Accurate prediction of patient drug response is critical for precision cancer medicine but remains constrained by limited clinical data. While in vitro cell line data offer a scalable alternative, effective cross-domain transfer remains challenging. Many existing methods tend to overlook heterogeneous domain shifts across biological contexts, underrepresent the intrinsic differences between cell lines and patient tissues, and insufficiently capture high-order gene-drug interactions. To address these challenges, we propose MACB-DRP, a hierarchical transfer learning framework comprising three complementary stages that progressively coordinate adaptation across tissue, drug, and sample levels while enabling representation separation. The framework begins with tissue-aware domain adaptation, leveraging cancer-type classification and unsupervised alignment to preserve biologically meaningful structure across domains. It then incorporates drug-conditioned adversarial transfer for distribution alignment, coupled with bilinear fusion to model nonlinear and high-order gene-drug interactions. Finally, contrastive anchoring with feature-matched pairs enables fine-grained sample-level alignment, while feature-mismatched negatives preserve irreducible biological disparities. Experimental evaluation demonstrates that MACB-DRP achieves comprehensive predictive performance for patient drug responses, with robust results across multiple cancer types and nine drugs, and further reveals hierarchical structure across drugs and tissues in the visualization. These findings highlight the potential of biologically guided domain adaptation for improving translational pharmacogenomics.

MOTIVATION: Accurately predicting anticancer drug response is a central challenge in precision oncology. Existing computational methods, although valuable, often depend on pairwise molecular descriptors or limited graph-based encodings that cannot fully capture the complexity of molecular structures or their interactions with cellular states. These constraints hinder their robustness and generalization across diverse drugs and biological contexts, underscoring the need for more expressive frameworks. RESULTS: To address this gap, we propose MolDr, a topological deep learning framework that represents molecules as multiscale simplicial complexes and propagates information across higher-order structures. By integrating these molecular representations with cellular profiles, MolDr unifies chemical topology and biological context within a single predictive model. Comprehensive experiments show that MolDr consistently outperforms or matches state-of-the-art baselines across multiple benchmarks. It achieves stronger accuracy and robustness on continuous drug response tasks, while also generalizing effectively to discrete classification settings. Moreover, sensitivity analysis confirms the benefit of incorporating multiple topological scales, further supporting the importance of higher-order representations. Together, these results demonstrate that MolDr delivers reliable performance across heterogeneous pharmacogenomic scenarios and highlight the promise of topological modeling for advancing drug response prediction. AVAILABILITY: Source code freely available at https://github.com/CS-BIO/MolDr.

Recent advances in spatial molecular imaging technologies have enabled gene expression profiling alongside high-resolution imaging, providing unprecedented opportunities to resolve molecular heterogeneity at subcellular resolution. However, these technologies fail to fully capture cellular characteristics due to the limited number of genes they can detect, which hinder downstream analysis. Spatial imaging data provide high-resolution and fine-grained morphology information, developing computational methods that effectively integrate image features with transcriptomic profiles is crucial for enabling comprehensive subcellular data analysis. In this study, we present SIMMT, an image-enhanced multi-modal contrastive transformer framework for identifying spatial domains and enhancing subcellular data. In the framework, we design a dual transformer architecture to learn multi-modal representations for cells by modeling transcriptomics and morphological images respectively. To fully capture modality interactions within spatial contexts, we introduce a contrastive learning module that enhances cell representation by aligning tissue morphology and gene expression at the cell level. We tested SIMMT on subcellular spatial transcriptomics datasets from human lung cancer tissue, mouse brain tissue, human colorectal cancer tissue, and human ovarian cancer tissue. The results demonstrated that SIMMT consistently outperformed state-of-the-art methods in spatial clustering and gene expression pattern analysis. Our method also effectively demonstrated its ability to identify tumor spatial heterogeneity and uncover potential gene biomarkers in the human bronchiolar adenoma (BA) dataset.

Spatial transcriptomics technologies enable the generation of gene expression profiles while retaining spatial coordinates. Identifying spatial domains and spatially variable genes (SVGs) are crucial tasks in spatial transcriptomics, offering valuable insights into biological functions. However, a deep learning framework that integrates SVGs detection with spatial domain identification is still lacking. In this study, we propose a multi-task ensemble analysis framework for spatial transcriptomics, named SpaMCI-DL, which adopts multi-constrained interpretable deep learning to jointly perform SVGs detection and spatial domain identification. SpaMCI-DL first employs a graph convolutional autoencoder to identify spatial domains by incorporating binary and graph structural constraints. Subsequently, based on the learned spatial domains, SpaMCI-DL utilizes a gradients-based method with multi-scale constraints to detect SVGs, enhancing the interpretability and biological relevance of the results. Comparative evaluations against state-of-the-art methods on five spatial transcriptomics datasets, spanning diverse species and tissues, demonstrate that SpaMCI-DL achieves superior performance in both spatial domain identification and SVGs detection. The code are available at https://github.com/liangxiao-cs/SpaMCI-DL.

Drug perturbation prediction aims to accelerate drug target discovery by simulating transcriptional responses induced by chemical interventions. Although deep learning methods have made some progress in this field, they often adopt coarse-grained linear integration strategies (e.g., summation or concatenation) to integrate a single, holistic representation of the gene expression profile with a drug representation, which makes it difficult to capture the subtle perturbations. Furthermore, these methods are predominantly composed of Multi-Layer Perceptrons (MLPs), which cannot dynamically focus on key gene features and tend to overfit on the majority of genes that remain unchanged. To address these challenges, we introduce DGCAP, a novel framework specifically designed for the finegrained modeling relationships between drug structures and gene perturbation responses. Crucially, a cross-attention mechanism dynamically identifies and weights the associations between specific drug structures and individual genes, which enables DGCAP to effectively capture subtle perturbation patterns and mitigate overfitting on unchanged genes. Extensive evaluations across diverse datasets indicate that DGCAP outperforms state-of-the-art methods.

Recent advances in spatial transcriptomics have enabled subcellular-resolution profiling of gene expression, offering unprecedented opportunities to investigate intracellular architecture and local microenvironmental interactions. Graph neural networks (GNNs) have shown great promise in modeling spatial transcriptomics data. However, existing GNN-based methods primarily focus on low-frequency signals, overlooking high-frequency signals critical for resolving transcriptional differences across subcellular compartments and cell boundaries. This limits their ability to characterize fine-grained structural and functional heterogeneity within tissues, hindering accurate spatial domain identification. In this study, we propose HiFi-ST, a High-Frequency-Aware Graph Integration framework for subcellular spatial transcriptomics. HiFi-ST employs a high-pass filter to extract high-frequency transcriptional differences, which are then integrated with spatial contexts through a transformer-based architecture. A contrastive learning module is designed to enhance cell representation by aligning spatial organization with transcriptional heterogeneity. Comprehensive experiments on subcellular datasets demonstrated that HiFi-ST consistently outperformed six state-of-the-art methods in spatial clustering, gene expression enhancement, and niche identification.

Systematically investigating interactions among molecules of the same type across different contexts is crucial for unraveling disease mechanisms and developing potential therapeutic strategies. The "A-A-B" triplet paradigm provides a principled approach to model such context-specific interactions, and leveraging third-order tensor to capture such type ternary relationships is an efficient strategy. However, effectively modeling both multilinear and nonlinear characteristics to accurately identify such triplets using tensor-based methods remains a challenge. In this paper, we propose a novel Convolutional Neural Tensor Completion (ConvNTC) framework that collaboratively learns the multilinear and nonlinear representations to model triplet-based network interactions. ConvNTC consists of a multilinear module and a nonlinear module. The former is a tensor decomposition approach that integrates multiple constraints to learn the tensor factor embeddings. The latter contains three components: an embedding generator to produce position-specific index embeddings for each tensor entry in addition to the factor embeddings, a convolutional encoder to perform nonlinear feature mapping while preserving the tensor's rank-one property, and a Kolmogorov-Arnold Network (KAN) based predictor to effectively capture high-dimensional relationships aligned with the intrinsic structure of real-world data. We evaluate ConvNTC on two types triplet datasets of the "A-A-B" type: miRNA-miRNA-disease and drug-drug-cell. Comprehensive experiments against 11 state-of-the-art methods demonstrate the superiority of ConvNTC in terms of triplet prediction. ConvNTC reveals promising prognostic values of the miRNA-miRNA interactions on breast cancer and detects synergistic drug combinations in cancer cell lines.

MOTIVATION: Spatial transcriptomics (ST) technologies have revolutionized our ability to map gene expression patterns within native tissue context, providing unprecedented insights into tissue architecture and cellular heterogeneity. However, accurately deconvolving cell-type compositions from ST spots remains challenging due to the sparse and averaged nature of ST data, which is essential for accurately depicting tissue architecture. While numerous computational methods have been developed for cell-type deconvolution and spatial distribution reconstruction, most fail to capture tissue complexity at the single-cell level, thereby limiting their applicability in practical scenarios. RESULTS: To this end, we propose a novel cycle-consistent generative adversarial network named STCGAN for cellular deconvolution in spatial transcriptomic. STCGAN first employs a cycle-consistent generative adversarial network (CGAN) to pre-train on ST data, ensuring that both the mapping from ST data to latent space and its reverse mapping are consistent, capturing complex spatial gene expression patterns and learning robust latent representations. Based on the learned representation, STCGAN then optimizes a trainable cell-to-spot mapping matrix to integrate scRNA-seq data with ST data, accurately estimating cellular composition within each capture spot and effectively reconstructing the spatial distribution of cells across the tissue. To further enhance deconvolution accuracy, we incorporate spatial-aware regularization that ensures accurate cellular distribution reconstruction within the spatial context. Benchmarking against seven state-of-the-art methods on five simulated and real datasets from various tissues, STCGAN consistently delivers superior cell-type deconvolution performance. AVAILABILITY: The code of STCGAN can be downloaded from https://github.com/cs-wangbo/STCGAN and all the mentioned datasets are available on Zenodo at https://zenodo.org/doi/10.5281/zenodo.10799113.

Geometric deep learning (GDL) models have demonstrated a great potential for the analysis of non-Euclidian data. They are developed to incorporate the geometric and topological information of non-Euclidian data into the end-to-end deep learning architectures. Motivated by the recent success of discrete Ricci curvature in graph neural network (GNNs), we propose TorGNN, an analytic Torsion enhanced Graph Neural Network model. The essential idea is to characterize graph local structures with an analytic torsion based weight formula. Mathematically, analytic torsion is a topological invariant that can distinguish spaces which are homotopy equivalent but not homeomorphic. In our TorGNN, for each edge, a corresponding local simplicial complex is identified, then the analytic torsion (for this local simplicial complex) is calculated, and further used as a weight (for this edge) in message-passing process. Our TorGNN model is validated on link prediction tasks from sixteen different types of networks and node classification tasks from four types of networks. It has been found that our TorGNN can achieve superior performance on both tasks, and outperform various state-of-the-art models. This demonstrates that analytic torsion is a highly efficient topological invariant in the characterization of graph structures and can significantly boost the performance of GNNs.

