A multi-view graph contrastive learning framework for deciphering spatially resolved transcriptomics data.

Spatially resolved transcriptomics data are being used in a revolutionary way to decipher the spatial pattern of gene expression and the spatial architecture of cell types. Much work has been done to exploit the genomic spatial architectures of cells. Such work is based on the common assumption that gene expression profiles of spatially adjacent spots are more similar than those of more distant spots. However, related work might not consider the nonlocal spatial co-expression dependency, which can better characterize the tissue architectures. Therefore, we propose MuCoST, a Multi-view graph Contrastive learning framework for deciphering complex Spatially resolved Transcriptomic architectures with dual scale structural dependency. To achieve this, we employ spot dependency augmentation by fusing gene expression correlation and spatial location proximity, thereby enabling MuCoST to model both nonlocal spatial co-expression dependency and spatially adjacent dependency. We benchmark MuCoST on four datasets, and we compare it with other state-of-the-art spatial domain identification methods. We demonstrate that MuCoST achieves the highest accuracy on spatial domain identification from various datasets. In particular, MuCoST accurately deciphers subtle biological textures and elaborates the variation of spatially functional patterns.

EGPDI: identifying protein-DNA binding sites based on multi-view graph embedding fusion.

Mechanisms of protein-DNA interactions are involved in a wide range of biological activities and processes. Accurately identifying binding sites between proteins and DNA is crucial for analyzing genetic material, exploring protein functions, and designing novel drugs. In recent years, several computational methods have been proposed as alternatives to time-consuming and expensive traditional experiments. However, accurately predicting protein-DNA binding sites still remains a challenge. Existing computational methods often rely on handcrafted features and a single-model architecture, leaving room for improvement. We propose a novel computational method, called EGPDI, based on multi-view graph embedding fusion. This approach involves the integration of Equivariant Graph Neural Networks (EGNN) and Graph Convolutional Networks II (GCNII), independently configured to profoundly mine the global and local node embedding representations. An advanced gated multi-head attention mechanism is subsequently employed to capture the attention weights of the dual embedding representations, thereby facilitating the integration of node features. Besides, extra node features from protein language models are introduced to provide more structural information. To our knowledge, this is the first time that multi-view graph embedding fusion has been applied to the task of protein-DNA binding site prediction. The results of five-fold cross-validation and independent testing demonstrate that EGPDI outperforms state-of-the-art methods. Further comparative experiments and case studies also verify the superiority and generalization ability of EGPDI.

Identifying spatial domains of spatially resolved transcriptomics via multi-view graph convolutional networks.

MOTIVATION: Recent advances in spatially resolved transcriptomics (ST) technologies enable the measurement of gene expression profiles while preserving cellular spatial context. Linking gene expression of cells with their spatial distribution is essential for better understanding of tissue microenvironment and biological progress. However, effectively combining gene expression data with spatial information to identify spatial domains remains challenging. RESULTS: To deal with the above issue, in this paper, we propose a novel unsupervised learning framework named STMGCN for identifying spatial domains using multi-view graph convolution networks (MGCNs). Specifically, to fully exploit spatial information, we first construct multiple neighbor graphs (views) with different similarity measures based on the spatial coordinates. Then, STMGCN learns multiple view-specific embeddings by combining gene expressions with each neighbor graph through graph convolution networks. Finally, to capture the importance of different graphs, we further introduce an attention mechanism to adaptively fuse view-specific embeddings and thus derive the final spot embedding. STMGCN allows for the effective utilization of spatial context to enhance the expressive power of the latent embeddings with multiple graph convolutions. We apply STMGCN on two simulation datasets and five real spatial transcriptomics datasets with different resolutions across distinct platforms. The experimental results demonstrate that STMGCN obtains competitive results in spatial domain identification compared with five state-of-the-art methods, including spatial and non-spatial alternatives. Besides, STMGCN can detect spatially variable genes with enriched expression patterns in the identified domains. Overall, STMGCN is a powerful and efficient computational framework for identifying spatial domains in spatial transcriptomics data.

