Multi-task prediction-based graph contrastive learning for inferring the relationship among lncRNAs, miRNAs and diseases.

MOTIVATION: Identifying the relationships among long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and diseases is highly valuable for diagnosing, preventing, treating and prognosing diseases. The development of effective computational prediction methods can reduce experimental costs. While numerous methods have been proposed, they often to treat the prediction of lncRNA-disease associations (LDAs), miRNA-disease associations (MDAs) and lncRNA-miRNA interactions (LMIs) as separate task. Models capable of predicting all three relationships simultaneously remain relatively scarce. Our aim is to perform multi-task predictions, which not only construct a unified framework, but also facilitate mutual complementarity of information among lncRNAs, miRNAs and diseases. RESULTS: In this work, we propose a novel unsupervised embedding method called graph contrastive learning for multi-task prediction (GCLMTP). Our approach aims to predict LDAs, MDAs and LMIs by simultaneously extracting embedding representations of lncRNAs, miRNAs and diseases. To achieve this, we first construct a triple-layer lncRNA-miRNA-disease heterogeneous graph (LMDHG) that integrates the complex relationships between these entities based on their similarities and correlations. Next, we employ an unsupervised embedding model based on graph contrastive learning to extract potential topological feature of lncRNAs, miRNAs and diseases from the LMDHG. The graph contrastive learning leverages graph convolutional network architectures to maximize the mutual information between patch representations and corresponding high-level summaries of the LMDHG. Subsequently, for the three prediction tasks, multiple classifiers are explored to predict LDA, MDA and LMI scores. Comprehensive experiments are conducted on two datasets (from older and newer versions of the database, respectively). The results show that GCLMTP outperforms other state-of-the-art methods for the disease-related lncRNA and miRNA prediction tasks. Additionally, case studies on two datasets further demonstrate the ability of GCLMTP to accurately discover new associations. To ensure reproducibility of this work, we have made the datasets and source code publicly available at https://github.com/sheng-n/GCLMTP.

KISL: knowledge-injected semi-supervised learning for biological co-expression network modules.

The exploration of important biomarkers associated with cancer development is crucial for diagnosing cancer, designing therapeutic interventions, and predicting prognoses. The analysis of gene co-expression provides a systemic perspective on gene networks and can be a valuable tool for mining biomarkers. The main objective of co-expression network analysis is to discover highly synergistic sets of genes, and the most widely used method is weighted gene co-expression network analysis (WGCNA). With the Pearson correlation coefficient, WGCNA measures gene correlation, and uses hierarchical clustering to identify gene modules. The Pearson correlation coefficient reflects only the linear dependence between variables, and the main drawback of hierarchical clustering is that once two objects are clustered together, the process cannot be reversed. Hence, readjusting inappropriate cluster divisions is not possible. Existing co-expression network analysis methods rely on unsupervised methods that do not utilize prior biological knowledge for module delineation. Here we present a method for identification of outstanding modules in a co-expression network using a knowledge-injected semi-supervised learning approach (KISL), which utilizes apriori biological knowledge and a semi-supervised clustering method to address the issue existing in the current GCN-based clustering methods. To measure the linear and non-linear dependence between genes, we introduce a distance correlation due to the complexity of the gene-gene relationship. Eight RNA-seq datasets of cancer samples are used to validate its effectiveness. In all eight datasets, the KISL algorithm outperformed WGCNA when comparing the silhouette coefficient, Calinski-Harabasz index and Davies-Bouldin index evaluation metrics. According to the results, KISL clusters had better cluster evaluation values and better gene module aggregation. Enrichment analysis of the recognition modules demonstrated their effectiveness in discovering modular structures in biological co-expression networks. In addition, as a general method, KISL can be applied to various co-expression network analyses based on similarity metrics. Source codes for the KISL and the related scripts are available online at https://github.com/Mowonhoo/KISL.git.

A Survey of Computational Methods and Databases for lncRNA-MiRNA Interaction Prediction.