Cell type annotation is crucial in single-cell RNA sequencing data analysis because it enables significant biological discoveries and deepens our understanding of tissue biology. Given the high-dimensional and highly sparse nature of single-cell RNA sequencing data, most existing annotation tools focus on highly variable genes to reduce dimensionality and computational load. However, this approach inevitably results in information loss, potentially weakening the model's generalization performance and adaptability to novel datasets. To mitigate this issue, we developed scTrans, a single cell Transformer-based model, which employs sparse attention to utilize all non-zero genes, thereby effectively reducing the input data dimensionality while minimizing information loss. We validated the speed and accuracy of scTrans by performing cell type annotation on 31 different tissues within the Mouse Cell Atlas. Remarkably, even with datasets nearing a million cells, scTrans efficiently perform cell type annotation in limited computational resources. Furthermore, scTrans demonstrates strong generalization capabilities, accurately annotating cells in novel datasets and generating high-quality latent representations, which are essential for precise clustering and trajectory analysis.

The advent of single-cell RNA sequencing (scRNA-seq) has offering unprecedented insights at the single-cell level. This groundbreaking technology has opened new pathways for understanding cellular diversity and revealing novel insights into disease mechanisms. However, the analysis of scRNA-seq data is challenging, primarily due to dropout events caused by technical noise. Developing effective imputation methods is crucial for the reliable and informative analysis of scRNA-seq data. While deep learning-based approaches have been proposed for scRNA-seq data imputation, they often fall short of optimal performance, especially in identifying rare cell types. Here we propose a novel self-supervised deep learning model named scGANCL for scRNA-seq data imputation. scGANCL combines bidirectional generative adversarial network (BiGAN) with contrastive learning (CL) to enhance imputation performance. To fully exploit gene expression profiles, a contrastive learning module is introduced to enhance the representation learning of cells by minimizing the discrepancy between the distributions of real and generated data. Comprehensive experiments have been conducted on ten simulated and seven real datasets to validate scGANCL's effectiveness. The results demonstrated scGANCL consistently outperformed seven state-of-the-art methods across various downstream tasks. Ablation studies further validated the contribution of each component to the overall performance of the model.

Biological research on single cells has witnessed remarkable progress in recent years, with downstream analyses playing a crucial role in uncovering cellular functions and mechanisms. Traditional single-cell analyses, which predominantly rely on single-omics data such as single-cell RNA sequencing, are inherently limited. These methods can only capture one aspect of cellular information, overlooking the complex interplay between different molecular layers, and thus are prone to introducing biases in results. The advent of single-cell multi-omics sequencing technologies has revolutionized this landscape. By enabling the integration of diverse molecular profiles, including transcriptomics, epigenomics, and proteomics, these technologies offer a more holistic view of cellular functions. However, existing integration methods often lack the ability to handle the complexity and heterogeneity of multi-omics data, limiting their application in in-depth single-cell studies. In this study, we propose an analysis method based on single-cell multi-omics data integration and dropout pattern (scMID). Specifically, scMID utilizes omics-independent deep autoencoders for the alignment of multi-omics data, employs GCN algorithm for data integration, and calculates the gene importance by combining the gene similarity obtained from the binarized dropout pattern. Meanwhile, scMID proposes a dual-strategy for feature gene screening, aiming to identify genes with high biological significance that best match the structural characteristics of reference data. Experimental results demonstrate that scMID significantly improves the accuracy of single-cell clustering in downstream analyses, breaking through the limitations of traditional feature selection methods and providing a superior analytical framework for decoding complex biological information.

Identifying synergistic drug combinations is a critical but difficult challenge in cancer treatment, owing to the sheer complexity and enormous number of possible drug combinations. However, most existing computational methods rely on a single data perspective and often overlooking the complexity of interactions between different biological entities. Furthermore, they fail to fully integrate the intrinsic properties of drugs and cell lines with the broader biological relationships that play a crucial role in drug synergy. To address these challenges, we propose a novel framework called LGSyn that integrates two types of information: local features, including molecular fingerprints, descriptors, and gene expression profiles, as well as global features that encompass broader biological interactions, including drug-protein, protein-cell line, protein-protein, and cell line-tissue interactions. By combining these two types of features, LGSyn leverages the full spectrum of biological knowledge to predict drug synergy. In LGSyn, we developed three fusion strategies to effectively integrate local and global information and identify the most suitable strategy. The resulting fused feature vectors are then fed into a deep neural network for training and synergy prediction. Experimental results demonstrate that the proposed method outperforms current state-of-the-art models, achieving superior accuracy and stability in drug synergy prediction.

MicroRNAs (miRNAs) mediates gene expression regulation by targeting specific messenger RNAs (mRNAs) in the cytoplasm. They can function as both tumor suppressors and oncogenes depending on the specific miRNA and its target genes. Detecting miRNA-target interactions (MTIs) is critical for unraveling the complex mechanisms of gene regulation and promising towards RNA therapy for cancer. There is currently a lack of MTIs prediction methods that simultaneously perform feature learning from heterogeneous gene regulatory network (GRN) and genomic sequences. To improve the prediction performance of MTIs, we present a novel transformer-based multi-view feature learning method – MiRGraph, which consists of two main modules for learning the sequence-based and GRN-based feature embedding. For the former, we utilize the mature miRNA sequences and the complete 3'UTR sequence of the target mRNAs to encode sequence features using a hybrid transformer and convolutional neural network (CNN) (TransCNN) architecture. For the latter, we utilize a heterogeneous graph transformer (HGT) module to extract the relational and structural information from the GRN consisting of miRNA-miRNA, gene-gene and miRNA-target interactions. The TransCNN and HGT modules can be learned end-to-end to predict experimentally validated MTIs from MiRTarBase. MiRGraph outperforms existing methods in not only recapitulating the true MTIs but also in predicting strength of the MTIs based on the in-vitro measurements of miRNA transfections. In a case study on breast cancer, we identified plausible target genes of an oncomir.

Recent advances in spatial omics technologies have allowed various omics data to be obtained from a single tissue section. To fully explore the relationships among these different types of omics data, it is urgent to develop more effective methods for spatial multi-omics data integration. In this work, we propose a novel Multi-level Graph Contrastive Learning framework, named SMMGCL, to simultaneously mine complementary information at both spot and graph levels for integrating Spatial Multi-omics data. Specifically, to adaptively fuse multi-omics modalities, we first design a multi-modality autoencoder that integrates spatial locations with spot omic expressions to extract modality-specific embeddings. These embeddings are then fused into a consensus representation using an attention mechanism to capture spot-level cross-omics representations. Next, to explore the complex inter-omic structural information, we connect corresponding spots across different omics adjacency graphs into a heterogeneous graph. We then employ a graph convolutional network (GCN) to extract spatial correlations across the omics, learning a graph-level cross-omics global representation. Finally, SMMGCL aligns feature similarity matrixes between spot-level and graph-level representations with their pseudo-label similarity matrix, ensuring multi-level clustering consistency and leading to more accurate spatial multi-omics integration. Experimental results on simulated and real datasets from across tissues show that SMMGCL consistently outperforms other state-of-the-art methods in spatial multi-omics integration performance. The code for SMMGCL is available for download from the GitHub repository at https://github.com/cs-wangbo/SMMGCL.

The functional study of proteins is a critical task in modern biology, playing a pivotal role in understanding the mechanisms of pathogenesis, developing new drugs, and discovering novel drug targets. However, existing computational models for subcellular localization face significant challenges, such as reliance on known Gene Ontology (GO) annotation databases or overlooking the relationship between GO annotations and subcellular localization. To address these issues, we propose DeepMTC, an end-to-end deep learning-based multi-task collaborative training model. DeepMTC integrates the interrelationship between subcellular localization and the functional annotation of proteins, leveraging multi-task collaborative training to eliminate dependence on known GO databases. This strategy gives DeepMTC a distinct advantage in predicting newly discovered proteins without prior functional annotations. First, DeepMTC leverages pre-trained language model with high accuracy to obtain the 3D structure and sequence features of proteins. Additionally, it employs a graph transformer module to encode protein sequence features, addressing the problem of long-range dependencies in graph neural networks. Finally, DeepMTC uses a functional cross-attention mechanism to efficiently combine upstream learned functional features to perform the subcellular localization task. The experimental results demonstrate that DeepMTC outperforms state-of-the-art models in both protein function prediction and subcellular localization. Moreover, interpretability experiments revealed that DeepMTC can accurately identify the key residues and functional domains of proteins, confirming its superior performance. The code and dataset of DeepMTC are freely available at https://github.com/ghli16/DeepMTC.

Spatial transcriptomics technologies enable the generation of gene expression profiles while preserving spatial context, providing the potential for in-depth understanding of spatial-specific tissue heterogeneity. Leveraging gene and spatial data effectively is fundamental to accurately identifying spatial domains in spatial transcriptomics analysis. However, many existing methods have not yet fully exploited the local neighborhood details within spatial information. To address this issue, we introduce SpaGIC, a novel graph-based deep learning framework integrating graph convolutional networks and self-supervised contrastive learning techniques. SpaGIC learns meaningful latent embeddings of spots by maximizing both edge-wise and local neighborhood-wise mutual information of graph structures, as well as minimizing the embedding distance between spatially adjacent spots. We evaluated SpaGIC on seven spatial transcriptomics datasets across various technology platforms. The experimental results demonstrated that SpaGIC consistently outperformed existing state-of-the-art methods in several tasks, such as spatial domain identification, data denoising, visualization, and trajectory inference. Additionally, SpaGIC is capable of performing joint analyses of multiple slices, further underscoring its versatility and effectiveness in spatial transcriptomics research.

MOTIVATION: Recent advances in spatial transcriptomics technologies have provided multi-modality data integrating gene expression, spatial context, and histological images. Accurately identifying spatial domains and spatially variable genes is crucial for understanding tissue structures and biological functions. However, effectively combining multi-modality data to identify spatial domains and determining SVGs closely related to these spatial domains remains a challenge. RESULTS: In this study, we propose spatial transcriptomics multi-modality and multi-granularity collaborative learning (spaMMCL). For detecting spatial domains, spaMMCL mitigates the adverse effects of modality bias by masking portions of gene expression data, integrates gene and image features using a shared graph convolutional network, and employs graph self-supervised learning to deal with noise from feature fusion. Simultaneously, based on the identified spatial domains, spaMMCL integrates various strategies to detect potential SVGs at different granularities, enhancing their reliability and biological significance. Experimental results demonstrate that spaMMCL substantially improves the identification of spatial domains and SVGs. AVAILABILITY AND IMPLEMENTATION: The code and data of spaMMCL are available on Github: Https://github.com/liangxiao-cs/spaMMCL.