Decoding functional cell-cell communication events by multi-view graph learning on spatial transcriptomics.

Cell-cell communication events (CEs) are mediated by multiple ligand-receptor (LR) pairs. Usually only a particular subset of CEs directly works for a specific downstream response in a particular microenvironment. We name them as functional communication events (FCEs) of the target responses. Decoding FCE-target gene relations is: important for understanding the mechanisms of many biological processes, but has been intractable due to the mixing of multiple factors and the lack of direct observations. We developed a method HoloNet for decoding FCEs using spatial transcriptomic data by integrating LR pairs, cell-type spatial distribution and downstream gene expression into a deep learning model. We modeled CEs as a multi-view network, developed an attention-based graph learning method to train the model for generating target gene expression with the CE networks, and decoded the FCEs for specific downstream genes by interpreting trained models. We applied HoloNet on three Visium datasets of breast cancer and liver cancer. The results detangled the multiple factors of FCEs by revealing how LR signals and cell types affect specific biological processes, and specified FCE-induced effects in each single cell. We conducted simulation experiments and showed that HoloNet is more reliable on LR prioritization in comparison with existing methods. HoloNet is a powerful tool to illustrate cell-cell communication landscapes and reveal vital FCEs that shape cellular phenotypes. HoloNet is available as a Python package at https://github.com/lhc17/HoloNet.

MGEGFP: a multi-view graph embedding method for gene function prediction based on adaptive estimation with GCN.

In recent years, a number of computational approaches have been proposed to effectively integrate multiple heterogeneous biological networks, and have shown impressive performance for inferring gene function. However, the previous methods do not fully represent the critical neighborhood relationship between genes during the feature learning process. Furthermore, it is difficult to accurately estimate the contributions of different views for multi-view integration. In this paper, we propose MGEGFP, a multi-view graph embedding method based on adaptive estimation with Graph Convolutional Network (GCN), to learn high-quality gene representations among multiple interaction networks for function prediction. First, we design a dual-channel GCN encoder to disentangle the view-specific information and the consensus pattern across diverse networks. By the aid of disentangled representations, we develop a multi-gate module to adaptively estimate the contributions of different views during each reconstruction process and make full use of the multiplexity advantages, where a diversity preservation constraint is designed to prevent the over-fitting problem. To validate the effectiveness of our model, we conduct experiments on networks from the STRING database for both yeast and human datasets, and compare the performance with seven state-of-the-art methods in five evaluation metrics. Moreover, the ablation study manifests the important contribution of the designed dual-channel encoder, multi-gate module and the diversity preservation constraint in MGEGFP. The experimental results confirm the superiority of our proposed method and suggest that MGEGFP can be a useful tool for gene function prediction.

Classifying breast cancer using multi-view graph neural network based on multi-omics data.

Introduction: As the evaluation indices, cancer grading and subtyping have diverse clinical, pathological, and molecular characteristics with prognostic and therapeutic implications. Although researchers have begun to study cancer differentiation and subtype prediction, most of relevant methods are based on traditional machine learning and rely on single omics data. It is necessary to explore a deep learning algorithm that integrates multi-omics data to achieve classification prediction of cancer differentiation and subtypes. Methods: This paper proposes a multi-omics data fusion algorithm based on a multi-view graph neural network (MVGNN) for predicting cancer differentiation and subtype classification. The model framework consists of a graph convolutional network (GCN) module for learning features from different omics data and an attention module for integrating multi-omics data. Three different types of omics data are used. For each type of omics data, feature selection is performed using methods such as the chi-square test and minimum redundancy maximum relevance (mRMR). Weighted patient similarity networks are constructed based on the selected omics features, and GCN is trained using omics features and corresponding similarity networks. Finally, an attention module integrates different types of omics features and performs the final cancer classification prediction. Results: To validate the cancer classification predictive performance of the MVGNN model, we conducted experimental comparisons with traditional machine learning models and currently popular methods based on integrating multi-omics data using 5-fold cross-validation. Additionally, we performed comparative experiments on cancer differentiation and its subtypes based on single omics data, two omics data, and three omics data. Discussion: This paper proposed the MVGNN model and it performed well in cancer classification prediction based on multiple omics data.

