microRNA-disease Associations Research Articles

DAE-CFR: detecting microRNA-disease associations using deep autoencoder and combined feature representation

BackgroundMicroRNA (miRNA) has been shown to play a key role in the occurrence and progression of diseases, making uncovering miRNA-disease associations vital for disease prevention and therapy. However, traditional laboratory methods for detecting these associations are slow, strenuous, expensive, and uncertain. Although numerous advanced algorithms have emerged, it is still a challenge to develop more effective methods to explore underlying miRNA-disease associations.ResultsIn the study, we designed a novel approach on the basis of deep autoencoder and combined feature representation (DAE-CFR) to predict possible miRNA-disease associations. We began by creating integrated similarity matrices of miRNAs and diseases, performing a logistic function transformation, balancing positive and negative samples with k-means clustering, and constructing training samples. Then, deep autoencoder was used to extract low-dimensional feature from two kinds of feature representations for miRNAs and diseases, namely, original association information-based and similarity information-based. Next, we combined the resulting features for each miRNA-disease pair and used a logistic regression (LR) classifier to infer all unknown miRNA-disease interactions. Under five and tenfold cross-validation (CV) frameworks, DAE-CFR not only outperformed six popular algorithms and nine classifiers, but also demonstrated superior performance on an additional dataset. Furthermore, case studies on three diseases (myocardial infarction, hypertension and stroke) confirmed the validity of DAE-CFR in practice.ConclusionsDAE-CFR achieved outstanding performance in predicting miRNA-disease associations and can provide evidence to inform biological experiments and clinical therapy.

MUSCLE: multi-view and multi-scale attentional feature fusion for microRNA-disease associations prediction.

MicroRNAs (miRNAs) synergize with various biomolecules in human cells resulting in diverse functions in regulating a wide range of biological processes. Predicting potential disease-associated miRNAs as valuable biomarkers contributes to the treatment of human diseases. However, few previous methods take a holistic perspective and only concentrate on isolated miRNA and disease objects, thereby ignoring that human cells are responsible for multiple relationships. In this work, we first constructed a multi-view graph based on the relationships between miRNAs and various biomolecules, and then utilized graph attention neural network to learn the graph topology features of miRNAs and diseases for each view. Next, we added an attention mechanism again, and developed a multi-scale feature fusion module, aiming to determine the optimal fusion results for the multi-view topology features of miRNAs and diseases. In addition, the prior attribute knowledge of miRNAs and diseases was simultaneously added to achieve better prediction results and solve the cold start problem. Finally, the learned miRNA and disease representations were then concatenated and fed into a multi-layer perceptron for end-to-end training and predicting potential miRNA-disease associations. To assess the efficacy of our model (called MUSCLE), we performed 5- and 10-fold cross-validation (CV), which got average the Area under ROC curves of 0.966${\pm }$0.0102 and 0.973${\pm }$0.0135, respectively, outperforming most current state-of-the-art models. We then examined the impact of crucial parameters on prediction performance and performed ablation experiments on the feature combination and model architecture. Furthermore, the case studies about colon cancer, lung cancer and breast cancer also fully demonstrate the good inductive capability of MUSCLE. Our data and code are free available at a public GitHub repository: https://github.com/zht-code/MUSCLE.git.

HMDD v4.0: a database for experimentally supported human microRNA-disease associations.

MicroRNAs (miRNAs) are a class of important small non-coding RNAs with critical molecular functions in almost all biological processes, and thus, they play important roles in disease diagnosis and therapy. Human MicroRNA Disease Database (HMDD) represents an important and comprehensive resource for biomedical researchers in miRNA-related medicine. Here, we introduce HMDD v4.0, which curates 53530 miRNA-disease association entries from literatures. In comparison to HMDD v3.0 released five years ago, HMDD v4.0 contains 1.5 times more entries. In addition, some new categories have been curated, including exosomal miRNAs implicated in diseases, virus-encoded miRNAs involved in human diseases, and entries containing miRNA-circRNA interactions. We also curated sex-biased miRNAs in diseases. Furthermore, in a case study, disease similarity analysis successfully revealed that sex-biased miRNAs related to developmental anomalies are associated with a number of human diseases with sex bias. HMDD can be freely visited at http://www.cuilab.cn/hmdd.