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are two prevalent non-coding RNAs in current research. They play critical regulatory roles in the life processes of animals and plants. Studies have shown that lncRNAs can interact with miRNAs to participate in post-transcriptional regulatory processes, mainly involved in regulating cancer development, metastatic progression, and drug resistance. Additionally, these interactions have significant effects on plant growth, development, and responses to biotic and abiotic stresses. Deciphering the potential relationships between lncRNAs and miRNAs may provide new insights into our understanding of the biological functions of lncRNAs and miRNAs, and the pathogenesis of complex diseases. In contrast, gathering information on lncRNA-miRNA interactions (LMIs) through biological experiments is expensive and time-consuming. With the accumulation of multi-omics data, computational models are extremely attractive in systematically exploring potential LMIs. To the best of our knowledge, this is the first comprehensive review of computational methods for identifying LMIs. Specifically, we first summarized the available public databases for predicting animal and plant LMIs. Second, we comprehensively reviewed the computational methods for predicting LMIs and classified them into two categories, including network-based methods and sequence-based methods. Third, we analyzed the standard evaluation methods and metrics used in LMI prediction. Finally, we pointed out some problems in the current study and discuss future research directions. Relevant databases and the latest advances in LMI prediction are summarized in a GitHub repository https://github.com/sheng-n/lncRNA-miRNA-interaction-methods, and we'll keep it updated.

Identification of Cancer Driver Genes by Integrating Multiomics Data with Graph Neural Networks.

Cancer is a heterogeneous disease that is driven by the accumulation of both genetic and nongenetic alterations, so integrating multiomics data and extracting effective information from them is expected to be an effective way to predict cancer driver genes. In this paper, we first generate comprehensive instructive features for each gene from genomic, epigenomic, transcriptomic levels together with protein-protein interaction (PPI)-networks-derived attributes and then propose a novel semisupervised deep graph learning framework GGraphSAGE to predict cancer driver genes according to the impact of the alterations on a biological system. When applied to eight tumor types, experimental results suggest that GGraphSAGE outperforms several state-of-the-art computational methods for driver genes identification. Moreover, it broadens our current understanding of cancer driver genes from multiomics level and identifies driver genes specific to the tumor type rather than pan-cancer. We expect GGraphSAGE to open new avenues in precision medicine and even further predict drivers for other complex diseases.

Predicting miRNA-disease associations based on multi-view information fusion.

MicroRNAs (miRNAs) play an important role in various biological processes and their abnormal expression could lead to the occurrence of diseases. Exploring the potential relationships between miRNAs and diseases can contribute to the diagnosis and treatment of complex diseases. The increasing databases storing miRNA and disease information provide opportunities to develop computational methods for discovering unobserved disease-related miRNAs, but there are still some challenges in how to effectively learn and fuse information from multi-source data. In this study, we propose a multi-view information fusion based method for miRNA-disease association (MDA)prediction, named MVIFMDA. Firstly, multiple heterogeneous networks are constructed by combining the known MDAs and different similarities of miRNAs and diseases based on multi-source information. Secondly, the topology features of miRNAs and diseases are obtained by using the graph convolutional network to each heterogeneous network view, respectively. Moreover, we design the attention strategy at the topology representation level to adaptively fuse representations including different structural information. Meanwhile, we learn the attribute representations of miRNAs and diseases from their similarity attribute views with convolutional neural networks, respectively. Finally, the complicated associations between miRNAs and diseases are reconstructed by applying a bilinear decoder to the combined features, which combine topology and attribute representations. Experimental results on the public dataset demonstrate that our proposed model consistently outperforms baseline methods. The case studies further show the ability of the MVIFMDA model for inferring underlying associations between miRNAs and diseases.

Molecular Subtyping of Cancer Based on Robust Graph Neural Network and Multi-Omics Data Integration.

Accurate molecular subtypes prediction of cancer patients is significant for personalized cancer diagnosis and treatments. Large amount of multi-omics data and the advancement of data-driven methods are expected to facilitate molecular subtyping of cancer. Most existing machine learning-based methods usually classify samples according to single omics data, fail to integrate multi-omics data to learn comprehensive representations of the samples, and ignore that information transfer and aggregation among samples can better represent them and ultimately help in classification. We propose a novel framework named multi-omics graph convolutional network (M-GCN) for molecular subtyping based on robust graph convolutional networks integrating multi-omics data. We first apply the Hilbert-Schmidt independence criterion least absolute shrinkage and selection operator (HSIC Lasso) to select the molecular subtype-related transcriptomic features and then construct a sample-sample similarity graph with low noise by using these features. Next, we take the selected gene expression, single nucleotide variants (SNV), and copy number variation (CNV) data as input and learn the multi-view representations of samples. On this basis, a robust variant of graph convolutional network (GCN) model is finally developed to obtain samples' new representations by aggregating their subgraphs. Experimental results of breast and stomach cancer demonstrate that the classification performance of M-GCN is superior to other existing methods. Moreover, the identified subtype-specific biomarkers are highly consistent with current clinical understanding and promising to assist accurate diagnosis and targeted drug development.

