributed heterogeneous network to jointly model interplays and multi-type attributes of different molecules, and applies multiple variational graph autoencoders on the network to generate cross-layer association matrices, then it performs adaptive weighted co-clustering on association matrices and attribute data to identify co-modules of heterogeneous molecules. Empirical study on Human and Maize datasets reveals that HetFCM can find out co-modules characterized with denser topology and more significant functions, which are associated with human breast cancer (subtypes) and maize phenotypes (i.e., lipid storage, drought tolerance and oil content). HetFCM is a useful tool to detect co-modules and can be applied to multi-layer functional modules, yielding novel insights for analyzing molecular mechanisms. We also developed a user-friendly module detection and analysis tool and shared it at http://www.sdu-idea.cn/FMDTool.