Improving the identification of miRNA-disease associations with multi-task learning on gene-disease networks.

MicroRNAs (miRNAs) are a family of non-coding RNA molecules with vital roles in regulating gene expression. Although researchers have recognized the importance of miRNAs in the development of human diseases, it is very resource-consuming to use experimental methods for identifying which dysregulated miRNA is associated with a specific disease. To reduce the cost of human effort, a growing body of studies has leveraged computational methods for predicting the potential miRNA-disease associations. However, the extant computational methods usually ignore the crucial mediating role of genes and suffer from the data sparsity problem. To address this limitation, we introduce the multi-task learning technique and develop a new model called MTLMDA (Multi-Task Learning model for predicting potential MicroRNA-Disease Associations). Different from existing models that only learn from the miRNA-disease network, our MTLMDA model exploits both miRNA-disease and gene-disease networks for improving the identification of miRNA-disease associations. To evaluate model performance, we compare our model with competitive baselines on a real-world dataset of experimentally supported miRNA-disease associations. Empirical results show that our model performs best using various performance metrics. We also examine the effectiveness of model components via ablation study and further showcase the predictive power of our model for six types of common cancers. The data and source code are available from https://github.com/qwslle/MTLMDA.

MiRdisNET: Discovering microRNA biomarkers that are associated with diseases utilizing biological knowledge-based machine learning.

During recent years, biological experiments and increasing evidence have shown that microRNAs play an important role in the diagnosis and treatment of human complex diseases. Therefore, to diagnose and treat human complex diseases, it is necessary to reveal the associations between a specific disease and related miRNAs. Although current computational models based on machine learning attempt to determine miRNA-disease associations, the accuracy of these models need to be improved, and candidate miRNA-disease relations need to be evaluated from a biological perspective. In this paper, we propose a computational model named miRdisNET to predict potential miRNA-disease associations. Specifically, miRdisNET requires two types of data, i.e., miRNA expression profiles and known disease-miRNA associations as input files. First, we generate subsets of specific diseases by applying the grouping component. These subsets contain miRNA expressions with class labels associated with each specific disease. Then, we assign an importance score to each group by using a machine learning method for classification. Finally, we apply a modeling component and obtain outputs. One of the most important outputs of miRdisNET is the performance of miRNA-disease prediction. Compared with the existing methods, miRdisNET obtained the highest AUC value of .9998. Another output of miRdisNET is a list of significant miRNAs for disease under study. The miRNAs identified by miRdisNET are validated via referring to the gold-standard databases which hold information on experimentally verified microRNA-disease associations. miRdisNET has been developed to predict candidate miRNAs for new diseases, where miRNA-disease relation is not yet known. In addition, miRdisNET presents candidate disease-disease associations based on shared miRNA knowledge. The miRdisNET tool and other supplementary files are publicly available at: https://github.com/malikyousef/miRdisNET.

Inferring Latent MicroRNA-Disease Associations on a Gene-Mediated Tripartite Heterogeneous Multiplexing Network.

MicroRNA (miRNA) is a class of non-coding single-stranded RNA molecules encoded by endogenous genes with a length of about 22 nucleotides. MiRNAs have been successfully identified as differentially expressed in various cancers. There is evidence that disorders of miRNAs are associated with a variety of complex diseases. Therefore, inferring potential miRNA-disease associations (MDAs) is very important for understanding the aetiology and pathogenesis of many diseases and is useful to disease diagnosis, prognosis and treatment. First, We creatively fused multiple similarity subnetworks from multi-sources for miRNAs, genes and diseases by multiplexing technology, respectively. Then, three multiplexed biological subnetworks are connected through the extended binary association to form a tripartite complete heterogeneous multiplexed network (Tri-HM). Finally, because the constructed Tri-HM network can retain subnetworks' original topology and biological functions and expands the binary association and dependence between the three biological entities, rich neighbourhood information is obtained iteratively from neighbours by a non-equilibrium random walk. Through cross-validation, our tri-HM-RWR model obtained an AUC value of 0.8657, and an AUPR value of 0.2139 in the global 5-fold cross-validation, which shows that our model can more fully speculate disease-related miRNAs.