BACKGROUND: Conducting traditional wet experiments to guide drug development is an expensive, time-consuming and risky process. Analyzing drug function and repositioning plays a key role in identifying new therapeutic potential of approved drugs and discovering therapeutic approaches for untreated diseases. Exploring drug-disease associations has far-reaching implications for identifying disease pathogenesis and treatment. However, reliable detection of drug-disease relationships via traditional methods is costly and slow. Therefore, investigations into computational methods for predicting drug-disease associations are currently needed. RESULTS: This paper presents a novel drug-disease association prediction method, RAFGAE. First, RAFGAE integrates known associations between diseases and drugs into a bipartite network. Second, RAFGAE designs the Re_GAT framework, which includes multilayer graph attention networks (GATs) and two residual networks. The multilayer GATs are utilized for learning the node embeddings, which is achieved by aggregating information from multihop neighbors. The two residual networks are used to alleviate the deep network oversmoothing problem, and an attention mechanism is introduced to combine the node embeddings from different attention layers. Third, two graph autoencoders (GAEs) with collaborative training are constructed to simulate label propagation to predict potential associations. On this basis, free multiscale adversarial training (FMAT) is introduced. FMAT enhances node feature quality through small gradient adversarial perturbation iterations, improving the prediction performance. Finally, tenfold cross-validations on two benchmark datasets show that RAFGAE outperforms current methods. In addition, case studies have confirmed that RAFGAE can detect novel drug-disease associations. CONCLUSIONS: The comprehensive experimental results validate the utility and accuracy of RAFGAE. We believe that this method may serve as an excellent predictor for identifying unobserved disease-drug associations.

Single-cell RNA sequencing (scRNA-seq) technology is utilized to analyze cellular heterogeneity, perform cellular-level biological research and derive novel insights from complex cellular systems. However, the raw scRNA-seq data is not directly suitable for downstream task analysis due to its high variability, sparsity and dimensionality. Therefore, in this study, we propose a new self-supervised framework based on siamese representation learning, named scSRL which can fully explore the intrinsic properties of cells by maximizing the similarity between positive pairs. These positive pairs are constructed by multiple data augmentation operations to further increase data diversity and better learn latent representation. Moreover, our method employs a gradient stopping strategy to mitigate collapsing in the siamese network. It is worth noting that the scSRL focuses on aggregating cells with similar functions without introducing negative samples, which can avoid additional computational cost. Finally, We evaluated scSRL on 10 real datasets for downstream tasks such as clustering, classification and visualization, and it consistently exhibited outstanding performance in all these fundamental tasks. Meanwhile, we did pseudotime inference experiments in two embryonic development datasets, and the scSRL model can accurately reconstruct cell trajectory and describe cell developmental process. scSRL is currently an open-source method, available at https://github.com/zysun17/scSRL.

MOTIVATION: Recent advances in spatial transcriptomics technologies have enabled gene expression profiles while preserving spatial context. Accurately identifying spatial domains is crucial for downstream analysis and it requires the effective integration of gene expression profiles and spatial information. While increasingly computational methods have been developed for spatial domain detection, most of them cannot adaptively learn the complex relationship between gene expression and spatial information, leading to sub-optimal performance. RESULTS: To overcome these challenges, we propose a novel deep learning method named Spatial-MGCN for identifying spatial domains, which is a Multi-view Graph Convolutional Network (GCN) with attention mechanism. We first construct two neighbor graphs using gene expression profiles and spatial information, respectively. Then, a multi-view GCN encoder is designed to extract unique embeddings from both the feature and spatial graphs, as well as their shared embeddings by combining both graphs. Finally, a zero-inflated negative binomial decoder is used to reconstruct the original expression matrix by capturing the global probability distribution of gene expression profiles. Moreover, Spatial-MGCN incorporates a spatial regularization constraint into the features learning to preserve spatial neighbor information in an end-to-end manner. The experimental results show that Spatial-MGCN outperforms state-of-the-art methods consistently in several tasks, including spatial clustering and trajectory inference.

MOTIVATION: Single-cell RNA-sequencing (scRNA-seq) is widely used to reveal cellular heterogeneity, complex disease mechanisms and cell differentiation processes. Due to high sparsity and complex gene expression patterns, scRNA-seq data present a large number of dropout events, affecting downstream tasks such as cell clustering and pseudo-time analysis. Restoring the expression levels of genes is essential for reducing technical noise and facilitating downstream analysis. However, existing scRNA-seq data imputation methods ignore the topological structure information of scRNA-seq data and cannot comprehensively utilize the relationships between cells. RESULTS: Here, we propose a single-cell Graph Contrastive Learning method for scRNA-seq data imputation, named scGCL, which integrates graph contrastive learning and Zero-inflated Negative Binomial (ZINB) distribution to estimate dropout values. scGCL summarizes global and local semantic information through contrastive learning and selects positive samples to enhance the representation of target nodes. To capture the global probability distribution, scGCL introduces an autoencoder based on the ZINB distribution, which reconstructs the scRNA-seq data based on the prior distribution. Through extensive experiments, we verify that scGCL outperforms existing state-of-the-art imputation methods in clustering performance and gene imputation on 14 scRNA-seq datasets. Further, we find that scGCL can enhance the expression patterns of specific genes in Alzheimer's disease datasets. AVAILABILITY AND IMPLEMENTATION: The code and data of scGCL are available on Github: https://github.com/zehaoxiong123/scGCL. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Clustering cells into subgroups plays a critical role in single cell-based analyses, which facilitates to reveal cell heterogeneity and diversity. Due to the ever-increasing scRNA-seq data and low RNA capture rate, it has become challenging to cluster high-dimensional and sparse scRNA-seq data. In this study, we propose a single-cell Multi-Constraint deep soft K-means Clustering(scMCKC) framework. Based on zero-inflated negative binomial (ZINB) model-based autoencoder, scMCKC constructs a novel cell-level compactness constraint by considering association between similar cell, to emphasize the compactness between clusters. Besides, scMCKC utilizes pairwise constraint encoded by prior information to guide clustering. Meanwhile, a weighted soft K-means algorithm is leveraged to determine the cell populations, which assigns the label based on affinity between data and clustering center. Experiments on eleven scRNA-seq datasets demonstrate that scMCKC is superior to the state-of-the-art methods and notably improves cluster performance. Moreover, we validate the robustness on human kidney dataset, which demonstrates that scMCKC exhibits comprehensively excellent performance on clustering analysis. The ablation study on eleven datasets proves that the novel cell-level compactness constraint is conductive to the clustering results.

single-cell RNA-sequencing (scRNA-seq) technology can reveal cellular heterogeneity with high throughput and resolution, facilitating the profiling of single-cell transcriptomes. However, due to some experimental factors, a large number of missing values are generated in scRNA-seq data, which are called dropout events, and this phenomenon affects the downstream analysis. Imputation is an effective denoising method, but existing imputation methods still face a huge challenge: lack of interpretability. In this study, we propose single-cell Self-Attention Generative Adversarial Networks(scSAGAN), a semi-supervised imputation method for scRNA-seq data. scSAGAN mainly uses Semi-Supervised Learning (SSL) and Probabilistic Latent Semantic Analysis (PLSA), which can not only learn the potential characteristics of different types of cells but explain their imputation behavior. In clustering experiments, scSAGAN exhibits better clustering performance than all baselines on 7 datasets. Next, we interpret the imputation behavior of scSAGAN on datasets such as Alzheimer’s disease and find causative genes associated with the corresponding datasets. scSAGAN is currently an open-source method, available at https://github.com/zehaoxiongl23/scSAGAN.

Circular RNAs (circRNAs) are a category of novelty discovered competing endogenous non-coding RNAs that have been proved to implicate many human complex diseases. A large number of circRNAs have been confirmed to be involved in cancer progression and are expected to become promising biomarkers for tumor diagnosis and targeted therapy. Deciphering the underlying relationships between circRNAs and diseases may provide new insights for us to understand the pathogenesis of complex diseases and further characterize the biological functions of circRNAs. As traditional experimental methods are usually time-consuming and laborious, computational models have made significant progress in systematically exploring potential circRNA-disease associations, which not only creates new opportunities for investigating pathogenic mechanisms at the level of circRNAs, but also helps to significantly improve the efficiency of clinical trials. In this review, we first summarize the functions and characteristics of circRNAs and introduce some representative circRNAs related to tumorigenesis. Then, we mainly investigate the available databases and tools dedicated to circRNA and disease studies. Next, we present a comprehensive review of computational methods for predicting circRNA-disease associations and classify them into five categories, including network propagating-based, path-based, matrix factorization-based, deep learning-based and other machine learning methods. Finally, we further discuss the challenges and future researches in this field.

Increasing biological evidence indicated that microRNAs (miRNAs) play a vital role in exploring the pathogenesis of various human diseases (especially in tumors). Mining disease-related miRNAs is of great significance for the clinical diagnosis and treatment of diseases. Compared with the traditional experimental methods with the significant limitations of high cost, long cycle and small scale, the methods based on computing have the advantages of being cost-effective. However, although the current methods based on computational biology can accurately predict the correlation between miRNAs and disease, they can not predict the detailed association information at a fine level. We propose a knowledge-driven approach to the fine-grained prediction of disease-related miRNAs (KDFGMDA). Different from the previous methods, this method can finely predict the clear associations between miRNA and disease, such as upregulation, downregulation or dysregulation. Specifically, KDFGMDA extracts triple information from massive experimental data and existing datasets to construct a knowledge graph and then trains a depth graph representation learning model based on knowledge graph to complete fine-grained prediction tasks. Experimental results show that KDFGMDA can predict the relationship between miRNA and disease accurately, which is of far-reaching significance for medical clinical research and early diagnosis, prevention and treatment of diseases. Additionally, the results of case studies on three types of cancers, Kaplan-Meier survival analysis and expression difference analysis further provide the effectiveness and feasibility of KDFGMDA to detect potential candidate miRNAs. Availability: Our work can be downloaded from https://github.com/ShengPengYu/KDFGMDA.

