基于图自编码器和协同训练预测miRNA[]与疾病的关联

近年来,越来越多的生物学实验研究表明,microRNA (miRNA)在人类复杂疾病的发展中发挥着重要作用。因此,预测miRNA与疾病之间的关联有助于疾病的准确诊断和有效治疗。由于传统的生物学实验是一种昂贵且耗时的方式,于是许多基于生物学数据的计算模型被提出来预测miRNA与疾病的关联。本研究提出了一种端到端的深度学习模型来预测miRNA-疾病关联关系,称为MDAGAC。首先,通过整合疾病语义相似性,miRNA功能相似性和高斯相互作用谱核相似性,构建miRNA和疾病的相似性图。然后,通过图自编码器和协同训练来改善标签传播的效果。该模型分别在miRNA图和疾病图上建立了两个图自编码器,并对这两个图自编码器进行了协同训练。miRNA图和疾病图上的图自编码器能够通过初始关联矩阵重构得分矩阵,这相当于在图上传播标签。miRNA-疾病关联的预测概率可以从得分矩阵得到。基于五折交叉验证的实验结果表明,MDAGAC方法可靠有效,优于现有的几种预测miRNA-疾病关联的方法。     

SNMDA: A novel method for predicting microRNA‐disease associations based on sparse neighbourhood

miRNAs are a class of small noncoding RNAs that are associated with a variety of complex biological processes. Increasing studies have shown that miRNAs have close relationships with many human diseases. The prediction of the associations between miRNAs and diseases has thus become a hot topic. Although traditional experimental methods are reliable, they could only identify a limited number of associations as they are time‐consuming and expensive. Consequently, great efforts have been made to effectively predict reliable disease‐related miRNAs based on computational methods. In this study, we present a novel approach to predict the potential microRNA‐disease associations based on sparse neighbourhood. Specifically, our method takes advantage of the sparsity of the miRNA‐disease association network and integrates the sparse information into the current similarity matrices for both miRNAs and diseases. To demonstrate the utility of our method, we applied global LOOCV, local LOOCV and five‐fold cross‐validation to evaluate our method, respectively. The corresponding AUCs are 0.936, 0.882 and 0.934. Three types of case studies on five common diseases further confirm the performance of our method in predicting unknown miRNA‐disease associations. Overall, results show that SNMDA can predict the potential associations between miRNAs and diseases effectively.     

DRMDA: deep representations‐based miRNA–disease association prediction

Recently, microRNAs (miRNAs) are confirmed to be important molecules within many crucial biological processes and therefore related to various complex human diseases. However, previous methods of predicting miRNA–disease associations have their own deficiencies. Under this circumstance, we developed a prediction method called deep representations‐based miRNA–disease association (DRMDA) prediction. The original miRNA–disease association data were extracted from HDMM database. Meanwhile, stacked auto‐encoder, greedy layer‐wise unsupervised pre‐training algorithm and support vector machine were implemented to predict potential associations. We compared DRMDA with five previous classical prediction models (HGIMDA, RLSMDA, HDMP, WBSMDA and RWRMDA) in global leave‐one‐out cross‐validation (LOOCV), local LOOCV and fivefold cross‐validation, respectively. The AUCs achieved by DRMDA were 0.9177, 08339 and 0.9156 ± 0.0006 in the three tests above, respectively. In further case studies, we predicted the top 50 potential miRNAs for colon neoplasms, lymphoma and prostate neoplasms, and 88%, 90% and 86% of the predicted miRNA can be verified by experimental evidence, respectively. In conclusion, DRMDA is a promising prediction method which could identify potential and novel miRNA–disease associations.     

