Microbe-disease Associations Research Articles

GCNPMDA: Human microbe-disease association prediction by hierarchical graph convolutional network with layer attention

Microorganisms play a crucial role in various physiological processes, including metabolism, immune defense, nutrition absorption, defense against cancer, and protection against pathogen colonization. Changes in microbial communities serve as potential biomarkers for diseases, offering significant insights into disease treatment and diagnosis. However, the association between microorganisms and diseases is still unclear, and more computational methods are needed to predict potential associations. In this paper, we introduce a novel computational model, the Graph Convolutional Network to Predict Microbe-Disease Associations (GCNPMDA), which employs layer attention mechanisms (see Figure 1). GCNPMDA integrates known microbe-disease associations, microbe–microbe similarities, and disease–disease similarities into a heterogeneous network. The model utilizes a Graph Convolutional Network (GCN) to learn embeddings for diseases and microbes. To enhance attribute information, microbe–microbe similarities are computed using Cosine similarity, Jaccard similarity, Gaussian kernel, and functional information, while disease–disease similarities are computed using Cosine similarity, Jaccard similarity, Gaussian kernel, and symptom information. Additionally, attention mechanisms are applied to combine embeddings from multiple graph convolution layers. The model’s predictive effectiveness is evaluated on Human Microbe-Disease Association Database (HMDAD). Leave-one-out cross-validation (LOOCV) was conducted. The Area Under ROC Curve (AUC) of LOOCV is 0.98. The 5-fold cross-validation (5-fold CV) on HMDAD yields average AUC of 0.98 ± 0.009. Furthermore, we carried out a case study of type 2 diabetes (T2D), inflammatory bowel disease (IBD), and rheumatoid arthritis. Based on existing literature evidence, it was confirmed that 6, 7, and 7 of the top-10 inferred microbes have established associations with T2D, IBD, and rheumatoid arthritis, respectively. GCNPMDA demonstrates potential efficacy in identifying disease-related microbes, offering a promising tool to uncover the intricate relationship between microorganisms and their human hosts.

Adversarial regularized autoencoder graph neural network for microbe-disease associations prediction.

Microorganisms inhabit various regions of the human body and significantly contribute to numerous diseases. Predicting the associations between microbes and diseases is crucial for understanding pathogenic mechanisms and informing prevention and treatment strategies. Biological experiments to determine these associations are time-consuming and costly. Therefore, integrating deep learning with biological networks can efficiently identify potential microbe-disease associations on a large scale. We propose an adversarial regularized autoencoder graph neural network algorithm, named Stacked Adversarial Regularization for Microbe-Disease Associations Prediction (SARMDA), for predicting associations between microbes and diseases. First, we integrate topological structural similarity and functional similarity metrics of microbes and diseases to construct a heterogeneous network. Then, utilizing an autoencoder based on GraphSAGE, we learn both the topological and attribute representations of nodes within the constructed network. Finally, we introduce an adversarial regularized autoencoder graph neural network embedding model to address the inherent limitations of traditional GraphSAGE autoencoders in capturing global information. Under the five-fold cross-validation on microbe-disease pairs, SARMDA was compared with eight advanced methods using the Human Microbe-Disease Association Database (HMDAD) and Disbiome databases. The best area under the ROC curve (AUC) achieved by SARMDA on HMDAD was 0.9891$\pm$0.0057, and the best area under the precision-recall curve (AUPR) was 0.9902$\pm$0.0128. On the Disbiome dataset, the AUC was 0.9328$\pm$0.0072, and the best AUPR was 0.9233$\pm$0.0089, outperforming the other eight MDAs prediction methods. Furthermore, the effectiveness of our model was demonstrated through a detailed analysis of asthma and inflammatory bowel disease cases.

Predicting disease-associated microbes based on similarity fusion and deep learning.