A brain structure learning-guided multi-view graph representation learning for brain network analysis.

Background: Resting-state brain networks represent the interconnectivity of different brain regions during rest. Utilizing brain network analysis methods to model these networks can enhance our understanding of how different brain regions collaborate and communicate without explicit external stimuli. However, analyzing resting-state brain networks faces challenges due to high heterogeneity and noise correlation between subjects. This study proposes a brain structure learning-guided multi-view graph representation learning method to address the limitations of current brain network analysis and improve the diagnostic accuracy (ACC) of mental disorders. Methods: We first used multiple thresholds to generate different sparse levels of brain networks. Subsequently, we introduced graph pooling to optimize the brain network representation by reducing noise edges and data inconsistency, thereby providing more reliable input for subsequent graph convolutional networks (GCNs). Following this, we designed a multi-view GCN to comprehensively capture the complexity and variability of brain structure. Finally, we employed an attention-based adaptive module to adjust the contributions of different views, facilitating their fusion. Considering that the Smith atlas offers superior characterization of resting-state brain networks, we utilized the Smith atlas to construct the graph network. Results: Experiments on two mental disorder datasets, the Autism Brain Imaging Data Exchange (ABIDE) dataset and the Mexican Cocaine Use Disorders (SUDMEX CONN) dataset, show that our model outperforms the state-of-the-art methods, achieving nearly 75% ACC and 70% area under the receiver operating characteristic curve (AUC) on both datasets. Conclusions: These findings demonstrate that our method of combining multi-view graph learning and brain structure learning can effectively capture crucial structural information in brain networks while facilitating the acquisition of feature information from diverse perspectives, thereby improving the performance of brain network analysis.

A multi-view feature representation for predicting drugs combination synergy based on ensemble and multi-task attention models.

This paper proposes a novel multi-view ensemble predictor model that is designed to address the challenge of determining synergistic drug combinations by predicting both the synergy score value values and synergy class label of drug combinations with cancer cell lines. The proposed methodology involves representing drug features through four distinct views: Simplified Molecular-Input Line-Entry System (SMILES) features, molecular graph features, fingerprint features, and drug-target features. On the other hand, cell line features are captured through four views: gene expression features, copy number features, mutation features, and proteomics features. To prevent overfitting of the model, two techniques are employed. First, each view feature of a drug is paired with each corresponding cell line view and input into a multi-task attention deep learning model. This multi-task model is trained to simultaneously predict both the synergy score value and synergy class label. This process results in sixteen input view features being fed into the multi-task model, producing sixteen prediction values. Subsequently, these prediction values are utilized as inputs for an ensemble model, which outputs the final prediction value. The 'MVME' model is assessed using the O'Neil dataset, which includes 38 distinct drugs combined across 39 distinct cancer cell lines to output 22,737 drug combination pairs. For the synergy score value, the proposed model scores a mean square error (MSE) of 206.57, a root mean square error (RMSE) of 14.30, and a Pearson score of 0.76. For the synergy class label, the model scores 0.90 for accuracy, 0.96 for precision, 0.57 for kappa, 0.96 for the area under the ROC curve (ROC-AUC), and 0.88 for the area under the precision-recall curve (PR-AUC).

HMM-GDAN: Hybrid multi-view and multi-scale graph duplex-attention networks for drug response prediction in cancer.