NDAMDA: Network distance analysis for MiRNA‐disease association prediction

In recent years, microRNAs (miRNAs) are attracting an increasing amount of researchers’ attention, as accumulating studies show that miRNAs play important roles in various basic biological processes and that dysregulation of miRNAs is connected with diverse human diseases, particularly cancers. However, the experimental methods to identify associations between miRNAs and diseases remain costly and laborious. In this study, we developed a computational method named Network Distance Analysis for MiRNA‐Disease Association prediction (NDAMDA) which could effectively predict potential miRNA‐disease associations. The highlight of this method was the use of not only the direct network distance between 2 miRNAs (diseases) but also their respective mean network distances to all other miRNAs (diseases) in the network. The model's reliable performance was certified by the AUC of 0.8920 in global leave‐one‐out cross‐validation (LOOCV), 0.8062 in local LOOCV and the average AUCs of 0.8935 ± 0.0009 in fivefold cross‐validation. Moreover, we applied NDAMDA to 3 different case studies to predict potential miRNAs related to breast neoplasms, lymphoma, oesophageal neoplasms, prostate neoplasms and hepatocellular carcinoma. Results showed that 86%, 72%, 86%, 86% and 84% of the top 50 predicted miRNAs were supported by experimental association evidence. Therefore, NDAMDA is a reliable method for predicting disease‐related miRNAs.     

GIMDA: Graphlet interaction‐based MiRNA‐disease association prediction

MicroRNAs (miRNAs) have been confirmed to be closely related to various human complex diseases by many experimental studies. It is necessary and valuable to develop powerful and effective computational models to predict potential associations between miRNAs and diseases. In this work, we presented a prediction model of Graphlet Interaction for MiRNA‐Disease Association prediction (GIMDA) by integrating the disease semantic similarity, miRNA functional similarity, Gaussian interaction profile kernel similarity and the experimentally confirmed miRNA‐disease associations. The related score of a miRNA to a disease was calculated by measuring the graphlet interactions between two miRNAs or two diseases. The novelty of GIMDA lies in that we used graphlet interaction to analyse the complex relationships between two nodes in a graph. The AUCs of GIMDA in global and local leave‐one‐out cross‐validation (LOOCV) turned out to be 0.9006 and 0.8455, respectively. The average result of five‐fold cross‐validation reached to 0.8927 ± 0.0012. In case study for colon neoplasms, kidney neoplasms and prostate neoplasms based on the database of HMDD V2.0, 45, 45, 41 of the top 50 potential miRNAs predicted by GIMDA were validated by dbDEMC and miR2Disease. Additionally, in the case study of new diseases without any known associated miRNAs and the case study of predicting potential miRNA‐disease associations using HMDD V1.0, there were also high percentages of top 50 miRNAs verified by the experimental literatures.     

In silico prediction of potential miRNA‐disease association using an integrative bioinformatics approach based on kernel fusion

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.     

Identifying miRNA-disease association based on integrating miRNA topological similarity and functional similarity

Background: MicroRNAs (miRNAs) are a significant type of non-coding RNAs, which usually were encoded by endogenous genes with about ~22 nt nucleotides. Accumulating biological experiments have shown that miRNAs have close associations with various human diseases. Although traditional experimental methods achieve great successes in miRNA-disease interaction identification, these methods also have some limitations. Therefore, it is necessary to develop computational method to predict miRNA-disease interactions. Methods: Here, we propose a computational framework (MDVSI) to predict interactions between miRNAs and diseases by integrating miRNA topological similarity and functional similarity. Firstly, the CosRA index is utilized to measure miRNA similarity based on network topological feature. Then, in order to enhance the reliability of miRNA similarity, the functional similarity and CosRA similarity are integrated based on linear weight method. Further, the potential miRNA-disease associations are predicted by using recommendation method. In addition, in order to overcome limitation of recommendation method, for new disease, a new strategy is proposed to predict potential interactions between miRNAs and new disease based on disease functional similarity. Results: To evaluate the performance of different methods, we conduct ten-fold cross validation and de novo test in experiment and compare MDVSI with two the-state-of-art methods. The experimental result shows that MDVSI achieves an AUC of 0.91, which is at least 0.012 higher than other compared methods. Conclusions: In summary, we propose a computational framework (MDSVI) for miRNA-disease interaction prediction. The experiment results demonstrate that it outperforms other the-state-of-the-art methods. Case study shows that it can effectively identify potential miRNA-disease interactions.     

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.     

