Predicting microRNA-disease Associations Research Articles

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.

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.

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.

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/.

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.

A Fast Linear Neighborhood Similarity-Based Network Link Inference Method to Predict MicroRNA-Disease Associations.

Increasing evidences revealed that microRNAs (miRNAs) play critical roles in important biological processes. The identification of disease-related miRNAs is critical to understand the molecular mechanisms of human diseases. Most existing computational methods require diverse features to predict miRNA-disease associations. However, diverse features are not available for all miRNAs or diseases. In addition, most methods can't predict links for miRNAs or diseases without association information. In this paper, we propose a fast linear neighborhood similarity-based network link inference method, named FLNSNLI, to predict miRNA-disease associations. First, known miRNA-disease associations are formulated as a bipartite network, and miRNAs (or diseases) are expressed as association profiles. Second, miRNA-miRNA similarity and disease-disease similarity are calculated by fast linear neighborhood similarity measure and association profiles. Third, the label propagation algorithm is respectively implemented on two sides to score candidate miRNA-disease associations. Finally, FLNSNLI adopts the weighted average strategy and makes predictions. Moreover, we develop a link complementing approach, and extend FLNSNLI to predict links for miRNAs (or diseases) without known associations. In computational experiments, FLNSNLI produces high-accuracy performances, and outperforms other state-of-the-art methods. More importantly, FLNSNLI requires less information but performs well. Case studies on three popular diseases show that FLNSNLI is useful for the microRNA-disease association prediction.

Predicting microRNA-disease associations using label propagation based on linear neighborhood similarity

Interactions between microRNAs (miRNAs) and diseases can yield important information for uncovering novel prognostic markers. Since experimental determination of disease-miRNA associations is time-consuming and costly, attention has been given to designing efficient and robust computational techniques for identifying undiscovered interactions. In this study, we present a label propagation model with linear neighborhood similarity, called LPLNS, to predict unobserved miRNA-disease associations. Additionally, a preprocessing step is performed to derive new interaction likelihood profiles that will contribute to the prediction since new miRNAs and diseases lack known associations. Our results demonstrate that the LPLNS model based on the known disease-miRNA associations could achieve impressive performance with an AUC of 0.9034. Furthermore, we observed that the LPLNS model based on new interaction likelihood profiles could improve the performance to an AUC of 0.9127. This was better than other comparable methods. In addition, case studies also demonstrated our method’s outstanding performance for inferring undiscovered interactions between miRNAs and diseases, especially for novel diseases.

Predicting MicroRNA-Disease Associations Using Transcription factors based on multiple types of genomic data

Predicting MicroRNA-Disease Associations Using Transcription factors based on multiple types of genomic data

DNRLMF-MDA:Predicting microRNA-Disease Associations Based on Similarities of microRNAs and Diseases.

MicroRNAs (miRNAs) are a class of non-coding RNAs about ∼22nt nucleotides. Studies have proven that miRNAs play key roles in many human complex diseases. Therefore, discovering miRNA-disease associations is beneficial to understanding disease mechanisms, developing drugs, and treating complex diseases. It is well known that it is a time-consuming and expensive process to discover the miRNA-disease associations via biological experiments. Alternatively, computational models could provide a low-cost and high-efficiency way for predicting miRNA-disease associations. In this study, we propose a method (called DNRLMF-MDA) to predict miRNA-disease associations based on dynamic neighborhood regularized logistic matrix factorization. DNRLMF-MDA integrates known miRNA-disease associations, functional similarity and Gaussian Interaction Profile (GIP) kernel similarity of miRNAs, and functional similarity and GIP kernel similarity of diseases. Especially, positive observations (known miRNA-disease associations) are assigned higher importance levels than negative observations (unknown miRNA-disease associations).DNRLMF-MDA computes the probability that a miRNA would interact with a disease by a logistic matrix factorization method, where latent vectors of miRNAs and diseases represent the properties of miRNAs and diseases, respectively, and further improve prediction performance via dynamic neighborhood regularized. The 5-fold cross validation is adopted to assess the performance of our DNRLMF-MDA, as well as other competing methods for comparison. The computational experiments show that DNRLMF-MDA outperforms the state-of-art method PBMDA. The AUC values of DNRLMF-MDA on three datasets are 0.9357, 0.9411, and 0.9416, respectively, which are superior to the PBMDA's results of 0.9218, 0.9187, and 0.9262. The average computation times per 5-fold cross validation of DNRLMF-MDA on three datasets are 38, 46, and 50 seconds, which are shorter than the PBMDA's average computation times of 10869, 916, and 8448 seconds, respectively. DNRLMF-MDA also can predict potential diseases for new miRNAs. Furthermore, case studies illustrate that DNRLMF-MDA is an effective method to predict miRNA-disease associations.