HLGNN-MDA: Heuristic Learning Based on Graph Neural Networks for miRNA-Disease Association Prediction.

Identifying disease-related miRNAs can improve the understanding of complex diseases. However, experimentally finding the association between miRNAs and diseases is expensive in terms of time and resources. The computational screening of reliable miRNA-disease associations has thus become a necessary tool to guide biological experiments. "Similar miRNAs will be associated with the same disease" is the assumption on which most current miRNA-disease association prediction methods rely; however, biased prior knowledge, and incomplete and inaccurate miRNA similarity data and disease similarity data limit the performance of the model. Here, we propose heuristic learning based on graph neural networks to predict microRNA-disease associations (HLGNN-MDA). We learn the local graph topology features of the predicted miRNA-disease node pairs using graph neural networks. In particular, our improvements to the graph convolution layer of the graph neural network enable it to learn information among homogeneous nodes and among heterogeneous nodes. We illustrate the performance of HLGNN-MDA by performing tenfold cross-validation against excellent baseline models. The results show that we have promising performance in multiple metrics. We also focus on the role of the improvements to the graph convolution layer in the model. The case studies are supported by evidence on breast cancer, hepatocellular carcinoma and renal cell carcinoma. Given the above, the experiments demonstrate that HLGNN-MDA can serve as a reliable method to identify novel miRNA-disease associations.

Predicting multiple types of MicroRNA-disease associations based on tensor factorization and label propagation

MicroRNAs (miRNAs) play important regulatory roles in the pathogenesis and progression of diseases. Most existing bioinformatics methods only study miRNA-disease binary association prediction. However, there are many types of associations between miRNA and disease. In addition, the miRNA-disease-type association dataset has inherent noise and incompleteness. In this paper, a novel method based on tensor factorization and label propagation (TFLP) is proposed to alleviate the above problems. First, as an effective tensor factorization method, tensor robust principal component analysis (TRPCA) is applied to the original multiple-type miRNA-disease associations to obtain a clean and complete low-rank prediction tensor. Second, the Gaussian interaction profile (GIP) kernel is used to describe the similarity of disease pairs and the similarity of miRNA pairs. Then, they are combined with disease semantic similarity and miRNA functional similarity to obtain an integrated disease similarity network and an integrated miRNA similarity network, respectively. Finally, the low-rank association tensor and the biological similarity as auxiliary information are introduced into label propagation. The prediction performance of the algorithm is improved by iterative propagation of labeled information to unlabeled samples. Extensive experiments reveal that the proposed TFLP method outperforms other state-of-the-art methods for predicting multiple types of miRNA-disease associations. The data and source codes are available at https://github.com/nayu0419/TFLP.

INTS-MFS: A novel method to predict microRNA-disease associations by integrating network topology similarity and microRNA function similarity

Identifying associations between microRNAs (miRNAs) and diseases is very important to understand the occurrence and development of human diseases. However, these existing methods suffer from the following limitation: first, some disease-related miRNAs are obtained from the miRNA functional similarity networks consisting of heterogeneous data sources, i.e., disease similarity, protein interaction network, gene expression. Second, little approaches infer disease-related miRNAs depending on the network topological features without the functional similarity of miRNAs. In this paper, we develop a novel model of Integrating Network Topology Similarity and MicroRNA Function Similarity (INTS-MFS). The integrated miRNA similarities are calculated based on miRNA functional similarity and network topological characteristics. INTS-MFS obtained AUC of 0.872 based on five-fold cross-validation and was applied to three common human diseases in case studies. As a results, 30 out of top 30 predicted Prostatic Neoplasm-related miRNAs were included in the two databases of dbDEMC and PhenomiR2.0. 29 out of top 30 predicted Lung Neoplasm-related miRNAs and Breast Neoplasm-related miRNAs were included in dbDEMC, PhenomiR2.0 and experimental reports. Moreover, INTS-MFS found unknown association with hsa-mir-371a in breast cancer and lung cancer, which have not been reported. It provides biologists new clues for diagnosing breast and lung cancer.