Predicting microRNA-disease association based on microRNA structural and functional similarity network

Background: Increasing evidences indicate that microRNAs (miRNAs) are functionally related to the development and progression of various human diseases. Inferring disease-related miRNAs can be helpful in promoting disease biomarker detection for the treatment, diagnosis, and prevention of complex diseases. Methods: To improve the prediction accuracy of miRNA-disease association and capture more potential disease-related miRNAs, we constructed a precise miRNA global similarity network (MSFSN) via calculating the miRNA similarity based on secondary structures, families, and functions. Results: We tested the network on the classical algorithms: WBSMDA and RWRMDA through the method of leave-one-out cross-validation. Eventually, AUCs of 0.8212 and 0.9657 are obtained, respectively. Also, the proposed MSFSN is applied to three cancers for breast neoplasms, hepatocellular carcinoma, and prostate neoplasms. Consequently, 82%, 76%, and 82% of the top 50 potential miRNAs for these diseases are respectively validated by the miRNA-disease associations database miR2Disease and oncomiRDB. Conclusion: Therefore, MSFSN provides a novel miRNA similarity network combining precise function network with global structure network of miRNAs to predict the associations between miRNAs and diseases in various models.     

Protein network-based Lasso regression model for the construction of disease-miRNA functional interactions

BackgroundThere is a growing body of evidence associating microRNAs (miRNAs) with human diseases. MiRNAs are new key players in the disease paradigm demonstrating roles in several human diseases. The functional association between miRNAs and diseases remains largely unclear and far from complete. With the advent of high-throughput functional genomics techniques that infer genes and biological pathways dysregulted in diseases, it is now possible to infer functional association between diseases and biological molecules by integrating disparate biological information.ResultsHere, we first used Lasso regression model to identify miRNAs associated with disease signature as a proof of concept. Then we proposed an integrated approach that uses disease-gene associations from microarray experiments and text mining, and miRNA-gene association from computational predictions and protein networks to build functional associations network between miRNAs and diseases. The findings of the proposed model were validated against gold standard datasets using ROC analysis and results were promising (AUC=0.81). Our protein network-based approach discovered 19 new functional associations between prostate cancer and miRNAs. The new 19 associations were validated using miRNA expression data and clinical profiles and showed to act as diagnostic and prognostic prostate biomarkers. The proposed integrated approach allowed us to reconstruct functional associations between miRNAs and human diseases and uncovered functional roles of newly discovered miRNAs.ConclusionsLasso regression was used to find associations between diseases and miRNAs using their gene signature. Defining miRNA gene signature by integrating the downstream effect of miRNAs demonstrated better performance than the miRNA signature alone. Integrating biological networks and multiple data to define miRNA and disease gene signature demonstrated high performance to uncover new functional associations between miRNAs and diseases.     

FMSM: a novel computational model for predicting potential miRNA biomarkers for various human diseases

Background

MicroRNA (miRNA) plays a key role in regulation mechanism of human biological processes, including the development of disease and disorder. It is necessary to identify potential miRNA biomarkers for various human diseases. Computational prediction model is expected to accelerate the process of identification.

Results

Considering the limitations of previously proposed models, we present a novel computational model called FMSM. It infers latent miRNA biomarkers involved in the mechanism of various diseases based on the known miRNA-disease association network, miRNA expression similarity, disease semantic similarity and Gaussian interaction profile kernel similarity. FMSM achieves reliable prediction performance in 5-fold and leave-one-out cross validations with area under ROC curve (AUC) values of 0.9629+/??0.0127 and 0.9433, respectively, which outperforms the state-of-the-art competitors and classical algorithms. In addition, 19 of top 25 predicted miRNAs have been validated to have associations with Colonic Neoplasms in case study.

Conclusions

A factored miRNA similarity based model and miRNA expression similarity substantially contribute to the well-performing prediction. The list of the predicted most latent miRNA biomarkers of various human diseases is publicized. It is anticipated that FMSM could serve as a useful tool guiding the future experimental validation for those promising miRNA biomarker candidates.

     

Potential miRNA-disease association prediction based on kernelized Bayesian matrix factorization

Many biological experimental studies have confirmed that microRNAs (miRNAs) play a significant role in human complex diseases. Exploring miRNA-disease associations could be conducive to understanding disease pathogenesis at the molecular level and developing disease diagnostic biomarkers. However, since conducting traditional experiments is a costly and time-consuming way, plenty of computational models have been proposed to predict miRNA-disease associations. In this study, we presented a neoteric Bayesian model (KBMFMDA) that combines kernel-based nonlinear dimensionality reduction, matrix factorization and binary classification. The main idea of KBMFMDA is to project miRNAs and diseases into a unified subspace and estimate the association network in that subspace. KBMFMDA obtained the AUCs of 0.9132, 0.8708, 0.9008±0.0044 in global and local leave-one-out and five-fold cross validation. Moreover, KBMFMDA was applied to three important human cancers in three different kinds of case studies and most of the top 50 potential disease-related miRNAs were confirmed by many experimental reports.     