MOTIVATION: Graphs or networks are widely utilized to model the interactions between different entities (e.g. proteins, drugs, etc.) for biomedical applications. Predicting potential interactions/links in biomedical networks is important for understanding the pathological mechanisms of various complex human diseases, as well as screening compound targets for drug discovery. Graph neural networks (GNNs) have been utilized for link prediction in various biomedical networks, which rely on the node features extracted from different data sources, e.g. sequence, structure and network data. However, it is challenging to effectively integrate these data sources and automatically extract features for different link prediction tasks. RESULTS: In this article, we propose a novel Pre-Training Graph Neural Networks-based framework named PT-GNN to integrate different data sources for link prediction in biomedical networks. First, we design expressive deep learning methods [e.g. convolutional neural network and graph convolutional network (GCN)] to learn features for individual nodes from sequence and structure data. Second, we further propose a GCN-based encoder to effectively refine the node features by modelling the dependencies among nodes in the network. Third, the node features are pre-trained based on graph reconstruction tasks. The pre-trained features can be used for model initialization in downstream tasks. Extensive experiments have been conducted on two critical link prediction tasks, i.e. synthetic lethality (SL) prediction and drug-target interaction (DTI) prediction. Experimental results demonstrate PT-GNN outperforms the state-of-the-art methods for SL prediction and DTI prediction. In addition, the pre-trained features benefit improving the performance and reduce the training time of existing models. AVAILABILITY AND IMPLEMENTATION: Python codes and dataset are available at: https://github.com/longyahui/PT-GNN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Cell-type annotation plays a crucial role in single-cell RNA-seq (scRNA-seq) data analysis. As more and more well-annotated scRNA-seq reference data are publicly available, automatical label transference algorithms are gaining popularity over manual marker gene-based annotation methods. However, most existing methods fail to unify cell-type annotation with dimensionality reduction and are unable to generate deep latent representation from the perspective of data generation. RESULTS: In this article, we propose scSemiGAN, a single-cell semi-supervised cell-type annotation and dimensionality reduction framework based on a generative adversarial network, to overcome these challenges, modeling scRNA-seq data from the aspect of data generation. Our proposed scSemiGAN is capable of performing deep latent representation learning and cell-type label prediction simultaneously. Through extensive comparison with four state-of-the-art annotation methods on diverse simulated and real scRNA-seq datasets, scSemiGAN achieves competitive or superior performance in multiple downstream tasks including cell-type annotation, latent representation visualization, confounding factor removal and enrichment analysis. AVAILABILITY AND IMPLEMENTATION: The code and data of scSemiGAN are available on GitHub: https://github.com/rafa-nadal/scSemiGAN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: There is a growing body of evidence from biological experiments suggesting that microRNAs (miRNAs) play a significant regulatory role in both diverse cellular activities and pathological processes. Exploring miRNA-disease associations not only can decipher pathogenic mechanisms but also provide treatment solutions for diseases. As it is inefficient to identify undiscovered relationships between diseases and miRNAs using biotechnology, an explosion of computational methods have been advanced. However, the prediction accuracy of existing models is hampered by the sparsity of known association network and single-category feature, which is hard to model the complicated relationships between diseases and miRNAs. RESULTS: In this study, we advance a new computational framework (GATMDA) to discover unknown miRNA-disease associations based on graph attention network with multi-source information, which effectively fuses linear and non-linear features. In our method, the linear features of diseases and miRNAs are constructed by disease-lncRNA correlation profiles and miRNA-lncRNA correlation profiles, respectively. Then, the graph attention network is employed to extract the non-linear features of diseases and miRNAs by aggregating information of each neighbor with different weights. Finally, the random forest algorithm is applied to infer the disease-miRNA correlation pairs through fusing linear and non-linear features of diseases and miRNAs. As a result, GATMDA achieves impressive performance: an average AUC of 0.9566 with five-fold cross validation, which is superior to other previous models. In addition, case studies conducted on breast cancer, colon cancer and lymphoma indicate that 50, 50 and 48 out of the top fifty prioritized candidates are verified by biological experiments. CONCLUSIONS: The extensive experimental results justify the accuracy and utility of GATMDA and we could anticipate that it may regard as a utility tool for identifying unobserved disease-miRNA relationships.

Precise identification of target sites of RNA-binding proteins (RBP) is important to understand their biochemical and cellular functions. A large amount of experimental data is generated by in vivo and in vitro approaches. The binding preferences determined from these platforms share similar patterns but there are discernable differences between these datasets. Computational methods trained on one dataset do not always work well on another dataset. To address this problem which resembles the classic "domain shift" in deep learning, we adopted the adversarial domain adaptation (ADDA) technique and developed a framework (RBP-ADDA) that can extract RBP binding preferences from an integration of in vivo and vitro datasets. Compared with conventional methods, ADDA has the advantage of working with two input datasets, as it trains the initial neural network for each dataset individually, projects the two datasets onto a feature space, and uses an adversarial framework to derive an optimal network that achieves an optimal discriminative predictive power. In the first step, for each RBP, we include only the in vitro data to pre-train a source network and a task predictor. Next, for the same RBP, we initiate the target network by using the source network and use adversarial domain adaptation to update the target network using both in vitro and in vivo data. These two steps help leverage the in vitro data to improve the prediction on in vivo data, which is typically challenging with a lower signal-to-noise ratio. Finally, to further take the advantage of the fused source and target data, we fine-tune the task predictor using both data. We showed that RBP-ADDA achieved better performance in modeling in vivo RBP binding data than other existing methods as judged by Pearson correlations. It also improved predictive performance on in vitro datasets. We further applied augmentation operations on RBPs with less in vivo data to expand the input data and showed that it can improve prediction performances. Lastly, we explored the predictive interpretability of RBP-ADDA, where we quantified the contribution of the input features by Integrated Gradients and identified nucleotide positions that are important for RBP recognition.

MicroRNAs (miRNAs) are consistently capable of regulating gene expression synergistically in a combination mode and play a key role in various biological processes associated with the initiation and development of human diseases, which indicate that comprehending the synergistic molecular mechanism of miRNAs may facilitate understanding the pathogenesis of diseases or even overcome it. However, most existing computational methods had an incomprehensive acknowledge of the miRNA synergistic effect on the pathogenesis of complex diseases, or were hard to be extended to a large-scale prediction task of miRNA synergistic combinations for different diseases. In this article, we propose a novel tensor completion framework integrating multi-view miRNAs and diseases information, called miRCom, for the discovery of potential disease-associated miRNA-miRNA pairs. We first construct an incomplete three-order association tensor and several types of similarity matrices based on existing biological knowledge. Then, we formulate an objective function via performing the factorizations of coupled tensor and matrices simultaneously. Finally, we build an optimization schema by adopting the ADMM algorithm. After that, we obtain the prediction of miRNA-miRNA pairs for different diseases from the full tensor. The contrastive experimental results with other approaches verified that miRCom effectively identify the potential disease-related miRNA-miRNA pairs. Moreover, case study results further illustrated that miRNA-miRNA pairs have more biologically significance and prognostic value than single miRNAs.

Dysfunction of miRNAs has an important relationship with diseases by impacting their target genes. Identifying disease-related miRNAs is of great significance to prevent and treat diseases. Integrating information of genes related miRNAs and/or diseases in calculational methods for miRNA-disease association studies is meaningful because of the complexity of biological mechanisms. Therefore, in this study, we propose a novel method based on tensor decomposition, termed TDMDA, to integrate multi-type data for identifying pathogenic miRNAs. First, we construct a three-order association tensor to express the associations of miRNA-disease pairs, the associations of miRNA-gene pairs, and the associations of gene-disease pairs simultaneously. Then, a tensor decomposition-based method with auxiliary information is applied to reconstruct the association tensor for predicting miRNA-disease associations, and the auxiliary information includes biological similarity information and adjacency information. The performance of TDMDA is compared with other advanced methods under 5-fold cross-validations. The experimental results indicate the TDMDA is a competitive method.

Accumulated studies have found that miRNAs are in charge of many complex diseases such as cancers by modulating gene expression. Predicting miRNA-target interactions is beneficial for uncovering the crucial roles of miRNAs in regulating target genes and the progression of diseases. The emergence of large-scale genomic and biological data as well as the recent development in heterogeneous networks provides new opportunities for miRNA target identification. Compared with conventional methods, computational methods become a decent solution for high efficiency. Thus, designing a method that could excavate valid information from the heterogeneous network and gene sequences is in great demand for improving the prediction accuracy. In this study, we proposed a graph-based model named MRMTI for the prediction of miRNA-target interactions. MRMTI utilized the multi-relation graph convolution module and the Bi-LSTM module to incorporate both network topology and sequential information. The learned embeddings of miRNAs and genes were then used to calculate the prediction scores of miRNA-target pairs. Comparisons with other state-of-the-art graph embedding methods and existing bioinformatic tools illustrated the superiority of MRMTI under multiple criteria metrics. Three variants of MRMTI implied the positive effect of multi-relation. The experimental results of case studies further demonstrated the prominent ability of MRMTI in predicting novel associations.

Piwi-interacting RNAs (piRNAs) fulfill the necessary requirements of epigenetic mechanisms, working to regulate gene expression in diseases and homeostasis in a coordinated manner. Hence, predicting new piRNAs that are associated with diseases conduces to understanding the pathogenicity mechanisms. In this study, we presented a deep feature learning model (DFLPiDA) to predict potential piRNA-disease associations based on the multi-model similarity features of piRNAs and diseases and the convolutional denoising auto-encoder. In particular, we firstly calculated four types of similarity features of piRNAs and diseases. Then, the convolutional denoising auto-encoder was utilized to perform deep learning on the fused similarity features. Finally, the extreme learning machine was employed as the training model as well as to predict unknown associations. The empirical results of five-fold cross-validation experiments show that the DFL-PiDA is efficient for predicting potential piRNA-disease associations. Furthermore, we proved the effectiveness of convolutional denoising auto-encoder neural network in piRNA and disease association prediction. Case studies also demonstrate the practical application of DFL-PiDA to discover potential associations.

MicroRNAs (miRNAs) play a significant role in regulating gene transcription and tend to act in a combinatorial way, which provides great insights to explore disease-related miRNA pairs or modules for comprehending the synergistic roles of miRNAs in complex diseases. As wet experiments are often laborious and costly, computational methods offer great convenience for predicting potential associations between miRNAs and diseases. Existing methods focus on either the ‘one miRNA-one disease’ paradigm, or merely the synergetic miRNA network about specific diseases, which may lead to the incomplete understanding of the synergistic effect of miRNAs on the pathogenesis of complex diseases. In this work, we present a novel tensor-based framework, named GraphTF1, to predict disease-associated miRNA-miRNA pairs. GraphTF exploits graph attention network to effectively capture node features over multi-source biological network. Then, the learned miRNA and disease representations are used to reconstruct the association tensor for predicting potential disease-associated miRNA-miRNA pairs. Empirical results showed that the proposed method outperformed all other state-of-the-art methods under five-fold cross-validation. Robustness experiments also indicated the stability of GraphTF. Moreover, case studies for Breast Neoplasms and Lung Neoplasms further demonstrated the effectiveness of GraphTF in identifying potential disease-related miRNA-miRNA pairs.

MOTIVATION: human microbes play a critical role in an extensive range of complex human diseases and become a new target in precision medicine. In silico methods of identifying microbe-disease associations not only can provide a deep insight into understanding the pathogenic mechanism of complex human diseases but also assist pharmacologists to screen candidate targets for drug development. However, the majority of existing approaches are based on linear models or label propagation, which suffers from limitations in capturing nonlinear associations between microbes and diseases. Besides, it is still a great challenge for most previous methods to make predictions for new diseases (or new microbes) with few or without any observed associations. RESULTS: in this work, we construct features for microbes and diseases by fully exploiting multiply sources of biomedical data, and then propose a novel deep learning framework of graph attention networks with inductive matrix completion for human microbe-disease association prediction, named GATMDA. To our knowledge, this is the first attempt to leverage graph attention networks for this important task. In particular, we develop an optimized graph attention network with talking-heads to learn representations for nodes (i.e. microbes and diseases). To focus on more important neighbours and filter out noises, we further design a bi-interaction aggregator to enforce representation aggregation of similar neighbours. In addition, we combine inductive matrix completion to reconstruct microbe-disease associations to capture the complicated associations between diseases and microbes. Comprehensive experiments on two data sets (i.e. HMDAD and Disbiome) demonstrated that our proposed model consistently outperformed baseline methods. Case studies on two diseases, i.e. asthma and inflammatory bowel disease, further confirmed the effectiveness of our proposed model of GATMDA. AVAILABILITY: python codes and data set are available at: https://github.com/yahuilong/GATMDA. CONTACT: [email protected].