Precision medicine is devoted to discovering personalized therapy for complex and difficult diseases like cancer. Many machine learning approaches have been developed for drug response prediction towards precision medicine. Notwithstanding, genetic profiles based multi-view graph learning schemes have not yet been explored for drug response prediction in previous works. Furthermore, multi-scale latent feature fusion is not considered sufficiently in the existing frameworks of graph neural networks (GNNs). Previous works on drug response prediction mainly depend on sequence data or single-view graph data. In this paper, we propose to construct multi-view graph by means of multi-omics data and STRING protein-protein association data, and develop a new architecture of GNNs for drug response prediction in cancer. Specifically, we propose hybrid multi-view and multi-scale graph duplex-attention networks (HMM-GDAN), in which both multi-view self-attention mechanism and view-level attention mechanism are devised to capture the complementary information of views and emphasize on the importance of each view collaboratively, and rich multi-scale features are constructed and integrated to further form high-level representations for better prediction. Experiments on GDSC2 dataset verify the superiority of the proposed HMM-GDAN when compared with state-of-the-art baselines. The effectiveness of multi-view and multi-scale strategies is demonstrated by the ablation study.

Multi-view graph network learning framework for identification of major depressive disorder.

Functional connectivity (FC) derived from resting-state functional magnetic resonance imaging (rs-fMRI) exhibits non-Euclidean topological structures, which have pathological foundations and serve as ideal objective data for intelligent diagnosis of major depressive disorder (MDD) patients. Additionally, the fully connected FC demonstrates uniform spatial structures. To learn and integrate information from these two structural forms for a more comprehensive identification of MDD patients, we propose a novel hierarchical learning structure called Multi-View Graph Neural Network (MV-GNN). In MV-GNN, the collaborative FC of subjects is filtered and reconstructed from topological view to obtain the reconstructed FC, incorporating various threshold values to calculate the topological attributes of brain regions. ROC analysis is performed on the average scores of these attributes for MDD and healthy control (HC) groups to determine an efficient threshold. Group differences analysis is conducted on the efficient topological attributes of brain regions, followed by their selection. These efficient attributes, along with the reconstructed FC, are combined to construct a graph view using self-attention graph pooling and graph convolutional neural networks, enabling efficient embedding. To extract efficient FC pattern difference information from spatial view, a dual leave-one-out cross-feature selection method is proposed. It selects and extracts relevant information from uniformly sized FC structures' high-dimensional spatial features, constructing a relationship view between brain regions. This approach incorporates both the whole graph topological view and spatial relationship view in a multi-layered structure, fusing them using gating mechanisms. By incorporating multiple views, it enhances the inference of whether subjects suffer from MDD and reveals differential information between MDD and HC groups across different perspectives. The proposed model structure is evaluated through leave-one-site cross-validation and achieves an average accuracy of 65.61% in identifying MDD patients at a single-center site, surpassing state-of-the-art methods in MDD recognition. The model provides valuable discriminatory information for objective diagnosis of MDD and serves as a reference for pathological foundations.

ScaffoldGVAE: scaffold generation and hopping of drug molecules via a variational autoencoder based on multi-view graph neural networks.

In recent years, drug design has been revolutionized by the application of deep learning techniques, and molecule generation is a crucial aspect of this transformation. However, most of the current deep learning approaches do not explicitly consider and apply scaffold hopping strategy when performing molecular generation. In this work, we propose ScaffoldGVAE, a variational autoencoder based on multi-view graph neural networks, for scaffold generation and scaffold hopping of drug molecules. The model integrates several important components, such as node-central and edge-central message passing, side-chain embedding, and Gaussian mixture distribution of scaffolds. To assess the efficacy of our model, we conduct a comprehensive evaluation and comparison with baseline models based on seven general generative model evaluation metrics and four scaffold hopping generative model evaluation metrics. The results demonstrate that ScaffoldGVAE can explore the unseen chemical space and generate novel molecules distinct from known compounds. Especially, the scaffold hopped molecules generated by our model are validated by the evaluation of GraphDTA, LeDock, and MM/GBSA. The case study of generating inhibitors of LRRK2 for the treatment of PD further demonstrates the effectiveness of ScaffoldGVAE in generating novel compounds through scaffold hopping. This novel approach can also be applied to other protein targets of various diseases, thereby contributing to the future development of new drugs. Source codes and data are available at https://github.com/ecust-hc/ScaffoldGVAE .