Predicting human disease-associated circRNAs based on locality-constrained linear coding

Circular RNAs (circRNAs) are a new kind of endogenous non-coding RNAs, which have been discovered continuously. More and more studies have shown that circRNAs are related to the occurrence and development of human diseases. Identification of circRNAs associated with diseases can contribute to understand the pathogenesis, diagnosis and treatment of diseases. However, experimental methods of circRNA prediction remain expensive and time-consuming. Therefore, it is urgent to propose novel computational methods for the prediction of circRNA-disease associations. In this study, we develop a computational method called LLCDC that integrates the known circRNA-disease associations, circRNA semantic similarity network, disease semantic similarity network, reconstructed circRNA similarity network, and reconstructed disease similarity network to predict circRNAs related to human diseases. Specifically, the reconstructed similarity networks are obtained by using Locality-Constrained Linear Coding (LLC) on the known association matrix, cosine similarities of circRNAs and diseases. Then, the label propagation method is applied to the similarity networks, and four relevant score matrices are respectively obtained. Finally, we use 5-fold cross validation (5-fold CV) to evaluate the performance of LLCDC, and the AUC value of the method is 0.9177, indicating that our method performs better than the other three methods. In addition, case studies on gastric cancer, breast cancer and papillary thyroid carcinoma further verify the reliability of our method in predicting disease-associated circRNAs.     

GCSENet: A GCN,CNN and SENet ensemble model for microRNA-disease association prediction

Recently, an increasing number of studies have demonstrated that miRNAs are involved in human diseases, indicating that miRNAs might be a potential pathogenic factor for various diseases. Therefore, figuring out the relationship between miRNAs and diseases plays a critical role in not only the development of new drugs, but also the formulation of individualized diagnosis and treatment. As the prediction of miRNA-disease association via biological experiments is expensive and time-consuming, computational methods have a positive effect on revealing the association. In this study, a novel prediction model integrating GCN, CNN and Squeeze-and-Excitation Networks (GCSENet) was constructed for the identification of miRNA-disease association. The model first captured features by GCN based on a heterogeneous graph including diseases, genes and miRNAs. Then, considering the different effects of genes on each type of miRNA and disease, as well as the different effects of the miRNA-gene and disease-gene relationships on miRNA-disease association, a feature weight was set and a combination of miRNA-gene and disease-gene associations was added as feature input for the convolution operation in CNN. Furthermore, the squeeze and excitation blocks of SENet were applied to determine the importance of each feature channel and enhance useful features by means of the attention mechanism, thus achieving a satisfactory prediction of miRNA-disease association. The proposed method was compared against other state-of-the-art methods. It achieved an AUROC score of 95.02% and an AUPR score of 95.55% in a 10-fold cross-validation, which led to the finding that the proposed method is superior to these popular methods on most of the performance evaluation indexes.     

MiRANN: a reliable approach for improved classification of precursor microRNA using Artificial Neural Network model

MicroRNA (miRNA) is a special class of short noncoding RNA that serves pivotal function of regulating gene expression. The computational prediction of new miRNA candidates involves various methods such as learning methods and methods using expression data. This article has proposed a reliable model - miRANN which is a supervised machine learning approach. MiRANN used known pre-miRNAs as positive set and a novel negative set from human CDS regions. The number of known miRNAs is now huge and diversified that could cover almost all characteristics of unknown miRNAs which increases the quality of the result (99.9% accuracy, 99.8% sensitivity, 100% specificity) and provides a more reliable prediction. MiRANN performs better than other state-of-the-art approaches and declares to be the most potential tool to predict novel miRNAs. We have also tested our result using a previous negative set. MiRANN, opens new ground using ANN for predicting pre-miRNAs with a promise of better performance.