Increasing studies have revealed the critical roles of human microbiome in a wide variety of disorders. Identification of disease-associated microbes might improve our knowledge and understanding of disease pathogenesis and treatment. Computational prediction of microbe-disease associations would provide helpful guidance for further biomedical screening, which has received lots of research interest in bioinformatics. In this study, a deep learning-based computational approach entitled SGJMDA is presented for predicting microbe-disease associations. Specifically, SGJMDA first fuses multiple similarities of microbes and diseases using a nonlinear strategy, and extracts feature information from homogeneous networks composed of the fused similarities via a graph convolution network. Second, a heterogeneous microbe-disease network is built to further capture the structural information of microbes and diseases by employing multi-neighborhood graph convolution network and jumping knowledge network. Finally, potential microbe-disease associations are inferred through computing the linear correlation coefficients of their embeddings. Results from cross-validation experiments show that SGJMDA outperforms 6 state-of-the-art computational methods. Furthermore, we carry out case studies on three important diseases using SGJMDA, in which 19, 20, and 11 predictions out of their top 20 results are successfully checked by the latest databases, respectively. The excellent performance of SGJMDA suggests that it could be a valuable and promising tool for inferring disease-associated microbes.

CMFHMDA: a prediction framework for human disease-microbe associations based on cross-domain matrix factorization.

Predicting associations between microbes and diseases opens up new avenues for developing diagnostic, preventive, and therapeutic strategies. Given that laboratory-based biological tests to verify these associations are often time-consuming and expensive, there is a critical need for innovative computational frameworks to predict new microbe-disease associations. In this work, we introduce a novel prediction algorithm called Predicting Human Disease-Microbe Associations using Cross-Domain Matrix Factorization (CMFHMDA). Initially, we calculate the composite similarity of diseases and the Gaussian interaction profile similarity of microbes. We then apply the Weighted K Nearest Known Neighbors (WKNKN) algorithm to refine the microbe-disease association matrix. Our CMFHMDA model is subsequently developed by integrating the network data of both microbes and diseases to predict potential associations. The key innovations of this method include using the WKNKN algorithm to preprocess missing values in the association matrix and incorporating cross-domain information from microbes and diseases into the CMFHMDA model. To validate CMFHMDA, we employed three different cross-validation techniques to evaluate the model's accuracy. The results indicate that the CMFHMDA model achieved Area Under the Receiver Operating Characteristic Curve scores of 0.9172, 0.8551, and 0.9351$\pm $0.0052 in global Leave-One-Out Cross-Validation (LOOCV), local LOOCV, and five-fold CV, respectively. Furthermore, many predicted associations have been confirmed by published experimental studies, establishing CMFHMDA as an effective tool for predicting potential disease-associated microbes.

Predicting microbe–disease association based on graph autoencoder and inductive matrix completion with multi-similarities fusion

BackgroundClinical studies have demonstrated that microbes play a crucial role in human health and disease. The identification of microbe-disease interactions can provide insights into the pathogenesis and promote the diagnosis, treatment, and prevention of disease. Although a large number of computational methods are designed to screen novel microbe-disease associations, the accurate and efficient methods are still lacking due to data inconsistence, underutilization of prior information, and model performance.MethodsIn this study, we proposed an improved deep learning-based framework, named GIMMDA, to identify latent microbe-disease associations, which is based on graph autoencoder and inductive matrix completion. By co-training the information from microbe and disease space, the new representations of microbes and diseases are used to reconstruct microbe-disease association in the end-to-end framework. In particular, a similarity fusion strategy is conducted to improve prediction performance.ResultsThe experimental results show that the performance of GIMMDA is competitive with that of existing state-of-the-art methods on 3 datasets (i.e., HMDAD, Disbiome, and multiMDA). In particular, it performs best with the area under the receiver operating characteristic curve (AUC) of 0.9735, 0.9156, 0.9396 on abovementioned 3 datasets, respectively. And the result also confirms that different similarity fusions can improve the prediction performance. Furthermore, case studies on two diseases, i.e., asthma and obesity, validate the effectiveness and reliability of our proposed model.ConclusionThe proposed GIMMDA model show a strong capability in predicting microbe-disease associations. We expect that GPUDMDA will help identify potential microbe-related diseases in the future.

ANS-SCMC: A matrix completion method based on adaptive neighbourhood similarity and sparse constraints for predicting microbe-disease associations.

