Prediction of miRNA-disease associations with a vector space model

MicroRNAs play critical roles in many physiological processes. Their dysregulations are also closely related to the development and progression of various human diseases, including cancer. Therefore, identifying new microRNAs that are associated with diseases contributes to a better understanding of pathogenicity mechanisms. MicroRNAs also represent a tremendous opportunity in biotechnology for early diagnosis. To date, several in silico methods have been developed to address the issue of microRNA-disease association prediction. However, these methods have various limitations. In this study, we investigate the hypothesis that information attached to miRNAs and diseases can be revealed by distributional semantics. Our basic approach is to represent distributional information on miRNAs and diseases in a high-dimensional vector space and to define associations between miRNAs and diseases in terms of their vector similarity. Cross validations performed on a dataset of known miRNA-disease associations demonstrate the excellent performance of our method. Moreover, the case study focused on breast cancer confirms the ability of our method to discover new disease-miRNA associations and to identify putative false associations reported in databases

MDA-SKF: Similarity Kernel Fusion for Accurately Discovering miRNA-Disease Association

Identifying accurate associations between miRNAs and diseases is beneficial for diagnosis and treatment of human diseases. It is especially important to develop an efficient method to detect the association between miRNA and disease. Traditional experimental method has high precision, but its process is complicated and time-consuming. Various computational methods have been developed to uncover potential associations based on an assumption that similar miRNAs are always related to similar diseases. In this paper, we propose an accurate method, MDA-SKF, to uncover potential miRNA-disease associations. We first extract three miRNA similarity kernels (miRNA functional similarity, miRNA sequence similarity, Hamming profile similarity for miRNA) and three disease similarity kernels (disease semantic similarity, disease functional similarity, Hamming profile similarity for disease) in two subspaces, respectively. Then, due to limitations that some initial information may be lost in the process and some noises may be exist in integrated similarity kernel, we propose a novel Similarity Kernel Fusion (SKF) method to integrate multiple similarity kernels. Finally, we utilize the Laplacian Regularized Least Squares (LapRLS) method on the integrated kernel to find potential associations. MDA-SKF is evaluated by three evaluation methods, including global leave-one-out cross validation (LOOCV) and local LOOCV and 5-fold cross validation (CV), and achieves AUCs of 0.9576, 0.8356, and 0.9557, respectively. Compared with existing seven methods, MDA-SKF has outstanding performance on global LOOCV and 5-fold. We also test case studies to further analyze the performance of MDA-SKF on 32 diseases. Furthermore, 3200 candidate associations are obtained and a majority of them can be confirmed. It demonstrates that MDA-SKF is an accurate and efficient computational tool for guiding traditional experiments

TLHNMDA: Triple Layer Heterogeneous Network Based Inference for MiRNA-Disease Association Prediction

In recent years, microRNAs (miRNAs) have been confirmed to be involved in many important biological processes and associated with various kinds of human complex diseases. Therefore, predicting potential associations between miRNAs and diseases with the huge number of verified heterogeneous biological datasets will provide a new perspective for disease therapy. In this article, we developed a novel computational model of Triple Layer Heterogeneous Network based inference for MiRNA-Disease Association prediction (TLHNMDA) by using the experimentally verified miRNA-disease associations, miRNA-long noncoding RNA (lncRNA) interactions, miRNA function similarity information, disease semantic similarity information and Gaussian interaction profile kernel similarity for lncRNAs into an triple layer heterogeneous network to predict new miRNA-disease associations. As a result, the AUCs of TLHNMDA are 0.8795 and 0.8795 ± 0.0010 based on leave-one-out cross validation (LOOCV) and 5-fold cross validation, respectively. Furthermore, TLHNMDA was implemented on three complex human diseases to evaluate predictive ability. As a result, 84% (kidney neoplasms), 78% (lymphoma) and 76% (prostate neoplasms) of top 50 predicted miRNAs for the three complex diseases can be verified by biological experiments. In addition, based on the HMDD v1.0 database, 98% of top 50 potential esophageal neoplasms-associated miRNAs were confirmed by experimental reports. It is expected that TLHNMDA could be a useful model to predict potential miRNA-disease associations with high prediction accuracy and stability

A Novel Computational Method for the Identification of Potential miRNA-Disease Association Based on Symmetric Non-negative Matrix Factorization and Kronecker Regularized Least Square