ISFMDA: Learning Interactions of Selected Features-Based Method for Predicting Potential MicroRNA-Disease Associations

Prediction of potential microRNA-disease associations is one of the important tasks in computational biology fields. Mining more sophisticated features can improve the performance of the prediction methods. This article proposes a novel algorithm (ISFMDA) that can effectively learn low- or high-order interactions of recursive feature elimination selected features by an extreme gradient boosting, a factorization machine, and a deep neural network. As a result, ISFMDA can obtain an area under receiver operating characteristic curve (AUROC) of 0.9342 ± 0.0007 in fivefold cross-validation tests with 51.25% of original features, which verifies the effectiveness of the methods.

A Constrained Probabilistic Matrix Decomposition Method for Predicting miRNA-disease Associations

Background: MicroRNA is a type of non-coding RNA molecule whose length is about 22 nucleotides. The growing evidence shows that microRNA makes critical regulations in the development of complex diseases, such as cancers, and cardiovascular diseases. Predicting potential microRNA-disease associations can provide a new perspective to achieve a better scheme of disease diagnosis and prognosis. However, there is a challenge to predict some potential essential microRNAs only with few known associations. Objective: In this paper, we propose a novel method, named as a constrained strategy for predicting microRNA-disease associations called CPMDA, which can predict some potential essential microRNAs only with few known associations. Methods: We firstly construct a disease similarity network and microRNA similarity network to preprocess the microRNAs with none available associations. Then, we apply probabilistic factorization to obtain two feature matrices of microRNA and disease. Meanwhile, we formulate a similarity feature matrix as constraints in the factorization process. Finally, we utilize obtained feature matrixes to identify potential associations for all diseases. Result and Conclusion: The results indicate that CPMDA is superior over other methods in predicting potential microRNA-disease associations. Moreover, the evaluation shows that CPMDA has a strong effect on microRNAs with few known associations. In case studies, CPMDA also demonstrated the effectiveness to infer unknown microRNA-disease associations for those novel diseases and microRNAs.

Identification and Analysis of microRNA-Disease Associations with Kernelized Bayesian Matrix Factorization

MicroRNA (miRNA) molecules, which are effective on the initiation and progression of many different diseases, are a type of non-coding RNA with a length of about 22 nucleotides. Scientists have reported the importance of miRNAs in the prevention, diagnosis, and treatment of complex human diseases. Therefore, in the last decade, researchers have been working hard to find potential miRNA-disease associations. Many computational techniques have been developed because of the experimental techniques are time-consuming and expensive used to find new relationships between miRNAs and diseases. In this study, we suggested Kernelized Bayesian matrix factorization (KBMF) technique to predict new miRNA-disease relationships. We applied 5-fold cross validation technique and obtained an average value AUC of 0.9450. Also, we applied case studies based on breast, lung, and colon neoplasms to prove the performance of KBMF technique. The results showed that KBMF can be used as a reliable computational model to reveal possible miRNA-disease relationships.

SCMFMDA: Predicting microRNA-disease associations based on similarity constrained matrix factorization.

miRNAs belong to small non-coding RNAs that are related to a number of complicated biological processes. Considerable studies have suggested that miRNAs are closely associated with many human diseases. In this study, we proposed a computational model based on Similarity Constrained Matrix Factorization for miRNA-Disease Association Prediction (SCMFMDA). In order to effectively combine different disease and miRNA similarity data, we applied similarity network fusion algorithm to obtain integrated disease similarity (composed of disease functional similarity, disease semantic similarity and disease Gaussian interaction profile kernel similarity) and integrated miRNA similarity (composed of miRNA functional similarity, miRNA sequence similarity and miRNA Gaussian interaction profile kernel similarity). In addition, the L2 regularization terms and similarity constraint terms were added to traditional Nonnegative Matrix Factorization algorithm to predict disease-related miRNAs. SCMFMDA achieved AUCs of 0.9675 and 0.9447 based on global Leave-one-out cross validation and five-fold cross validation, respectively. Furthermore, the case studies on two common human diseases were also implemented to demonstrate the prediction accuracy of SCMFMDA. The out of top 50 predicted miRNAs confirmed by experimental reports that indicated SCMFMDA was effective for prediction of relationship between miRNAs and diseases.