The use of matrix completion methods to predict the association between microbes and diseases can effectively improve treatment efficiency. However, the similarity measures used in the existing methods are often influenced by various factors such as neighbourhood size, choice of similarity metric, or multiple parameters for similarity fusion, making it challenging. Additionally, matrix completion is currently limited by the sparsity of the initial association matrix, which restricts its predictive performance. To address these problems, we propose a matrix completion method based on adaptive neighbourhood similarity and sparse constraints (ANS-SCMC) for predict microbe-disease potential associations. Adaptive neighbourhood similarity learning dynamically uses the decomposition results as effective information for the next learning iteration by simultaneously performing local manifold structure learning and decomposition. This approach effectively preserves fine local structure information and avoids the influence of weight parameters directly involved in similarity measurement. Additionally, the sparse constraint-based matrix completion approach can better handle the sparsity challenge in the association matrix. Finally, the algorithm we proposed has achieved significantly higher predictive performance in the validation compared to several commonly used prediction methods proposed to date. Furthermore, in the case study, the prediction algorithm achieved an accuracy of up to 80% for the top 10 microbes associated with type 1 diabetes and 100% for Crohn's disease respectively.

Identification of microbe–disease signed associations via multi-scale variational graph autoencoder based on signed message propagation

BackgroundPlenty of clinical and biomedical research has unequivocally highlighted the tremendous significance of the human microbiome in relation to human health. Identifying microbes associated with diseases is crucial for early disease diagnosis and advancing precision medicine.ResultsConsidering that the information about changes in microbial quantities under fine-grained disease states helps to enhance a comprehensive understanding of the overall data distribution, this study introduces MSignVGAE, a framework for predicting microbe-disease sign associations using signed message propagation. MSignVGAE employs a graph variational autoencoder to model noisy signed association data and extends the multi-scale concept to enhance representation capabilities. A novel strategy for propagating signed message in signed networks addresses heterogeneity and consistency among nodes connected by signed edges. Additionally, we utilize the idea of denoising autoencoder to handle the noise in similarity feature information, which helps overcome biases in the fused similarity data. MSignVGAE represents microbe-disease associations as a heterogeneous graph using similarity information as node features. The multi-class classifier XGBoost is utilized to predict sign associations between diseases and microbes.ConclusionsMSignVGAE achieves AUROC and AUPR values of 0.9742 and 0.9601, respectively. Case studies on three diseases demonstrate that MSignVGAE can effectively capture a comprehensive distribution of associations by leveraging signed information.

Discovering Microbe-disease Associations with Weighted Graph Convolution Networks and Taxonomy Common Tree

Background: Microbe-disease associations are integral to understanding complex diseases and their screening procedures. Objective: While numerous computational methods have been developed to detect these associations, their performance remains limited due to inadequate utilization of weighted inherent similarities and microbial taxonomy hierarchy. To address this limitation, we have introduced WTHMDA (weighted taxonomic heterogeneous network-based microbe-disease association), a novel deep learning framework. Methods: WTHMDA combines a weighted graph convolution network and the microbial taxonomy common tree to predict microbe-disease associations effectively. The framework extracts multiple microbe similarities from the taxonomy common tree, facilitating the construction of a microbe- disease heterogeneous interaction network. Utilizing a weighted DeepWalk algorithm, node embeddings in the network incorporate weight information from the similarities. Subsequently, a deep neural network (DNN) model accurately predicts microbe-disease associations based on this interaction network. Results: Extensive experiments on multiple datasets and case studies demonstrate WTHMDA's superiority over existing approaches, particularly in predicting unknown associations. Conclusion: Our proposed method offers a new strategy for discovering microbe-disease linkages, showcasing remarkable performance and enhancing the feasibility of identifying disease risk.

Predicting potential microbe-disease associations based on dual branch graph convolutional network.