A novel method of predicting microRNA-disease associations based on microRNA, disease, gene and environment factor networks.

MicroRNAs have been reported to have close relationship with diseases due to their deregulation of the expression of target mRNAs. Detecting disease-related microRNAs is helpful for disease therapies. With the development of high throughput experimental techniques, a large number of microRNAs have been sequenced. However, it is still a big challenge to identify which microRNAs are related to diseases. Recently, researchers are interesting in combining multiple-biological information to identify the associations between microRNAs and diseases. In this work, we have proposed a novel method to predict the microRNA-disease associations based on four biological properties. They are microRNA, disease, gene and environment factor. Compared with previous methods, our method makes predictions not only by using the prior knowledge of associations among microRNAs, disease, environment factors and genes, but also by using the internal relationship among these biological properties. We constructed four biological networks based on the similarity of microRNAs, diseases, environment factors and genes, respectively. Then random walking was implemented on the four networks unequally. In the walking course, the associations can be inferred from the neighbors in the same networks. Meanwhile the association information can be transferred from one network to another. The results of experiment showed that our method achieved better prediction performance than other existing state-of-the-art methods.

A novel approach for predicting microRNA-disease associations by unbalanced bi-random walk on heterogeneous network

MicroRNAs (miRNAs) play a critical role by regulating their targets in post-transcriptional level. Identification of potential miRNA-disease associations will aid in deciphering the pathogenesis of human polygenic diseases. Several computational models have been developed to uncover novel miRNA-disease associations based on the predicted target genes. However, due to the insufficient number of experimentally validated miRNA-target interactions as well as the relatively high false-positive and false-negative rates of predicted target genes, it is still challenging for these prediction models to obtain remarkable performances. The purpose of this study is to prioritize miRNA candidates for diseases. We first construct a heterogeneous network, which consists of a disease similarity network, a miRNA functional similarity network and a known miRNA-disease association network. Then, an unbalanced bi-random walk-based algorithm on the heterogeneous network (BRWH) is adopted to discover potential associations by exploiting bipartite subgraphs. Based on 5-fold cross validation, the proposed network-based method achieves AUC values ranging from 0.782 to 0.907 for the 22 human diseases and an average AUC of almost 0.846. The experiments indicated that BRWH can achieve better performances compared with several popular methods. In addition, case studies of some common diseases further demonstrated the superior performance of our proposed method on prioritizing disease-related miRNA candidates.

Predicting MicroRNA-Disease Associations Using Kronecker Regularized Least Squares Based on Heterogeneous Omics Data

MicroRNAs (miRNAs) play critical roles in many biological processes. Predicting the miRNA-disease associations will aid in deciphering the underlying pathogenesis of human polygenic diseases. However, existing in silico prediction methods typically utilize a single or limited data sources for disease-related miRNA prioritization and most of the methods are biased toward known miRNA-disease associations. Due to the insufficient number of experimentally validated interactions as well as no experimentally verified negative samples, obtaining remarkable performances is still challenging for these methods. In this paper, we present a semi-supervised method of Kronecker regularized least squares for predicting the potential or missing miRNA-disease associations (KRLSM). KRLSM integrates different omics data to assist various diseases or miRNAs with sparsely known associations to make predictions, and combines the disease space and miRNA space into a whole miRNA-disease space by Kronecker product. Finally, the semi-supervised classifier of regularized least squares is adopted to identify disease-related miRNAs. The experiment results demonstrate that the proposed method outperforms the other state-of-the-art approaches. In addition, case studies of several common diseases further indicate the effectiveness of KRLSM to identify potential miRNA-disease associations.

