A Unified Framework for the Prediction of Small Molecule–MicroRNA Association Based on Cross-Layer Dependency Inference on Multilayered Networks

MicroRNAs (miRNAs) play a key role in many critical biological processes and are involved in the occurrence and development of complex human diseases. Many studies demonstrated that discovering the associations between small molecules (SMs) and miRNAs will facilitate the design of miRNA targeted therapeutic strategies for complex human diseases. This work presents a calculation model of cross-layer dependency inference on multilayered networks for small molecule–miRNA association prediction (CLDISMMA), which constructed multilayered networks composed of SMs, miRNAs, and diseases. It utilized the within layer topology and the known cross-layer associations to infer latent representations of all layers for SM–miRNA association prediction. In CLDISMMA, the novelties lie in introducing disease information for SM–miRNA association prediction and utilizing a regularized optimization model to describe the SM–miRNA association prediction problem. To evaluate the performance of CLDISMMA, global leave-one-out cross validation (LOOCV) and miRNA-fixed and SM-fixed local LOOCV were implemented in two data sets. In data set 1, CLDISMMA achieved AUCs of 0.9889, 0.9886, and 0.7755 in turns. The corresponding AUCs were 0.8726, 0.8798, and 0.7021 based on data set 2. In addition, CLDISMMA obtained average AUCs of 0.9887 and 0.8647 in data sets 1 and 2 under 100 times 5-fold cross validation. Furthermore, we employed CLDISMMA to predict SM–miRNA associations based on data set 1, and 21 out of the top 50 predicted associations were confirmed by experimental reports. In the case study for new SMs, 5-fluorouracil and 5-aza-2′-deoxycytidine, 40 and 30 miRNAs, respectively, were verified to be associated with them among the top 50 miRNAs predicted by CLDISMMA.