Studying the association between microbes and diseases not only aids in the prevention and diagnosis of diseases, but also provides crucial theoretical support for new drug development and personalized treatment. Due to the time-consuming and costly nature of laboratory-based biological tests to confirm the relationship between microbes and diseases, there is an urgent need for innovative computational frameworks to anticipate new associations between microbes and diseases. Here, we propose a novel computational approach based on a dual branch graph convolutional network (GCN) module, abbreviated as DBGCNMDA, for identifying microbe-disease associations. First, DBGCNMDA calculates the similarity matrix of diseases and microbes by integrating functional similarity and Gaussian association spectrum kernel (GAPK) similarity. Then, semantic information from different biological networks is extracted by two GCN modules from different perspectives. Finally, the scores of microbe-disease associations are predicted based on the extracted features. The main innovation of this method lies in the use of two types of information for microbe/disease similarity assessment. Additionally, we extend the disease nodes to address the issue of insufficient features due to low data dimensionality. We optimize the connectivity between the homogeneous entities using random walk with restart (RWR), and then use the optimized similarity matrix as the initial feature matrix. In terms of network understanding, we design a dual branch GCN module, namely GlobalGCN and LocalGCN, to fine-tune node representations by introducing side information, including homologous neighbour nodes. We evaluate the accuracy of the DBGCNMDA model using five-fold cross-validation (5-fold-CV) technique. The results show that the area under the receiver operating characteristic curve (AUC) and area under the precision versus recall curve (AUPR) of the DBGCNMDA model in the 5-fold-CV are 0.9559 and 0.9630, respectively. The results from the case studies using published experimental data confirm a significant number of predicted associations, indicating that DBGCNMDA is an effective tool for predicting potential microbe-disease associations.

A computational model for potential microbe-disease association detection based on improved graph convolutional networks and multi-channel autoencoders.

Accumulating evidence shows that human health and disease are closely related to the microbes in the human body. In this manuscript, a new computational model based on graph attention networks and sparse autoencoders, called GCANCAE, was proposed for inferring possible microbe-disease associations. In GCANCAE, we first constructed a heterogeneous network by combining known microbe-disease relationships, disease similarity, and microbial similarity. Then, we adopted the improved GCN and the CSAE to extract neighbor relations in the adjacency matrix and novel feature representations in heterogeneous networks. After that, in order to estimate the likelihood of a potential microbe associated with a disease, we integrated these two types of representations to create unique eigenmatrices for diseases and microbes, respectively, and obtained predicted scores for potential microbe-disease associations by calculating the inner product of these two types of eigenmatrices. Based on the baseline databases such as the HMDAD and the Disbiome, intensive experiments were conducted to evaluate the prediction ability of GCANCAE, and the experimental results demonstrated that GCANCAE achieved better performance than state-of-the-art competitive methods under the frameworks of both 2-fold and 5-fold CV. Furthermore, case studies of three categories of common diseases, such as asthma, irritable bowel syndrome (IBS), and type 2 diabetes (T2D), confirmed the efficiency of GCANCAE.

A Comprehensive Pilot Study to Elucidate the Distinct Gut Microbial Composition and Its Functional Significance in Cardio-Metabolic Disease.

Cardio-metabolic disease is a significant global health challenge with increasing prevalence. Recent research underscores the disruption of gut microbial balance as a key factor in disease susceptibility. We aimed to characterize the gut microbiota composition and function in cardio-metabolic disease and healthy controls. For this purpose, we collected stool samples of 18 subjects (12 diseased, 6 healthy) and we performed metagenomics analysis and functional prediction using QIIME2 and PICRUSt. Furthermore, we carried out assessments of microbe-gene interactions, gene ontology, and microbe-disease associations. Our findings revealed distinct microbial patterns in the diseased group, particularly evident in lower taxonomic levels with significant variations in 14 microbial features. The diseased cohort exhibited an enrichment of Lachnospiraceae family, correlating with obesity, insulin resistance, and metabolic disturbances. Conversely, reduced levels of Clostridium, Gemmiger, and Ruminococcus genera indicated a potential inflammatory state, linked to compromised butyrate production and gut permeability. Functional analyses highlighted dysregulated pathways in amino acid metabolism and energy equilibrium, with perturbations correlating with elevated branch-chain amino acid levels-a known contributor to insulin resistance and type 2 diabetes. These findings were consistent across biomarker assessments, microbe-gene associations, and gene ontology analyses, emphasizing the intricate interplay between gut microbial dysbiosis and cardio-metabolic disease progression. In conclusion, our study unveils significant shifts in gut microbial composition and function in cardio-metabolic disease, emphasizing the broader implications of microbial dysregulation. Addressing gut microbial balance emerges as a crucial therapeutic target in managing cardio-metabolic disease burden.