Learning multi-scale heterogenous network topologies and various pairwise attributes for drug-disease association prediction.

MOTIVATION: Identifying new therapeutic effects for the approved drugs is beneficial for effectively reducing the drug development cost and time. Most of the recent computational methods concentrate on exploiting multiple kinds of information about drugs and disease to predict the candidate associations between drugs and diseases. However, the drug and disease nodes have neighboring topologies with multiple scales, and the previous methods did not fully exploit and deeply integrate these topologies. RESULTS: We present a prediction method, multi-scale topology learning for drug-disease (MTRD), to integrate and learn multi-scale neighboring topologies and the attributes of a pair of drug and disease nodes. First, for multiple kinds of drug similarities, multiple drug-disease heterogenous networks are constructed respectively to integrate the similarities and associations related to drugs and diseases. Moreover, each heterogenous network has its specific topology structure, which is helpful for learning the corresponding specific topology representation. We formulate the topology embeddings for each drug node and disease node by random walking on each heterogeneous network, and the embeddings cover the neighboring topologies with different scopes. Because the multi-scale topology embeddings have context relationships, we construct Bi-directional long short-term memory-based module to encode these embeddings and their relationships and learn the neighboring topology representation. We also design the attention mechanisms at feature level and at scale level to obtain the more informative pairwise features and topology embeddings. A module based on multi-layer convolutional networks is constructed to learn the representative attributes of the drug-disease node pair according to their related similarity and association information. Comprehensive experimental results indicate that MTRD achieves the superior performance than several state-of-the-art methods for predicting drug-disease associations. MTRD also retrieves more actual drug-disease associations in the top-ranked candidates of the prediction result. Case studies on five drugs further demonstrate MTRD's ability in discovering the potential candidate diseases for the interested drugs.

Multi-channel graph attention autoencoders for disease-related lncRNAs prediction.

MOTIVATION: Predicting disease-related long non-coding RNAs (lncRNAs) can be used as the biomarkers for disease diagnosis and treatment. The development of effective computational prediction approaches to predict lncRNA-disease associations (LDAs) can provide insights into the pathogenesis of complex human diseases and reduce experimental costs. However, few of the existing methods use microRNA (miRNA) information and consider the complex relationship between inter-graph and intra-graph in complex-graph for assisting prediction. RESULTS: In this paper, the relationships between the same types of nodes and different types of nodes in complex-graph are introduced. We propose a multi-channel graph attention autoencoder model to predict LDAs, called MGATE. First, an lncRNA-miRNA-disease complex-graph is established based on the similarity and correlation among lncRNA, miRNA and diseases to integrate the complex association among them. Secondly, in order to fully extract the comprehensive information of the nodes, we use graph autoencoder networks to learn multiple representations from complex-graph, inter-graph and intra-graph. Thirdly, a graph-level attention mechanism integration module is adopted to adaptively merge the three representations, and a combined training strategy is performed to optimize the whole model to ensure the complementary and consistency among the multi-graph embedding representations. Finally, multiple classifiers are explored, and Random Forest is used to predict the association score between lncRNA and disease. Experimental results on the public dataset show that the area under receiver operating characteristic curve and area under precision-recall curve of MGATE are 0.964 and 0.413, respectively. MGATE performance significantly outperformed seven state-of-the-art methods. Furthermore, the case studies of three cancers further demonstrate the ability of MGATE to identify potential disease-correlated candidate lncRNAs. The source code and supplementary data are available at https://github.com/sheng-n/MGATE. CONTACT: huanglan@jlu.edu.cn, wy6868@jlu.edu.cn.

Autoencoder-based drug-target interaction prediction by preserving the consistency of chemical properties and functions of drugs.