MOTIVATION: In recent years, a growing number of studies have proved that microRNAs (miRNAs) play significant roles in the development of human complex diseases. Discovering the associations between miRNAs and diseases has become an important part of the discovery and treatment of disease. Since uncovering associations via traditional experimental methods is complicated and time-consuming, many computational methods have been proposed to identify the potential associations. However, there are still challenges in accurately determining potential associations between miRNA and disease by using multisource data. RESULTS: In this study, we develop a Multi-view Multichannel Attention Graph Convolutional Network (MMGCN) to predict potential miRNA-disease associations. Different from simple multisource information integration, MMGCN employs GCN encoder to obtain the features of miRNA and disease in different similarity views, respectively. Moreover, our MMGCN can enhance the learned latent representations for association prediction by utilizing multichannel attention, which adaptively learns the importance of different features. Empirical results on two datasets demonstrate that MMGCN model can achieve superior performance compared with nine state-of-the-art methods on most of the metrics. Furthermore, we prove the effectiveness of multichannel attention mechanism and the validity of multisource data in miRNA and disease association prediction. Case studies also indicate the ability of the method for discovering new associations.

Many studies have evidenced that circular RNAs (circRNAs) are important regulators in various pathological processes and play vital roles in many human diseases, which could serve as promising biomarkers for disease diagnosis, treatment and prognosis. However, the functions of most of circRNAs remain to be unraveled, and it is time-consuming and costly to uncover those relationships between circRNAs and diseases by conventional experimental methods. Thus, identifying candidate circRNAs for human diseases offers new opportunities to understand the functional properties of circRNAs and the pathogenesis of diseases. In this study, we propose a novel network embedding-based adaptive subspace learning method (NSL2CD) for predicting potential circRNA-disease associations and discovering those disease-related circRNA candidates. The proposed method first calculates disease similarities and circRNA similarities by fully utilizing different data sources and learns low-dimensional node representations with network embedding methods. Then, we adopt an adaptive subspace learning model to discover potential associations between circRNAs and diseases. Meanwhile, an integrated weighted graph regularization term is imposed to preserve local geometric structures of data spaces, and L1,2-norm constraint is also incorporated into the model to realize the smoothness and sparsity of projection matrices. The experiment results show that NSL2CD achieves comparable performance under different evaluation metrics, and case studies further confirm its ability to discover potential candidate circRNAs for human diseases.

Accumulating evidence has shown that microRNAs (miRNAs) play crucial roles in different biological processes, and their mutations and dysregulations have been proved to contribute to tumorigenesis. In silico identification of disease-associated miRNAs is a cost-effective strategy to discover those most promising biomarkers for disease diagnosis and treatment. The increasing available omics data sources provide unprecedented opportunities to decipher the underlying relationships between miRNAs and diseases by computational models. However, most existing methods are biased towards a single representation of miRNAs or diseases and are also not capable of discovering unobserved associations for new miRNAs or diseases without association information. In this study, we present a novel computational method with adaptive multi-source multi-view latent feature learning (M2LFL) to infer potential disease-associated miRNAs. First, we adopt multiple data sources to obtain similarity profiles and capture different latent features according to the geometric characteristic of miRNA and disease spaces. Then, the multi-modal latent features are projected to a common subspace to discover unobserved miRNA-disease associations in both miRNA and disease views, and an adaptive joint graph regularization term is developed to preserve the intrinsic manifold structures of multiple similarity profiles. Meanwhile, the Lp,q-norms are imposed into the projection matrices to ensure the sparsity and improve interpretability. The experimental results confirm the superior performance of our proposed method in screening reliable candidate disease miRNAs, which suggests that M2LFL could be an efficient tool to discover diagnostic biomarkers for guiding laborious clinical trials.

MOTIVATION: MircroRNAs (miRNAs) regulate target genes and are responsible for lethal diseases such as cancers. Accurately recognizing and identifying miRNA and gene pairs could be helpful in deciphering the mechanism by which miRNA affects and regulates the development of cancers. Embedding methods and deep learning methods have shown their excellent performance in traditional classification tasks in many scenarios. But not so many attempts have adapted and merged these two methods into miRNA-gene relationship prediction. Hence, we proposed a novel computational framework. We first generated representational features for miRNAs and genes using both sequence and geometrical information and then leveraged a deep learning method for the associations' prediction. RESULTS: We used long short-term memory (LSTM) to predict potential relationships and proved that our method outperformed other state-of-the-art methods. Results showed that our framework SG-LSTM got an area under curve of 0.94 and was superior to other methods. In the case study, we predicted the top 10 miRNA-gene relationships and recommended the top 10 potential genes for hsa-miR-335-5p for SG-LSTM-core. We also tested our model using a larger dataset, from which 14 668 698 miRNA-gene pairs were predicted. The top 10 unknown pairs were also listed. AVAILABILITY: Our work can be download in https://github.com/Xshelton/SG_LSTM. CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Briefings in Bioinformatics online.

MOTIVATION: Cancer subtype identification aims to divide cancer patients into subgroups with distinct clinical phenotypes and facilitate the development for subgroup specific therapies. The massive amount of multi-omics datasets accumulated in the public databases have provided unprecedented opportunities to fulfill this task. As a result, great computational efforts have been made to accurately identify cancer subtypes via integrative analysis of these multi-omics datasets. RESULTS: In this article, we propose a Consensus Guided Graph Autoencoder (CGGA) to effectively identify cancer subtypes. First, we learn for each omic a new feature matrix by using graph autoencoders, where both structure information and node features can be effectively incorporated during the learning process. Second, we learn a set of omic-specific similarity matrices together with a consensus matrix based on the features obtained in the first step. The learned omic-specific similarity matrices are then fed back to the graph autoencoders to guide the feature learning. By iterating the two steps above, our method obtains a final consensus similarity matrix for cancer subtyping. To comprehensively evaluate the prediction performance of our method, we compare CGGA with several approaches ranging from general-purpose multi-view clustering algorithms to multi-omics-specific integrative methods. The experimental results on both generic datasets and cancer datasets confirm the superiority of our method. Moreover, we validate the effectiveness of our method in leveraging multi-omics datasets to identify cancer subtypes. In addition, we investigate the clinical implications of the obtained clusters for glioblastoma and provide new insights into the treatment for patients with different subtypes. AVAILABILITYAND IMPLEMENTATION: The source code of our method is freely available at https://github.com/alcs417/CGGA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Synthetic Lethality (SL) plays an increasingly critical role in the targeted anticancer therapeutics. In addition, identifying SL interactions can create opportunities to selectively kill cancer cells without harming normal cells. Given the high cost of wet-lab experiments, in silico prediction of SL interactions as an alternative can be a rapid and cost-effective way to guide the experimental screening of candidate SL pairs. Several matrix factorization-based methods have recently been proposed for human SL prediction. However, they are limited in capturing the dependencies of neighbors. In addition, it is also highly challenging to make accurate predictions for new genes without any known SL partners. RESULTS: In this work, we propose a novel graph contextualized attention network named GCATSL to learn gene representations for SL prediction. First, we leverage different data sources to construct multiple feature graphs for genes, which serve as the feature inputs for our GCATSL method. Second, for each feature graph, we design node-level attention mechanism to effectively capture the importance of local and global neighbors and learn local and global representations for the nodes, respectively. We further exploit multi-layer perceptron (MLP) to aggregate the original features with the local and global representations and then derive the feature-specific representations. Third, to derive the final representations, we design feature-level attention to integrate feature-specific representations by taking the importance of different feature graphs into account. Extensive experimental results on three datasets under different settings demonstrated that our GCATSL model outperforms 14 state-of-the-art methods consistently. In addition, case studies further validated the effectiveness of our proposed model in identifying novel SL pairs. AVAILABILITYAND IMPLEMENTATION: Python codes and dataset are freely available on GitHub (https://github.com/longyahui/GCATSL) and Zenodo (https://zenodo.org/record/4522679) under the MIT license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Protein kinases have been the focus of drug discovery research for many years because they play a causal role in many human diseases. Understanding the binding profile of kinase inhibitors is a prerequisite for drug discovery, and traditional methods of predicting kinase inhibitors are time-consuming and inefficient. Calculation-based predictive methods provide a relatively low-cost and high-efficiency approach to the rapid development and effective understanding of the binding profile of kinase inhibitors. Particularly, the continuous improvement of network pharmacology methods provides unprecedented opportunities for drug discovery, network-based computational methods could be employed to aggregate the effective information from heterogeneous sources, which have become a new way for predicting the binding profile of kinase inhibitors. RESULTS: In this study, we proposed a network-based influence deep diffusion model, named IDDkin, for enhancing the prediction of kinase inhibitors. IDDkin uses deep graph convolutional networks, graph attention networks and adaptive weighting methods to diffuse the effective information of heterogeneous networks. The updated kinase and compound representations are used to predict potential compound-kinase pairs. The experimental results show that the performance of IDDkin is superior to the comparison methods, including the state-of-the-art kinase inhibitor prediction method and the classic model widely used in relationship prediction. In experiments conducted to verify its generalizability and in case studies, the IDDkin model also shows excellent performance. All of these results demonstrate the powerful predictive ability of the IDDkin model in the field of kinase inhibitors. AVAILABILITY AND IMPLEMENTATION: Source code and data can be downloaded from https://github.com/CS-BIO/IDDkin. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Combinatorial drug therapy is a promising way for treating cancers, which can reduce drug side effects and improve drug efficacy. However, due to the large-scale combinatorial space, it is difficult to quickly and effectively identify novel synergistic drug combinations for further implementing combinatorial drug therapy. The computational method of fusing multi-source knowledge is a time- and cost-efficient strategy to infer synergistic drug combinations for testing. However, for the existing computational methods of inferring synergistic drug combinations, it still remains a challenging to effectively combine multi-source information to achieve the desired results. Hence, in this study, we developed a novel Inference method of Synergistic Drug Combinations based on Symmetric Meta-Path (ISDCSMP), which can systematically and accurately prioritize synergistic drug combinations in a novel drug-target heterogeneous network integrating multi-source information. In the experiment, ISDCSMP outperformed the state-of-the-art methods in terms of AUC and precision on the benchmark dataset in five-fold cross validation. Moreover, we further illustrated performances of different ways for obtaining the combination coefficients, and analyzed the influences of the maximum meta-path length. The performances of various single meta-paths were described in five-fold cross validation. Finally, we confirmed the practical usefulness of ISDCSMP with the predicted novel synergistic drug combinations. The source code of ISDCSMP is available at https://github.com/KDDing/ISDCSMP.