Sparse graph cascade multi-kernel fusion contrastive learning for microbe–disease association prediction

Predicting microbe–disease associations (MDA) is crucial for proactively demystifying diseases causes and preventing them. Traditional prediction methods endure labor-intensive, time-consuming, and expensive. Therefore, this paper proposes CasMF-GCL, a novel Graph Contrastive Learning model based on sparse relation augmentation and a Cascaded Multi-kernel Fusion Network for MDA prediction. CasMF-GCL maximizes the use of sparse correlation information and eliminates data noise through an association augmentation technique based on low-rank sparse matrix completion. We employ diverse strategies to enhance the features of heterogeneous networks by exploring the similarity between microbes and diseases. Our model employs a new multi-layer graph convolutional network variant with a cascaded multi-kernel fusion mechanism, enabling weighted coding of local and global features for diseases and microbes. To further improve performance, we incorporate a self-supervised contrastive learning schema using multi-grain disease and microbe features and large-scale relation augmentations. Extensive experiments on two renowned datasets demonstrate that CasMF-GCL outperforms current state-of-the-art methods in seven indexes. The AUC values from 5-fold cross-validation are 0.997 and 0.989 for the two datasets, respectively. Ablation studies confirm the effectiveness of graph data augmentation, the power of the contrastive strategy, and the indispensability of the cascaded multi-kernel fusion network. Furthermore, case studies validate the prediction performance of CasMF-GCL.

Predicting Microbe-Disease Associations Based on a Linear Neighborhood Label Propagation Method with Multi-order Similarity Fusion Learning.

Computational approaches employed for predicting potential microbe-disease associations often rely on similarity information between microbes and diseases. Therefore, it is important to obtain reliable similarity information by integrating multiple types of similarity information. However, existing similarity fusion methods do not consider multi-order fusion of similarity networks. To address this problem, a novel method of linear neighborhood label propagation with multi-order similarity fusion learning (MOSFL-LNP) is proposed to predict potential microbe-disease associations. Multi-order fusion learning comprises two parts: low-order global learning and high-order feature learning. Low-order global learning is used to obtain common latent features from multiple similarity sources. High-order feature learning relies on the interactions between neighboring nodes to identify high-order similarities and learn deeper interactive network structures. Coefficients are assigned to different high-order feature learning modules to balance the similarities learned from different orders and enhance the robustness of the fusion network. Overall, by combining low-order global learning with high-order feature learning, multi-order fusion learning can capture both the shared and unique features of different similarity networks, leading to more accurate predictions of microbe-disease associations. In comparison to six other advanced methods, MOSFL-LNP exhibits superior prediction performance in the leave-one-out cross-validation and 5-fold validation frameworks. In the case study, the predicted 10 microbes associated with asthma and type 1 diabetes have an accuracy rate of up to 90% and 100%, respectively.

MLFLHMDA: predicting human microbe-disease association based on multi-view latent feature learning.

A growing body of research indicates that microorganisms play a crucial role in human health. Imbalances in microbial communities are closely linked to human diseases, and identifying potential relationships between microbes and diseases can help elucidate the pathogenesis of diseases. However, traditional methods based on biological or clinical experiments are costly, so the use of computational models to predict potential microbe-disease associations is of great importance. In this paper, we present a novel computational model called MLFLHMDA, which is based on a Multi-View Latent Feature Learning approach to predict Human potential Microbe-Disease Associations. Specifically, we compute Gaussian interaction profile kernel similarity between diseases and microbes based on the known microbe-disease associations from the Human Microbe-Disease Association Database and perform a preprocessing step on the resulting microbe-disease association matrix, namely, weighting K nearest known neighbors (WKNKN) to reduce the sparsity of the microbe-disease association matrix. To obtain unobserved associations in the microbe and disease views, we extract different latent features based on the geometrical structure of microbes and diseases, and project multi-modal latent features into a common subspace. Next, we introduce graph regularization to preserve the local manifold structure of Gaussian interaction profile kernel similarity and add -norms to the projection matrix to ensure the interpretability and sparsity of the model. The AUC values for global leave-one-out cross-validation and 5-fold cross validation implemented by MLFLHMDA are 0.9165 and 0.8942+/-0.0041, respectively, which perform better than other existing methods. In addition, case studies of different diseases have demonstrated the superiority of the predictive power of MLFLHMDA. The source code of our model and the data are available on https://github.com/LiangzheZhang/MLFLHMDA_master.