Predicting MicroRNA-Disease Associations Using Network Topological Similarity Based on DeepWalk

Recently, increasing experimental studies have shown that microRNAs (miRNAs) involved in multiple physiological processes are connected with several complex human diseases. Identifying human disease-related miRNAs will be useful in uncovering novel prognostic markers for cancer. Currently, several computational approaches have been developed for miRNA-disease association prediction based on the integration of additional biological information of diseases and miRNAs, such as disease semantic similarity and miRNA functional similarity. However, these methods do not work well when this information is unavailable. In this paper, we present a similarity-based miRNA-disease prediction method that enhances the existing association discovery methods through a topology-based similarity measure. DeepWalk, a deep learning method, is utilized in this paper to calculate similarities within a miRNA-disease association network. It shows superior predictive performance for 22 complex diseases, with area under the ROC curve scores ranging from 0.805 to 0.937 by using five-fold cross-validation. In addition, case studies on breast cancer, lung cancer, and prostatic cancer further justify the use of our method to discover latent miRNA-disease pairs.

A network similarity integration method for predicting microRNA-disease associations

The NSIM integrates the disease similarity network, miRNA similarity network, and known miRNA-disease association network on the basis of cousin similarity to predict not only novel miRNA-disease associations but also isolated diseases.

A Framework for Integrating Multiple Biological Networks to Predict MicroRNA-Disease Associations.

MicroRNAs have close relationship with human diseases. Therefore, identifying disease related MicroRNAs plays an important role in disease diagnosis, prognosis and therapy. However, designing an effective computational method which can make good use of various biological resources and correctly predict the associations between MicroRNA and disease is still a big challenge. Previous researchers have pointed out that there are complex relationships among microRNAs, diseases and environment factors. There are inter-relationships between microRNAs, diseases or environment factors based on their functional similarity or phenotype similarity or chemical structure similarity and so on. There are also intra-relationships between microRNAs and diseases, microRNAs and environment factors, diseases and environment factors. Moreover, functionally similar microRNAs tend to associate with common diseases and common environment factors. The diseases with similar phenotypes are likely caused by common microRNAs and common environment factors. In this work, we propose a framework namely ThrRWMDE which can integrate these complex relationships to predict microRNA-disease associations. In this framework, microRNA similarity network (MFN), disease similarity network (DSN) and environmental factor similarity network (ESN) are constructed according to certain biological properties. Then, an unbalanced three random walking algorithm is implemented on the three networks so as to obtain information from neighbors in corresponding networks. This algorithm not only can flexibly infer information from different levels of neighbors with respect to the topological and structural differences of the three networks, but also in the course of working the functional information will be transferred from one network to another according to the associations between the nodes in different networks. The results of experiment show that our method achieves better prediction performance than other state-of-the-art methods.

Predicting MicroRNA-Disease Associations Based on Improved MicroRNA and Disease Similarities.

MicroRNAs (miRNAs) are a type of non-coding RNAs with about ∼22nt nucleotides. Increasing evidences have shown that miRNAs play critical roles in many human diseases. The identification of human disease-related miRNAs is helpful to explore the underlying pathogenesis of diseases. More and more experimental validated associations between miRNAs and diseases have been reported in the recent studies, which provide useful information for new miRNA-disease association discovery. In this study, we propose a computational framework, KBMF-MDI, to predict the associations between miRNAs and diseases based on their similarities. The sequence and function information of miRNAs are used to measure similarity among miRNAs while the semantic and function information of disease are used to measure similarity among diseases, respectively. In addition, the kernelized Bayesian matrix factorization method is employed to infer potential miRNA-disease associations by integrating these data sources. We applied this method to 6,084 known miRNA-disease associations and utilized 5-fold cross validation to evaluate the performance. The experimental results demonstrate that our method can effectively predict unknown miRNA-disease associations.

Predicting human microRNA-disease associations based on support vector machine

The identification of disease-related microRNAs is vital for understanding the pathogenesis of disease at the molecular level and may lead to the design of specific molecular tools for diagnosis, treatment and prevention. Experimental identification of disease-related microRNAs poses difficulties. Computational prediction of microRNA-disease associations is one of the complementary means. However, one major issue in microRNA studies is the lack of bioinformatics programs to accurately predict microRNA-disease associations. Herein, we present a machine-learning-based approach for distinguishing positive microRNA-disease associations from negative microRNA-disease associations. A set of features was extracted for each positive and negative microRNA-disease association, and a Support Vector Machine (SVM) classifier was trained, which achieved the area under the ROC curve of up to 0.8884 in 10-fold cross-validation procedure, indicating that the SVM-based approach described here can be used to predict potential microRNA-disease associations and formulate testable hypotheses to guide future biological experiments.