Small molecule(SM) drugs can affect the expression of miRNAs, which plays crucial roles in many important biological processes. The chemical structure and clinical information of small molecule can simultaneously incorporate information such as anatomical distribution, therapeutic effects and structural characteristics. It is necessary to develop a novel model that incorporates small molecule chemical structure and clinical information to reveal the unknown small molecule-miRNA associations. In this study, we developed a new framework based on non-negative matrix factorization, called SMANMF, to discover the potential small molecules-miRNAs associations. First, the functional similarity of two miRNAs can be obtained by computing the overlap of the target gene sets in which the miRNAs interact together, and we integrated two types of small molecule similarities, including chemical similarity and clinical similarity. Then, we utilized a non-negative matrix factorization model to discover the unknown relationship between small molecules and miRNAs. The evaluation results indicate that our model can achieve superior prediction performance compared with previous approaches in 5-fold cross-validation. At the same time, the results of case studies also reveal that the SMANMF model has good predictive performance for predicting the potential association between small molecules and miRNAs.

Accurately identifying microbe-drug associations plays a critical role in drug development and precision medicine. Considering that the conventional wet-lab method is time-consuming, labor-intensive and expensive, computational approach is an alternative choice. The increasing availability of numerous biological data provides a great opportunity to systematically understand complex interaction mechanisms between microbes and drugs. However, few computational methods have been developed for microbe drug prediction. In this work, we leverage multiple sources of biomedical data to construct a heterogeneous network for microbes and drugs, including drug-drug interactions, microbe-microbe interactions and microbe-drug associations. And then we propose a novel Heterogeneous Network Embedding Representation framework for Microbe-Drug Association prediction, named (HNERMDA), by combining metapath2vec with bipartite network recommendation. In this framework, we introduce metapath2vec, a heterogeneous network representation learning method, to learn low-dimensional embedding representations for microbes and drugs. Following that, we further design a bias bipartite network projection recommendation algorithm to improve prediction accuracy. Comprehensive experiments on two datasets, named MDAD and aBiofilm, demonstrated that our model consistently outperformed five baseline methods in three types of cross-validations. Case study on two popular drugs (i.e., Ciprofloxacin and Pefloxacin) further validated the effectiveness of our HNERMDA model in inferring potential target microbes for drugs.

Coronavirus Disease-19 (COVID-19) has led to global epidemics with high morbidity and mortality. However, there are currently no proven effective drugs targeting COVID19. Identifying drug-virus associations can not only provide insights into the understanding of drug-virus interaction mechanism, but also guide and facilitate the screening of compound candidates for antiviral drug discovery. In this work, we propose a novel framework of Heterogeneous Graph Attention Networks for Drug-Virus Association predictions, named HGATDVA. First, we fully incorporate multiple sources of biomedical data to construct abundant features for drugs and viruses. Second, we construct two drug-virus heterogeneous graphs. For each graph, we design a self-enhanced graph attention network (SGAT) to explicitly model the dependency between a node and its local neighbors and derive the graph-specific representations for nodes. Third, we further develop a neural network architecture with tri-aggregator to aggregate the graph-specific representations to generate the final node representations. Experiments on two datasets were conducted to demonstrate the effectiveness of our proposed method in identifying candidate drugs for viruses.

The quality of herbal medicine has an important impact on human health. In this paper, we proposed a blockchain-based herbal quality and safety supervisory model for the current frequent herbal counterfeiting phenomenon. We manage the production, processing, and trading processes of herbal medicines by exploiting the blockchain's immutable and traceable properties. We proposed a segmented encryption method for information to encrypt the private information of enterprises. We use shared cloud storage to reduce waste of local storage space, and we proposed a verifiable random chain cutting mechanism based on the verifiable random function to handle the redundant blocks of the chain. Our article addressed the problem of herbal source falsification. Automated recording of key factors such as soil and temperature that affect the quality of herbal medicines is done from the seedling stage. Our herbal quality and safety supervisory model used blockchain technology to increase control over the production and distribution of herbal products, reduce herbal counterfeiting, and improve the efficiency of the system.

The molecular components with the functional interdependencies in human cell form complicated biological network. Diseases are mostly caused by the perturbations of the composite of the interaction multi-biomolecules, rather than an abnormality of a single biomolecule. Furthermore, new biological functions and processes could be revealed by discovering novel biological entity relationships. Hence, more and more biologists focus on studying the complex biological system instead of the individual biological components. The emergence of heterogeneous information network (HIN) offers a promising way to systematically explore complicated and heterogeneous relationships between various molecules for apparently distinct phenotypes. In this review, we first present the basic definition of HIN and the biological system considered as a complex HIN. Then, we discuss the topological properties of HIN and how these can be applied to detect network motif and functional module. Afterwards, methodologies of discovering relationships between disease and biomolecule are presented. Useful insights on how HIN aids in drug development and explores human interactome are provided. Finally, we analyze the challenges and opportunities for uncovering combinatorial patterns among pharmacogenomics and cell-type detection based on single-cell genomic data.

MOTIVATION: Human microbes get closely involved in an extensive variety of complex human diseases and become new drug targets. In silico methods for identifying potential microbe-drug associations provide an effective complement to conventional experimental methods, which can not only benefit screening candidate compounds for drug development but also facilitate novel knowledge discovery for understanding microbe-drug interaction mechanisms. On the other hand, the recent increased availability of accumulated biomedical data for microbes and drugs provides a great opportunity for a machine learning approach to predict microbe-drug associations. We are thus highly motivated to integrate these data sources to improve prediction accuracy. In addition, it is extremely challenging to predict interactions for new drugs or new microbes, which have no existing microbe-drug associations. RESULTS: In this work, we leverage various sources of biomedical information and construct multiple networks (graphs) for microbes and drugs. Then, we develop a novel ensemble framework of graph attention networks with a hierarchical attention mechanism for microbe-drug association prediction from the constructed multiple microbe-drug graphs, denoted as EGATMDA. In particular, for each input graph, we design a graph convolutional network with node-level attention to learn embeddings for nodes (i.e. microbes and drugs). To effectively aggregate node embeddings from multiple input graphs, we implement graph-level attention to learn the importance of different input graphs. Experimental results under different cross-validation settings (e.g. the setting for predicting associations for new drugs) showed that our proposed method outperformed seven state-of-the-art methods. Case studies on predicted microbe-drug associations further demonstrated the effectiveness of our proposed EGATMDA method. AVAILABILITY: Source codes and supplementary materials are available at: https://github.com/longyahui/EGATMDA/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Human microbes play critical roles in drug development and precision medicine. How to systematically understand the complex interaction mechanism between human microbes and drugs remains a challenge nowadays. Identifying microbe-drug associations can not only provide great insights into understanding the mechanism, but also boost the development of drug discovery and repurposing. Considering the high cost and risk of biological experiments, the computational approach is an alternative choice. However, at present, few computational approaches have been developed to tackle this task. RESULTS: In this work, we leveraged rich biological information to construct a heterogeneous network for drugs and microbes, including a microbe similarity network, a drug similarity network and a microbe-drug interaction network. We then proposed a novel graph convolutional network (GCN)-based framework for predicting human Microbe-Drug Associations, named GCNMDA. In the hidden layer of GCN, we further exploited the Conditional Random Field (CRF), which can ensure that similar nodes (i.e. microbes or drugs) have similar representations. To more accurately aggregate representations of neighborhoods, an attention mechanism was designed in the CRF layer. Moreover, we performed a random walk with restart-based scheme on both drug and microbe similarity networks to learn valuable features for drugs and microbes, respectively. Experimental results on three different datasets showed that our GCNMDA model consistently achieved better performance than seven state-of-the-art methods. Case studies for three microbes including SARS-CoV-2 and two antimicrobial drugs (i.e. Ciprofloxacin and Moxifloxacin) further confirmed the effectiveness of GCNMDA in identifying potential microbe-drug associations. AVAILABILITY AND IMPLEMENTATION: Python codes and dataset are available at: https://github.com/longyahui/GCNMDA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Accumulating clinic evidences have demonstrated that the microbes residing in human bodies play a significantly important role in the formation, development, and progression of various complex human diseases. Identifying latent related microbes for disease could provide insight into human disease mechanisms and promote disease prevention, diagnosis, and treatment. In this paper, we first construct a heterogeneous network by connecting the disease similarity network and the microbe similarity network through known microbe-disease association network, and then develop a novel computational model to predict human microbe-disease associations based on random walk by integrating network topological similarity (NTSHMDA). Specifically, each microbe-disease association pair is regarded as a distinct relationship level and, thus, assigned different weights based on network topological similarity. The experimental results show that NTSHMDA outperforms some state-of-the-art methods with average AUCs of 0.9070, 0.8896 ± 0.0038 in the frameworks of Leave-one-out cross validation and 5-fold cross validation, respectively. In case studies, 9, 18, 38 and 9, 18, 45 out of top-10, 20, 50 candidate microbes are verified by recently published literatures for asthma and inflammatory bowel disease, respectively. In conclusion, NTSHMDA has potential ability to identify novel disease-microbe associations and can also provide valuable information for drug discovery and biological researches.

Systematic identification of gene regulatory modules can provide invaluable knowledge towards understanding aberrant transcriptional/post-transcriptional collaborative regulatory (co-regulatory) effects in cancer. Transcription factor (TF) and microRNA (miRNA) are known as two classes of prominent regulators that play crucial roles in gene regulation. Existing studies on gene regulatory modules identification mainly focused on the miRNA-mediated regulatory network, and few considered these two regulators in a co-occurring network. In this current study, we developed a computational method called BiModule for systematically identifying TF-miRNA co-regulatory modules. BiModule operates in two main stages: it first constructs a cancer-specific regulator-mRNA network and then identifies modules based on maximal bicliques by employing biclique modularity strategy, which is a novel flexible method for bipartite graph mining. We applied our model to a cervical cancer dataset. The results showed that the TF-miRNA co-regulatory modules identified by BiModule exhibit denser connections and stronger expression correlations than another existing related method. Moreover, the BiModule-modules exhibit high biological functional enrichment. In addition, based on Kaplan-Meier survival analysis, we found a number of modules with significant prognostic associations. Availability: the R source code of BiModule is available at https://github.com/chupan1218/BiModule.

Long non-coding RNAs (lncRNAs) have been shown to be involved in multiple biological processes and play critical roles in tumorigenesis. Numerous lncRNAs have been discovered in diverse species, but the functions of most lncRNAs still remain unclear. Meanwhile, their expression patterns and regulation mechanisms are also far from being fully understood. With the advances of high-throughput technologies, the increasing availability of genomic data creates opportunities for deciphering the molecular mechanism and underlying pathogenesis of human diseases. Here, we develop an integrative framework called JONMF to identify lncRNA-mRNA co-expression modules based on the sample-matched lncRNA and mRNA expression profiles. We formulate the module detection task as an optimization problem with joint orthogonal non-negative matrix factorization that could effectively prevent multicollinearity and produce a good modularity interpretation. The constructed lncRNA-mRNA co-expression network and the gene-gene interaction network are used as the network-regularized constraints to improve the module accuracy, while the sparsity constraints are simultaneously utilized to achieve modular sparse solutions. We applied JONMF to human ovarian cancer dataset and the experiment results demonstrate that the proposed method can effectively discover biologically functional co-expression modules, which may provide insights into the function of lncRNAs and molecular mechanism of human diseases.