DANE-MDA: Predicting microRNA-disease associations via deep attributed network embedding

SummaryPredicting the microRNA-disease associations by using computational methods is conductive to the efficiency of costly and laborious traditional bio-experiments. In this study, we propose a computational machine learning-based method (DANE-MDA) that preserves integrated structure and attribute features via deep attributed network embedding to predict potential miRNA-disease associations. Specifically, the integrated features are extracted by using deep stacked auto-encoder on the diverse orders of matrixes containing structure and attribute information and are then trained by using random forest classifier. Under 5-fold cross-validation experiments, DANE-MDA yielded average accuracy, sensitivity, and AUC at 85.59%, 84.23%, and 0.9264 in term of HMDD v3.0 dataset, and 83.21%, 80.39%, and 0.9113 in term of HMDD v2.0 dataset, respectively. Additionally, case studies on breast, colon, and lung neoplasms related disease show that 47, 47, and 46 of the top 50 miRNAs can be predicted and retrieved in the other database.

Tensor decomposition with relational constraints for predicting multiple types of microRNA-disease associations.

MicroRNAs (miRNAs) play crucial roles in multifarious biological processes associated with human diseases. Identifying potential miRNA-disease associations contributes to understanding the molecular mechanisms of miRNA-related diseases. Most of the existing computational methods mainly focus on predicting whether a miRNA-disease association exists or not. However, the roles of miRNAs in diseases are prominently diverged, for instance, Genetic variants of miRNA (mir-15) may affect the expression level of miRNAs leading to B cell chronic lymphocytic leukemia, while circulating miRNAs (including mir-1246, mir-1307-3p, etc.) have potentials to detecting breast cancer in the early stage. In this paper, we aim to predict multi-type miRNA-disease associations instead of taking them as binary. To this end, we innovatively represent miRNA-disease-type triples as a tensor and introduce tensor decomposition methods to solve the prediction task. Experimental results on two widely-adopted miRNA-disease datasets: HMDD v2.0 and HMDD v3.2 show that tensor decomposition methods improve a recent baseline in a large scale (up to $38\%$ in Top-1F1). We then propose a novel method, Tensor Decomposition with Relational Constraints (TDRC), which incorporates biological features as relational constraints to further the existing tensor decomposition methods. Compared with two existing tensor decomposition methods, TDRC can produce better performance while being more efficient.

Predicting microRNA-disease associations from lncRNA-microRNA interactions via Multiview Multitask Learning.

Identifying microRNAs that are associated with different diseases as biomarkers is a problem of great medical significance. Existing computational methods for uncovering such microRNA-diseases associations (MDAs) are mostly developed under the assumption that similar microRNAs tend to associate with similar diseases. Since such an assumption is not always valid, these methods may not always be applicable to all kinds of MDAs. Considering that the relationship between long noncoding RNA (lncRNA) and different diseases and the co-regulation relationships between the biological functions of lncRNA and microRNA have been established, we propose here a multiview multitask method to make use of the known lncRNA-microRNA interaction to predict MDAs on a large scale. The investigation is performed in the absence of complete information of microRNAs and any similarity measurement for it and to the best knowledge, the work represents the first ever attempt to discover MDAs based on lncRNA-microRNA interactions. In this paper, we propose to develop a deep learning model called MVMTMDA that can create a multiview representation of microRNAs. The model is trained based on an end-to-end multitasking approach to machine learning so that, based on it, missing data in the side information can be determined automatically. Experimental results show that the proposed model yields an average area under ROC curve of 0.8410+/-0.018, 0.8512+/-0.012 and 0.8521+/-0.008 when k is set to 2, 5 and 10, respectively. In addition, we also propose here a statistical approach to predicting lncRNA-disease associations based on these associations and the MDA discovered using MVMTMDA. Python code and the datasets used in our studies are made available at https://github.com/yahuang1991polyu/MVMTMDA/.

Inferring MicroRNA-Disease Associations Based on the Identification of a Functional Module.

Inferring potential associations between microRNAs (miRNAs) and human diseases can help people understand the pathogenesis of complex human diseases. Several computational approaches have been presented to discover novel miRNA-disease associations based on a top-ranked association model. However, some top-ranked miRNAs are not easily used to reveal the association between miRNAs and diseases. This study aims to infer miRNA-disease relationship by identifying a functional module. We first construct a miRNA functional similarity network derived from a disease similarity network and a known miRNA-disease relationship network. We then present an improved K-means (i.e., IK-means) algorithm to detect miRNA functional modules and used 243 diseases to validate the performance of our proposed method. Experimental results indicate that the performance of IK-means is better compared with classical K-means algorithms. Case studies on some functional modules further demonstrate the applicability of IK-means in the identification of new miRNA-disease associations.

