DMirNet: Inferring direct microRNA-mRNA association networks

Abstract

Background: MicroRNAs (miRNAs) play important regulatory roles in the wide range of biological processes by inducing target mRNA degradation or translational repression. Based on the correlation between expression profiles of a miRNA and its target mRNA, various computational methods have previously been proposed to identify miRNA-mRNA association networks by incorporating the matched miRNA and mRNA expression profiles. However, there remain three major issues to be resolved in the conventional computation approaches for inferring miRNA-mRNA association networks from expression profiles. 1) Inferred correlations from the observed expression profiles using conventional correlation-based methods include numerous erroneous links or over-estimated edge weight due to the transitive information flow among direct associations. 2) Due to the high-dimension-low-sample-size problem on the microarray dataset, it is difficult to obtain an accurate and reliable estimate of the empirical correlations between all pairs of expression profiles. 3) Because the previously proposed computational methods usually suffer from varying performance across different datasets, a more reliable model that guarantees optimal or suboptimal performance across different datasets is highly needed. Results: In this paper, we present DMirNet, a new framework for identifying direct miRNA-mRNA association networks. To tackle the aforementioned issues, DMirNet incorporates 1) three direct correlation estimation methods (namely Corpcor, SPACE, Network deconvolution) to infer direct miRNA-mRNA association networks, 2) the bootstrapping method to fully utilize insufficient training expression profiles, and 3) a rank-based Ensemble aggregation to build a reliable and robust model across different datasets. Our empirical experiments on three datasets demonstrate the combinatorial effects of necessary components in DMirNet. Additional performance comparison experiments show that DMirNet outperforms the state-of-the-art Ensemble-based model [1] which has shown the best performance across the same three datasets, with a factor of up to 1.29. Further, we identify 43 putative novel multi-cancer-related miRNA-mRNA association relationships from an inferred Top 1000 direct miRNA-mRNA association network. Conclusions: We believe that DMirNet is a promising method to identify novel direct miRNA-mRNA relations and to elucidate the direct miRNA-mRNA association networks. Since DMirNet infers direct relationships from the observed data, DMirNet can contribute to reconstructing various direct regulatory pathways, including, but not limited to, the direct miRNA-mRNA association networks.