Systematic identification of miRNA prognostic signature can help decipher the effects of biomarkers in cancer treatment. A number of previous studies have only characterized a single miRNA as a promising prognostic biomarker. There is currently a trend toward combining several miRNAs as a panel of prognostic signatures, but few attempts to explain the mechanism of miRNA combination. Throughout this paper, we refer to "miRNA-mediated prognostic modules" and propose a novel computational approach called ProModule to analyze prognostic biomarkers from the module perspective. ProModule works in two main stages: it first uses univariate and multivariable Cox proportional hazard regressions to find individual miRNA biomarkers and then employs a clustering method to systematically detect miRNA-mediated modules with statistical prognostic significance. We applied ProModule to three data sets in bladder cancer, breast cancer, and liver cancer, and identified several miRNA prognostic modules for each data set. We found that miRNA prognostic modules have more powerful prognostic value than individuals while presenting coherent miRNA-miRNA expression as well as significant functional enrichment, and thus are likely to be biologically meaningful. Availability: ProModule is implemented in R and available at https://github.com/chupan1218/ProModule.

BACKGROUND: An increasing number of biological and clinical evidences have indicated that the microorganisms significantly get involved in the pathological mechanism of extensive varieties of complex human diseases. Inferring potential related microbes for diseases can not only promote disease prevention, diagnosis and treatment, but also provide valuable information for drug development. Considering that experimental methods are expensive and time-consuming, developing computational methods is an alternative choice. However, most of existing methods are biased towards well-characterized diseases and microbes. Furthermore, existing computational methods are limited in predicting potential microbes for new diseases. RESULTS: Here, we developed a novel computational model to predict potential human microbe-disease associations (MDAs) based on Weighted Meta-Graph (WMGHMDA). We first constructed a heterogeneous information network (HIN) by combining the integrated microbe similarity network, the integrated disease similarity network and the known microbe-disease bipartite network. And then, we implemented iteratively pre-designed Weighted Meta-Graph search algorithm on the HIN to uncover possible microbe-disease pairs by cumulating the contribution values of weighted meta-graphs to the pairs as their probability scores. Depending on contribution potential, we described the contribution degree of different types of meta-graphs to a microbe-disease pair with bias rating. Meta-graph with higher bias rating will be assigned greater weight value when calculating probability scores. CONCLUSIONS: The experimental results showed that WMGHMDA outperformed some state-of-the-art methods with average AUCs of 0.9288, 0.9068 ±0.0031 in global leave-one-out cross validation (LOOCV) and 5-fold cross validation (5-fold CV), respectively. In the case studies, 9, 19, 37 and 10, 20, 45 out of top-10, 20, 50 candidate microbes were manually verified by previous reports for asthma and inflammatory bowel disease (IBD), respectively. Furthermore, three common human diseases (Crohn's disease, Liver cirrhosis, Type 1 diabetes) were adopted to demonstrate that WMGHMDA could be efficiently applied to make predictions for new diseases. In summary, WMGHMDA has a high potential in predicting microbe-disease associations.

BACKGROUND: Non-coding RNAs (ncRNAs) are emerging as key regulators and play critical roles in a wide range of tumorigenesis. Recent studies have suggested that long non-coding RNAs (lncRNAs) could interact with microRNAs (miRNAs) and indirectly regulate miRNA targets through competing interactions. Therefore, uncovering the competing endogenous RNA (ceRNA) regulatory mechanism of lncRNAs, miRNAs and mRNAs in post-transcriptional level will aid in deciphering the underlying pathogenesis of human polygenic diseases and may unveil new diagnostic and therapeutic opportunities. However, the functional roles of vast majority of cancer specific ncRNAs and their combinational regulation patterns are still insufficiently understood. RESULTS: Here we develop an integrative framework called CeModule to discover lncRNA, miRNA and mRNA-associated regulatory modules. We fully utilize the matched expression profiles of lncRNAs, miRNAs and mRNAs and establish a model based on joint orthogonality non-negative matrix factorization for identifying modules. Meanwhile, we impose the experimentally verified miRNA-lncRNA interactions, the validated miRNA-mRNA interactions and the weighted gene-gene network into this framework to improve the module accuracy through the network-based penalties. The sparse regularizations are also used to help this model obtain modular sparse solutions. Finally, an iterative multiplicative updating algorithm is adopted to solve the optimization problem. CONCLUSIONS: We applied CeModule to two cancer datasets including ovarian cancer (OV) and uterine corpus endometrial carcinoma (UCEC) obtained from TCGA. The modular analysis indicated that the identified modules involving lncRNAs, miRNAs and mRNAs are significantly associated and functionally enriched in cancer-related biological processes and pathways, which may provide new insights into the complex regulatory mechanism of human diseases at the system level.

Increasing evidence has indicated that microRNAs(miRNAs) play vital roles in various pathological processes and thus are closely related with many complex human diseases. The identification of potential disease-related miRNAs offers new opportunities to understand disease etiology and pathogenesis. Although there have been numerous computational methods proposed to predict reliable miRNA-disease associations, they suffer from various limitations that affect the prediction accuracy and their applicability. In this study, we develop a novel method to discover disease-related candidate miRNAs based on Adaptive Multi-View Multi-Label learning(AMVML). Specifically, considering the inherent noise existed in the current dataset, we propose to learn a new affinity graph adaptively for both diseases and miRNAs from multiple similarity profiles. We then simultaneously update the miRNA-disease association predicted from both spaces based on multi-label learning. In particular, we prove the convergence of AMVML theoretically and the corresponding analysis indicates that it has a fast convergence rate. To comprehensively illustrate the prediction performance of our method, we compared AMVML with four state-of-the-art methods under different validation frameworks. As a result, our method achieved comparable performance under various evaluation metrics, which suggests that our method is capable of discovering greater number of true miRNA-disease associations. The case study conducted on thyroid neoplasms further identified a potential diagnostic biomarker. Together, the experimental results confirms the utility of our method and we anticipate that our method could serve as a reliable and efficient tool for uncovering novel disease-related miRNAs.

The identification of miRNA regulatory modules can help decipher miRNAs combinatorial regulation effects on the pathogenesis underlying complex diseases, especially in cancer. By integrating miRNA/mRNA expression profiles and sequence-based predicted target site information, we develop a novel cluster-based computational method named CoModule for identifying miRNA regulatory modules (MRMs). The ultimate goal of CoModule is to detect the MRMs, in which the miRNAs in each module are expected to present cooperative mechanisms in regulating their targets mRNAs. Here, the co-expression of miRNAs are believed to present cooperative regulatory relationship, therefore, the critical step of CoModule is first to partition the miRNAs with similar expression into a cluster by employing rough set clustering. After gaining credible miRNA clusters, the targets of regulator are naturally added into corresponding clusters to produce the final miRNA regulatory modules. We apply this present method to ovarian cancer datasets and make a comparison with the other two existing prominent approaches. The results indicate that the modules identified by CoModule perform better than the other two methods ranging from the topological aspects to the biological function. Survival analysis detects a number of prognostic modules with statistical significance, which can help reveal the potential diagnostic for ovarian cancer.

Combinatorial therapy may reduce drug side effects and improve drug efficacy, making combination therapy a promising strategy to treat complex diseases. However, in the existing computational methods, the natural properties and network knowledge of drugs have not been adequately and simultaneously considered, making it difficult to identify effective drug combinations. Computational methods that incorporate multiple sources of information (biological, chemical, pharmacological, and network knowledge) offer more opportunities to screen synergistic drug combinations. Therefore, we developed a novel Ensemble Prediction framework of Synergistic Drug Combinations (EPSDC) to accurately and efficiently predict drug combinations by integrating information from multiple-sources. EPSDC constructs feature vector of drug pair by concatenating different types of drug similarities, and then uses these groups in a feature-based base predictor. Next, transductive learning is applied on heterogeneous drug-target networks to achieve a network-based score for the drug pair. Finally, two types of ensemble rules are introduced to combine the feature-based score and the network-based score, and then potential drug combinations are prioritized. To demonstrate the effect of the ensemble rule, comprehensive experiments were conducted to compare single models and ensemble models. The experimental results indicated that our method outperformed the state-of-the-art method in five-fold cross validation and de novo prediction tests on the two benchmark datasets. We further analyzed the effect of maximum length of the meta-path and the impacts of different types of features. Moreover, the practical usefulness of our method was confirmed in the predicted novel drug combinations. The source code of EPSDC is available at https://github.com/KDDing/EPSDC.

Predicting the miRNA-target interactions (MTIs) is a critical task for elucidating mechanistic roles of miRNAs in pathophysiology. However, most existing techniques have a higher false positive because the precise miRNA target mechanisms are poorly known. Considering that ensemble methods can take advantage of the complementary knowledge in different methods, we propose an alternative optimization framework, Inferring MiRNA Targets based on Restricted Boltzmann Machines (IMTRBM), to enhance the accuracy of previous prediction results. First, the proposed method directly constructs a weighted MTI network though the results predicted by individual methods and each miRNA target pair is weighted based on the frequency appearing in these results. Second, we transform the miRNA-target prediction problem into a complete bipartite graph model, named restricted Boltzmann machine, and utilize a practical learning procedure to train our model and make predictions. Our results show that the algorithm outperforms individual miRNA-target prediction approach in the number of validated miRNA targets at cutoffs of top list. Moreover, our framework can tolerate the decrease and increase of predicted MTIs and even discover new miRNA targets, which have been a challenge to predict for any individual methods. Finally, for the miRNAs that are not appearing in IMTRBM, we design a new method to supplement IMTRBM based on the intuition that similar miRNAs have similar functions, which also achieves a comparable result. The source code of IMTRBM is available at https://github.com/liuying201705/IMTRBM.

The accumulating evidences regarding circular RNAs (circRNAs) indicate that they play crucial roles in a wide range of biological processes and participate in tumorigenesis and progression. The number of newly discovered circRNAs have increased dramatically in recent years, but the functions of vast majority of circRNAs remain unknown, and little effort has been devoted to discover disease-associated circRNAs on a large scale until now. With the advancement of high-throughput technology, the increasing availability of omics data has provided an unprecedented opportunity for prioritizing candidate circRNAs for diseases by computational models, which will contribute to exploring the pathogenesis of complex diseases at the circRNA level and provide promising applications in disease diagnosis and treatment. Here we propose the assumption that circRNAs with similar functions are normally associated with similar diseases and vice versa, and develop an integrated computational framework called MRLDC to identify disease-associated circRNAs. To our knowledge, little efforts have been developed for uncovering circRNA-disease associations on a large scale. By fully exploiting the experimentally validated associations between diseases and circRNAs, we first compute the Gaussian interaction profile kernel similarity for circRNAs and diseases, and then a heterogeneous circRNA-disease bilayer network is constructed by combining a circRNA similar network, a disease similar network, and known circRNA-disease associations. Subsequently, we develop a weighted low-rank approximation optimization algorithm with dual-manifold regularizations for predicting disease-associated circRNAs. Experimental results indicate that MRLDC can effectively identify disease circRNA candidates with high accuracy. In addition, case studies further demonstrate the ability of our method in discovering potential circRNA-disease associations.