MOTIVATION: Exploring the potential drug-target interactions (DTIs) is a key step in drug discovery and repurposing. In recent years, predicting the probable DTIs through computational methods has gradually become a research hot spot. However, most of the previous studies failed to judiciously take into account the consistency between the chemical properties of drug and its functions. The changes of these relationships may lead to a severely negative effect on the prediction of DTIs. RESULTS: We propose an autoencoder-based method, AEFS, under spatial consistency constraints to predict DTIs. A heterogeneous network is established to integrate the information of drugs, proteins and diseases. The original drug features are projected to an embedding (protein) space by a multi-layer encoder, and further projected into label (disease) space by a decoder. In this process, the clinical information of drugs is introduced to assist the DTI prediction. By maintaining the distribution of drug correlation in the original feature, embedding and label space, AEFS keeps the consistency between chemical properties and functions of drugs. Experimental comparisons indicate that AEFS is more robust for imbalanced data and of significantly superior performance in DTI prediction. Case studies further confirm its ability to mine the latent DTIs. AVAILABILITY AND IMPLEMENTATION: The code of AEFS is available at https://github.com/JackieSun818/AEFS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Dual Convolutional Neural Networks With Attention Mechanisms Based Method for Predicting Disease-Related lncRNA Genes.

A lot of studies indicated that aberrant expression of long non-coding RNA genes (lncRNAs) is closely related to human diseases. Identifying disease-related lncRNAs (disease lncRNAs) is critical for understanding the pathogenesis and etiology of diseases. Most of the previous methods focus on prioritizing the potential disease lncRNAs based on shallow learning methods. The methods fail to extract the deep and complex feature representations of lncRNA-disease associations. Furthermore, nearly all the methods ignore the discriminative contributions of the similarity, association, and interaction relationships among lncRNAs, disease, and miRNAs for the association prediction. A dual convolutional neural networks with attention mechanisms based method is presented for predicting the candidate disease lncRNAs, and it is referred to as CNNLDA. CNNLDA deeply integrates the multiple source data like the lncRNA similarities, the disease similarities, the lncRNA-disease associations, the lncRNA-miRNA interactions, and the miRNA-disease associations. The diverse biological premises about lncRNAs, miRNAs, and diseases are combined to construct the feature matrix from the biological perspectives. A novel framework based on the dual convolutional neural networks is developed to learn the global and attention representations of the lncRNA-disease associations. The left part of the framework exploits the various information contained by the feature matrix to learn the global representation of lncRNA-disease associations. The different connection relationships among the lncRNA, miRNA, and disease nodes and the different features of these nodes have the discriminative contributions for the association prediction. Hence we present the attention mechanisms from the relationship level and the feature level respectively, and the right part of the framework learns the attention representation of associations. The experimental results based on the cross validation indicate that CNNLDA yields superior performance than several state-of-the-art methods. Case studies on stomach cancer, lung cancer, and colon cancer further demonstrate CNNLDA's ability to discover the potential disease lncRNAs.

Drug repositioning through integration of prior knowledge and projections of drugs and diseases.

MOTIVATION: Identifying and developing novel therapeutic effects for existing drugs contributes to reduction of drug development costs. Most of the previous methods focus on integration of the heterogeneous data of drugs and diseases from multiple sources for predicting the candidate drug-disease associations. However, they fail to take the prior knowledge of drugs and diseases and their sparse characteristic into account. It is essential to develop a method that exploits the more useful information to predict the reliable candidate associations. RESULTS: We present a method based on non-negative matrix factorization, DisDrugPred, to predict the drug-related candidate disease indications. A new type of drug similarity is firstly calculated based on their associated diseases. DisDrugPred completely integrates two types of disease similarities, the associations between drugs and diseases, and the various similarities between drugs from different levels including the chemical structures of drugs, the target proteins of drugs, the diseases associated with drugs and the side effects of drugs. The prior knowledge of drugs and diseases and the sparse characteristic of drug-disease associations provide a deep biological perspective for capturing the relationships between drugs and diseases. Simultaneously, the possibility that a drug is associated with a disease is also dependant on their projections in the low-dimension feature space. Therefore, DisDrugPred deeply integrates the diverse prior knowledge, the sparse characteristic of associations and the projections of drugs and diseases. DisDrugPred achieves superior prediction performance than several state-of-the-art methods for drug-disease association prediction. During the validation process, DisDrugPred also can retrieve more actual drug-disease associations in the top part of prediction result which often attracts more attention from the biologists. Moreover, case studies on five drugs further confirm DisDrugPred's ability to discover potential candidate disease indications for drugs. AVAILABILITY AND IMPLEMENTATION: The fourth type of drug similarity and the predicted candidates for all the drugs are available at https://github.com/pingxuan-hlju/DisDrugPred. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.