Increasing evidence has indicated that microRNAs (miRNAs) are associated with numerous human diseases. Studying the associations between miRNAs and diseases contributes to the exploration of effective diagnostic and treatment approaches for diseases. Unfortunately, the use of biological experiments to reveal the potential associations between miRNAs and diseases is time consuming and costly. Therefore, it is very necessary to use simple and efficient calculation models to predict potential disease-related miRNAs. Considering the limitations of other previous methods, we proposed a novel computational model of Symmetric Nonnegative Matrix Factorization for MiRNA-Disease Association prediction (SNMFMDA) to reveal the relation of miRNA-disease pairs. SNMFMDA could be applied to predict miRNAs associated with new diseases. Compared to the direct use of the integrated similarity in previous computational models, the integrated similarity need to be interpolated by symmetric non-negative matrix factorization (SymNMF) before application in SNMFMDA, and the relevant probability of disease-miRNA was obtained mainly through Kronecker regularized least square (KronRLS) method in our model. What's more, the AUC of global leave-one-out cross validation (LOOCV) reached 0.9007, and the AUC based on local LOOCV was 0.8426. Besides, the mean and the standard deviation of AUCs achieved 0.8830 and 0.0017 respectively in 5-fold cross validation. All of the above results demonstrated the superior prediction performance of SNMFMDA. We also conducted three different case studies on Esophageal Neoplasms, Breast Neoplasms and Lung Neoplasms, and 49, 49, and 48 of the top 50 of their predicted miRNAs respectively were confirmed by databases or related literatures. It could be expected that SNMFMDA would be a model with the ability to predict disease-related miRNAs efficiently and accurately

Inferring Disease-Associated MicroRNAs Using Semi-supervised Multi-Label Graph Convolutional Networks

Disease; Gene Network; Biocomputational Method; Computer ModelingMicroRNAs (miRNAs) play crucial roles in biological processes involved in diseases. The associations between diseases and protein-coding genes (PCGs) have been well investigated, and miRNAs interact with PCGs to trigger them to be functional. We present a computational method, DimiG, to infer miRNA-associated diseases using a semi-supervised Graph Convolutional Network model (GCN). DimiG uses a multi-label framework to integrate PCG-PCG interactions, PCG-miRNA interactions, PCG-disease associations, and tissue expression profiles. DimiG is trained on disease-PCG associations and an interaction network using a GCN, which is further used to score associations between diseases and miRNAs. We evaluate DimiG on a benchmark set from verified disease-miRNA associations. Our results demonstrate that DimiG outperforms the best unsupervised method and is comparable to two supervised methods. Three case studies of prostate cancer, lung cancer, and inflammatory bowel disease further demonstrate the efficacy of DimiG, where top miRNAs predicted by DimiG are supported by literature

Predicting miRNA-Disease Association Based on Modularity Preserving Heterogeneous Network Embedding

MicroRNAs (miRNAs) are a category of small non-coding RNAs that profoundly impact various biological processes related to human disease. Inferring the potential miRNA-disease associations benefits the study of human diseases, such as disease prevention, disease diagnosis, and drug development. In this work, we propose a novel heterogeneous network embedding-based method called MDN-NMTF (Module-based Dynamic Neighborhood Non-negative Matrix Tri-Factorization) for predicting miRNA-disease associations. MDN-NMTF constructs a heterogeneous network of disease similarity network, miRNA similarity network and a known miRNA-disease association network. After that, it learns the latent vector representation for miRNAs and diseases in the heterogeneous network. Finally, the association probability is computed by the product of the latent miRNA and disease vectors. MDN-NMTF not only successfully integrates diverse biological information of miRNAs and diseases to predict miRNA-disease associations, but also considers the module properties of miRNAs and diseases in the course of learning vector representation, which can maximally preserve the heterogeneous network structural information and the network properties. At the same time, we also extend MDN-NMTF to a new version (called MDN-NMTF2) by using modular information to improve the miRNA-disease association prediction ability. Our methods and the other four existing methods are applied to predict miRNA-disease associations in four databases. The prediction results show that our methods can improve the miRNA-disease association prediction to a high level compared with the four existing methods

Bipartite Heterogeneous Network Method Based on Co-neighbor for MiRNA-Disease Association Prediction

In recent years, miRNA variation and dysregulation have been found to be closely related to human tumors, and identifying miRNA-disease associations is helpful for understanding the mechanisms of disease or tumor development and is greatly significant for the prognosis, diagnosis, and treatment of human diseases. This article proposes a Bipartite Heterogeneous network link prediction method based on co-neighbor to predict miRNA-disease association (BHCN). According to the structural characteristics of the bipartite network, the concept of bipartite network co-neighbors is proposed, and the co-neighbors were used to represent the probability of association between disease and miRNA. To predict the isolated diseases and the new miRNA based on the association probability expressed by co-neighbors, we utilized the similarity between disease nodes and the similarity between miRNA nodes in heterogeneous networks to represent the association probability between disease and miRNA. The model's predictive performance was evaluated by the leave-one-out cross validation (LOOCV) on different datasets. The AUC value of BHCN on the gold benchmark dataset was 0.7973, and the AUC obtained on the prediction dataset was 0.9349, which was better than that of the classic global algorithm. In this case study, we conducted predictive studies on breast neoplasms and colon neoplasms. Most of the top 50 predicted results were confirmed by three databases, namely, HMDD, miR2disease, and dbDEMC, with accuracy rates of 96 and 82%. In addition, BHCN can be used for predicting isolated diseases (without any known associated diseases) and new miRNAs (without any known associated miRNAs). In the isolated disease case study, the top 50 of breast neoplasm and colon neoplasm potentials associated with miRNAs predicted an accuracy of 100 and 96%, respectively, thereby demonstrating the favorable predictive power of BHCN for potentially relevant miRNAs