MOTIVATION: MicroRNAs (miRNAs) play crucial roles in post-transcriptional regulations and various cellular processes. The identification of disease-related miRNAs provides great insights into the underlying pathogenesis of diseases at a system level. However, most existing computational approaches are biased towards known miRNA-disease associations, which is inappropriate for those new diseases or miRNAs without any known association information. RESULTS: In this study, we propose a new method with graph regularized non-negative matrix factorization in heterogeneous omics data, called GRNMF, to discover potential associations between miRNAs and diseases, especially for new diseases and miRNAs or those diseases and miRNAs with sparse known associations. First, we integrate the disease semantic information and miRNA functional information to estimate disease similarity and miRNA similarity, respectively. Considering that there is no available interaction observed for new diseases or miRNAs, a preprocessing step is developed to construct the interaction score profiles that will assist in prediction. Next, a graph regularized non-negative matrix factorization framework is utilized to simultaneously identify potential associations for all diseases. The results indicated that our proposed method can effectively prioritize disease-associated miRNAs with higher accuracy compared with other recent approaches. Moreover, case studies also demonstrated the effectiveness of GRNMF to infer unknown miRNA-disease associations for those novel diseases and miRNAs. AVAILABILITY AND IMPLEMENTATION: The code of GRNMF is freely available at https://github.com/XIAO-HN/GRNMF/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MicroRNAs (miRNAs) play an essential role in many biological processes by regulating the target genes, especially in the initiation and development of cancers. Therefore, the identification of the miRNA-mRNA regulatory modules is important for understanding the regulatory mechanisms. Most computational methods only used statistical correlations in predicting miRNA-mRNA modules, and neglected the fact there are causal relationships between miRNAs and their target genes. In this paper, we propose a novel approach called CALM(the causal regulatory modules) to identify the miRNA-mRNA regulatory modules through integrating the causal interactions and statistical correlations between the miRNAs and their target genes. Our algorithm largely consists of three steps: it first forms the causal regulatory relationships of miRNAs and genes from gene expression profiles and detects the miRNA clusters according to the GO function information of their target genes, then expands each miRNA cluster by greedy adding(discarding) the target genes to maximize the modularity score. To show the performance of our method, we apply CALM on four datasets including EMT, breast, ovarian, thyroid cancer and validate our results. The experiment results show that our method can not only outperform the compared method, but also achieve ideal overall performance in terms of the functional enrichment.

The discovery of human disease-related miRNA is a challenging problem for complex disease biology research. For existing computational methods, it is difficult to achieve excellent performance with sparse known miRNA-disease association verified by biological experiment. Here, we develop CPTL, a Collective Prediction based on Transduction Learning, to systematically prioritize miRNAs related to disease. By combining disease similarity, miRNA similarity with known miRNA-disease association, we construct a miRNA-disease network for predicting miRNA-disease association. Then, CPTL calculates relevance score and updates the network structure iteratively, until a convergence criterion is reached. The relevance score of node including miRNA and disease is calculated by the use of transduction learning based on its neighbors. The network structure is updated using relevance score, which increases the weight of important links. To show the effectiveness of our method, we compared CPTL with existing methods based on HMDD datasets. Experimental results indicate that CPTL outperforms existing approaches in terms of AUC, precision, recall, and F1-score. Moreover, experiments performed with different number of iterations verify that CPTL has good convergence. Besides, it is analyzed that the varying of weighted parameters affect predicted results. Case study on breast cancer has further confirmed the identification ability of CPTL.

Detecting overlapping protein complexes in protein-protein interaction (PPI) networks can provide insight into cellular functional organization and thus elucidate underlying cellular mechanisms. Recently, various algorithms for protein complex detection have been developed for PPI networks. However, the majority of algorithms primarily depend on network topological features and/or gene expression profile, failing to consider the inherent biological meanings between protein pairs. In this paper, we propose a method of pseudo-clique extension based on fuzzy relation (PCE-FR) that detects protein complexes from PPI networks weighted with the biological significance hidden in protein pairs. The proposed algorithm operates in three stages: it first forms the non-overlapping protein sub-structure based on fuzzy relation and then expands each sub-structure by adding neighbor proteins to maximize the cohesive score. Finally, highly overlapped candidate protein complexes are merged to form the final protein complex set. We apply PCE-FR to two yeast PPI networks and a human PPI network and validate our results by using CYC2008 and CHPC2012, respectively. Experimental results show that our method outperforms classical algorithms such as CFinder, ClusterONE, CMC, RRW, HC-PIN and ProRank+, and that it achieves ideal overall performance in terms of Precision, Accuracy, and Separation.

UNLABELLED: MicroRNAs (miRNAs) are post-transcriptional regulators that repress the expression of their targets. They are known to work cooperatively with genes and play important roles in numerous cellular processes. Identification of miRNA regulatory modules (MRMs) would aid deciphering the combinatorial effects derived from the many-to-many regulatory relationships in complex cellular systems. Here, we develop an effective method called BiCliques Merging (BCM) to predict MRMs based on bicliques merging. By integrating the miRNA/mRNA expression profiles from The Cancer Genome Atlas (TCGA) with the computational target predictions, we construct a weighted miRNA regulatory network for module discovery. The maximal bicliques detected in the network are statistically evaluated and filtered accordingly. We then employed a greedy-based strategy to iteratively merge the remaining bicliques according to their overlaps together with edge weights and the gene-gene interactions. Comparing with existing methods on two cancer datasets from TCGA, we showed that the modules identified by our method are more densely connected and functionally enriched. Moreover, our predicted modules are more enriched for miRNA families and the miRNA-mRNA pairs within the modules are more negatively correlated. Finally, several potential prognostic modules are revealed by Kaplan-Meier survival analysis and breast cancer subtype analysis. AVAILABILITY: BCM is implemented in Java and available for download in the supplementary materials, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/ TCBB.2015.2462370.

Prediction of essential proteins which is aided by computer science and supported from high throughput data is a more efficient method compared with time consuming and expensive experimental approaches. There are many computational approaches reported, however they are usually sensitive to various network structures so that their robustness are generally poor. In this paper, a novel topological centrality measure for predicting essential proteins based on local interaction density, named as LID, is proposed. It is different from previous measures that LID takes the essentiality of a node from interaction densities among its neighbors through topological analyses of real proteins in a protein complex set first time at the viewpoint of biological modules. LID is applied to four different yeast protein interaction networks, which are obtained, respectively, from the DIP database and the BioGRID database. The experimental results show that the number of essential proteins detected by LID universally exceeds or approximates the best performance of other 10 topological centrality measures in all 24 comparisons of four networks: DC, BC, ClusterC, CloseC, MNC, SoECC(NC), LAC, SC, EigC, and InfoC. The better robustness of LID for multiple data sets will make it to be a new core topological centrality measure to improve the performance of prediction for more species protein interaction networks.

MOTIVATION: Interplays between transcription factors (TFs) and microRNAs (miRNAs) in gene regulation are implicated in various physiological processes. It is thus important to identify biologically meaningful network motifs involving both types of regulators to understand the key co-regulatory mechanisms underlying the cellular identity and function. However, existing motif finders do not scale well for large networks and are not designed specifically for co-regulatory networks. RESULTS: In this study, we propose a novel algorithm CoMoFinder to accurately and efficiently identify composite network motifs in genome-scale co-regulatory networks. We define composite network motifs as network patterns involving at least one TF, one miRNA and one target gene that are statistically significant than expected. Using two published disease-related co-regulatory networks, we show that CoMoFinder outperforms existing methods in both accuracy and robustness. We then applied CoMoFinder to human TF-miRNA co-regulatory network derived from The Encyclopedia of DNA Elements project and identified 44 recurring composite network motifs of size 4. The functional analysis revealed that genes involved in the 44 motifs are enriched for significantly higher number of biological processes or pathways comparing with non-motifs. We further analyzed the identified composite bi-fan motif and showed that gene pairs involved in this motif structure tend to physically interact and are functionally more similar to each other than expected. AVAILABILITY AND IMPLEMENTATION: CoMoFinder is implemented in Java and available for download at http://www.cs.utoronto.ca/∼yueli/como.html.

MOTIVATION: Identification of microRNA regulatory modules (MiRMs) will aid deciphering aberrant transcriptional regulatory network in cancer but is computationally challenging. Existing methods are stochastic or require a fixed number of regulatory modules. RESULTS: We propose Mirsynergy, an efficient deterministic overlapping clustering algorithm adapted from a recently developed framework. Mirsynergy operates in two stages: it first forms MiRMs based on co-occurring microRNA (miRNA) targets and then expands each MiRM by greedily including (excluding) mRNAs into (from) the MiRM to maximize the synergy score, which is a function of miRNA-mRNA and gene-gene interactions. Using expression data for ovarian, breast and thyroid cancer from The Cancer Genome Atlas, we compared Mirsynergy with internal controls and existing methods. Mirsynergy-MiRMs exhibit significantly higher functional enrichment and more coherent miRNA-mRNA expression anti-correlation. Based on Kaplan-Meier survival analysis, we proposed several prognostically promising MiRMs and envisioned their utility in cancer research. AVAILABILITY AND IMPLEMENTATION: Mirsynergy is implemented/available as an R/Bioconductor package at www.cs.utoronto.ca/∼yueli/Mirsynergy.html.

ABSTRACT Traditional intrusion detection systems are known for triggering large volumes of alerts. An average commercial intrusion detection system reports thousands of alerts on daily basis. A large proportion of these alerts are false alerts. In the field of alert management, alert verification is cited as critical component in determining the success of intrusions. It helps to eliminate any alert that does not have a corresponding vulnerability in a network, hence improving the effectiveness of alert management approaches. Alert verification alone cannot guarantee alerts of high quality because the validated alerts may contain massive number of redundant alerts. The analysts who review alerts are likely to take longer time to understand the complete security incident because it would involve evaluating each single redundant alert. Consequently, the analysts would not only encounter difficulties when taking the correct decision but would also take longer time to respond against the intrusions. Therefore, the unnecessary alerts diminish the value and urgency of the relevant alerts. This paper seeks to address the aforementioned issue to strengthen the vulnerability‐based alert management approaches. Our approach verifies alerts prior to merging them. Central to this approach is the use of two components: verifier and alert merger. The verifier component improves the quality of alerts by validating them with enhanced vulnerability assessment data. The alert merger component reduces huge number of redundant alerts. Experiments conducted in our test bed have demonstrated the success of our approach in reducing most of the unnecessary alerts for a range of attacks with high accuracy yet closely maintaining the detection rate. Copyright © 2012 John Wiley & Sons, Ltd.