Dual adaptive learning multi-task multi-view for graph network representation learning.

Graph network analysis, which achieves widely application, is to explore and mine the graph structure data. However, existing graph network analysis methods with graph representation learning technique ignore the correlation between multiple graph network analysis tasks, and they need massive repeated calculation to obtain each graph network analysis results. Or they cannot adaptively balance the relative importance of multiple graph network analysis tasks, that lead to weak model fitting. Besides, most of existing methods ignore multiplex views semantic information and global graph information, which fail to learn robust node embeddings resulting in unsatisfied graph analysis results. To solve these issues, we propose a multi-task multi-view adaptive graph network representation learning model, called M2agl. The highlights of M2agl are as follows: (1) Graph convolutional network with the linear combination of the adjacency matrix and PPMI (positive point-wise mutual information) matrix is utilized as encoder to extract the local and global intra-view graph feature information of the multiplex graph network. Each intra-view graph information of the multiplex graph network can adaptively learn the parameters of graph encoder. (2) We use regularization to capture the interaction information among different graph views, and the importance of different graph views are learned by view attention mechanism for further inter-view graph network fusion. (3) The model is trained oriented by multiple graph network analysis tasks. The relative importance of multiple graph network analysis tasks are adjusted adaptively with the homoscedastic uncertainty. The regularization can be considered as an auxiliary task to further boost the performance. Experiments on real-worlds attributed multiplex graph networks demonstrate the effectiveness of M2agl in comparison with other competing approaches.

MGN-Net: A multi-view graph normalizer for integrating heterogeneous biological network populations.

With the recent technological advances, biological datasets, often represented by networks (i.e., graphs) of interacting entities, proliferate with unprecedented complexity and heterogeneity. Although modern network science opens new frontiers of analyzing connectivity patterns in such datasets, we still lack data-driven methods for extracting an integral connectional fingerprint of a multi-view graph population, let alone disentangling the typical from the atypical variations across the population samples. We present the multi-view graph normalizer network (MGN-Net2), a graph neural network based method to normalize and integrate a set of multi-view biological networks into a single connectional template that is centered, representative, and topologically sound. We demonstrate the use of MGN-Net by discovering the connectional fingerprints of healthy and neurologically disordered brain network populations including Alzheimer's disease and Autism spectrum disorder patients. Additionally, by comparing the learned templates of healthy and disordered populations, we show that MGN-Net significantly outperforms conventional network integration methods across extensive experiments in terms of producing the most centered templates, recapitulating unique traits of populations, and preserving the complex topology of biological networks. Our evaluations showed that MGN-Net is powerfully generic and easily adaptable in design to different graph-based problems such as identification of relevant connections, normalization and integration.

Schizophrenia Identification Using Multi-View Graph Measures of Functional Brain Networks.

Schizophrenia (SZ) is a functional mental disorder that seriously affects the social life of patients. Therefore, accurate diagnosis of SZ has raised extensive attention of researchers. At present, study of brain network based on resting-state functional magnetic resonance imaging (rs-fMRI) has provided promising results for SZ identification by studying functional network alteration. However, previous studies based on brain network analysis are not very effective for SZ identification. Therefore, we propose an improved SZ identification method using multi-view graph measures of functional brain networks. Firstly, we construct an individual functional connectivity network based on Brainnetome atlas for each subject. Then, multi-view graph measures are calculated by the brain network analysis method as feature representations. Next, in order to consider the relationships between measures within the same brain region in feature selection, multi-view measures are grouped according to the corresponding regions and Sparse Group Lasso is applied to identify discriminative features based on this feature grouping structure. Finally, a support vector machine (SVM) classifier is employed to perform SZ identification task. To evaluate our proposed method, computational experiments are conducted on 145 subjects (71 schizophrenic patients and 74 healthy controls) using a leave-one-out cross-validation (LOOCV) scheme. The results show that our proposed method can obtain an accuracy of 93.10% for SZ identification. By comparison, our method is more effective for SZ identification than some existing methods.