The important role of microRNAs (miRNAs) in the formation, development, diagnosis, and treatment of diseases has attracted much attention among researchers recently. In this study, we present an unsupervised deep learning model of the variational autoencoder for MiRNA–disease association prediction (VAEMDA). Through combining the integrated miRNA similarity and the integrated disease similarity with known miRNA–disease associations, respectively, we constructed two spliced matrices. These matrices were applied to train the variational autoencoder (VAE), respectively. The final predicted association scores between miRNAs and diseases were obtained by integrating the scores from the two trained VAE models. Unlike previous models, VAEMDA can avoid noise introduced by the random selection of negative samples and reveal associations between miRNAs and diseases from the perspective of data distribution. Compared with previous methods, VAEMDA obtained higher area under the receiver operating characteristics curves (AUCs) of 0.9118, 0.8652, and 0.9091 ± 0.0065 in global leave-one-out cross validation (LOOCV), local LOOCV, and five-fold cross validation, respectively. Further, the AUCs of VAEMDA were 0.8250 and 0.8237 in global leave-one-disease-out cross validation (LODOCV), and local LODOCV, respectively. In three different types of case studies on three important diseases, the results showed that most of the top 50 potentially associated miRNAs were verified by databases and the literature.

Accumulating experimental evidence has demonstrated that microRNAs (miRNAs) have a huge impact on numerous critical biological processes and they are associated with different complex human diseases. Nevertheless, the task to predict potential miRNAs related to diseases remains difficult. In this paper, we developed a Kernel Fusion‐based Regularized Least Squares for MiRNA‐Disease Association prediction model (KFRLSMDA), which applied kernel fusion technique to fuse similarity matrices and then utilized regularized least squares to predict potential miRNA‐disease associations. To prove the effectiveness of KFRLSMDA, we adopted leave‐one‐out cross‐validation (LOOCV) and 5‐fold cross‐validation and then compared KFRLSMDA with 10 previous computational models (MaxFlow, MiRAI, MIDP, RKNNMDA, MCMDA, HGIMDA, RLSMDA, HDMP, WBSMDA and RWRMDA). Outperforming other models, KFRLSMDA achieved AUCs of 0.9246 in global LOOCV, 0.8243 in local LOOCV and average AUC of 0.9175 ± 0.0008 in 5‐fold cross‐validation. In addition, respectively, 96%, 100% and 90% of the top 50 potential miRNAs for breast neoplasms, colon neoplasms and oesophageal neoplasms were confirmed by experimental discoveries. We also predicted potential miRNAs related to hepatocellular cancer by removing all known related miRNAs of this cancer and 98% of the top 50 potential miRNAs were verified. Furthermore, we predicted potential miRNAs related to lymphoma using the data set in the old version of the HMDD database and 80% of the top 50 potential miRNAs were confirmed. Therefore, it can be concluded that KFRLSMDA has reliable prediction performance.