Deep belief network-Based Matrix Factorization Model for MicroRNA-Disease Associations Prediction.

MicroRNAs (miRNAs) are small single-stranded noncoding RNAs that have shown to play a critical role in regulating gene expression. In past decades, cumulative experimental studies have verified that miRNAs are implicated in many complex human diseases and might be potential biomarkers for various types of diseases. With the increase of miRNA-related data and the development of analysis methodologies, some computational methods have been developed for predicting miRNA-disease associations, which are more economical and time-saving than traditional biological experimental approaches. In this study, a novel computational model, deep belief network (DBN)-based matrix factorization (DBN-MF), is proposed for miRNA-disease association prediction. First, the raw interaction features of miRNAs and diseases were obtained from the miRNA-disease adjacent matrix. Second, 2 DBNs were used for unsupervised learning of the features of miRNAs and diseases, respectively, based on the raw interaction features. Finally, a classifier consisting of 2 DBNs and a cosine score function was trained with the initial weights of DBN from the last step. During the training, the miRNA-disease adjacent matrix was factorized into 2 feature matrices for the representation of miRNAs and diseases, and the final prediction label was obtained according to the feature matrices. The experimental results show that the proposed model outperforms the state-of-the-art approaches in miRNA-disease association prediction based on the 10-fold cross-validation. Besides, the effectiveness of our model was further demonstrated by case studies.

Benchmark of computational methods for predicting microRNA-disease associations

BackgroundA series of miRNA-disease association prediction methods have been proposed to prioritize potential disease-associated miRNAs. Independent benchmarking of these methods is warranted to assess their effectiveness and robustness.ResultsBased on more than 8000 novel miRNA-disease associations from the latest HMDD v3.1 database, we perform systematic comparison among 36 readily available prediction methods. Their overall performances are evaluated with rigorous precision-recall curve analysis, where 13 methods show acceptable accuracy (AUPRC > 0.200) while the top two methods achieve a promising AUPRC over 0.300, and most of these methods are also highly ranked when considering only the causal miRNA-disease associations as the positive samples. The potential of performance improvement is demonstrated by combining different predictors or adopting a more updated miRNA similarity matrix, which would result in up to 16% and 46% of AUPRC augmentations compared to the best single predictor and the predictors using the previous similarity matrix, respectively. Our analysis suggests a common issue of the available methods, which is that the prediction results are severely biased toward well-annotated diseases with many associated miRNAs known and cannot further stratify the positive samples by discriminating the causal miRNA-disease associations from the general miRNA-disease associations.ConclusionOur benchmarking results not only provide a reference for biomedical researchers to choose appropriate miRNA-disease association predictors for their purpose, but also suggest the future directions for the development of more robust miRNA-disease association predictors.

A Novel Computational Model for Predicting microRNA-Disease Associations Based on Heterogeneous Graph Convolutional Networks.

Identifying the interactions between disease and microRNA (miRNA) can accelerate drugs development, individualized diagnosis, and treatment for various human diseases. However, experimental methods are time-consuming and costly. So computational approaches to predict latent miRNA–disease interactions are eliciting increased attention. But most previous studies have mainly focused on designing complicated similarity-based methods to predict latent interactions between miRNAs and diseases. In this study, we propose a novel computational model, termed heterogeneous graph convolutional network for miRNA–disease associations (HGCNMDA), which is based on known human protein–protein interaction (PPI) and integrates four biological networks: miRNA–disease, miRNA–gene, disease–gene, and PPI network. HGCNMDA achieved reliable performance using leave-one-out cross-validation (LOOCV). HGCNMDA is then compared to three state-of-the-art algorithms based on five-fold cross-validation. HGCNMDA achieves an AUC of 0.9626 and an average precision of 0.9660, respectively, which is ahead of other competitive algorithms. We further analyze the top-10 unknown interactions between miRNA and disease. In summary, HGCNMDA is a useful computational model for predicting miRNA–disease interactions.