M3HOGAT: A Multi-View Multi-Modal Multi-Scale High-Order Graph Attention Network for Microbe-Disease Association Prediction.

Numerous scientific studies have found a link between diverse microorganisms in the human body and complex human diseases. Because traditional experimental approaches are time-consuming and expensive, using computational methods to identify microbes correlated with diseases is critical. In this paper, a new microbe-disease association prediction model is proposed that combines a multi-view multi-modal network and a multi-scale feature fusion mechanism, called M3HOGAT. Firstly, a microbe-disease association network and multiple similarity views are constructed based on multi-source information. Then, consider that neighbor information from disparate orders might be more adept at learning node representations. Consequently, the higher-order graph attention network (HOGAT) is devised to aggregate neighbor information from disparate orders to extract microbe and disease features from different networks and views. Given that the embedding features of microbe and disease from different views possess varying importance, a multi-scale feature fusion mechanism is employed to learn their interaction information, thereby generating the final feature of microbes and diseases. Finally, an inner product decoder is used to reconstruct the microbe-disease association matrix. Compared with five state-of-the-art methods on the HMDAD and Disbiome datasets, the results of 5-fold cross-validations show that M3HOGAT achieves the best performance. Furthermore, case studies on asthma and obesity confirm the effectiveness of M3HOGAT in identifying potential disease-related microbes.

Predicting potential microbe-disease associations based on auto-encoder and graph convolution network

The increasing body of research has consistently demonstrated the intricate correlation between the human microbiome and human well-being. Microbes can impact the efficacy and toxicity of drugs through various pathways, as well as influence the occurrence and metastasis of tumors. In clinical practice, it is crucial to elucidate the association between microbes and diseases. Although traditional biological experiments accurately identify this association, they are time-consuming, expensive, and susceptible to experimental conditions. Consequently, conducting extensive biological experiments to screen potential microbe-disease associations becomes challenging. The computational methods can solve the above problems well, but the previous computational methods still have the problems of low utilization of node features and the prediction accuracy needs to be improved. To address this issue, we propose the DAEGCNDF model predicting potential associations between microbes and diseases. Our model calculates four similar features for each microbe and disease. These features are fused to obtain a comprehensive feature matrix representing microbes and diseases. Our model first uses the graph convolutional network module to extract low-rank features with graph information of microbes and diseases, and then uses a deep sparse Auto-Encoder to extract high-rank features of microbe-disease pairs, after which the low-rank and high-rank features are spliced to improve the utilization of node features. Finally, Deep Forest was used for microbe-disease potential relationship prediction. The experimental results show that combining low-rank and high-rank features helps to improve the model performance and Deep Forest has better classification performance than the baseline model.

Microbe-Disease Association Prediction Using RGCN Through Microbe-Drug-Disease Network.

Accumulating evidence has shown that microbes play significant roles in human health and diseases. Therefore, identifying microbe-disease associations is conducive to disease prevention. In this article, a predictive method called TNRGCN is designed for microbe-disease associations based on Microbe-Drug-Disease Network and Relation Graph Convolutional Network (RGCN). First, considering that indirect links between microbes and diseases will be increased by introducing drug related associations, we construct a Microbe-Drug-Disease tripartite network through data processing from four databases including Human Microbe-Disease Association Database (HMDAD), Disbiome Database, Microbe-Drug Association Database (MDAD) and Comparative Toxicoge-nomics Database (CTD). Second, we construct similarity networks for microbes, diseases and drugs via microbe function similarity, disease semantic similarity and Gaussian interaction profile kernel similarity, respectively. Based on the similarity networks, Principal Component Analysis (PCA) is utilized to extract main features of nodes. These features will be input into the RGCN as initial features. Finally, based on the tripartite network and initial features, we design two-layer RGCN to predict microbe-disease associations. Experimental results indicate that TNRGCN achieves best performance in cross validation compared with other methods. Meanwhile, case studies for Type 2 diabetes (T2D), Bipolar disorder and Autism demonstrate the favorable effectiveness of TNRGCN in association prediction.

Dual Network Contrastive Learning for Predicting Microbe-Disease Associations

Predicting microbe-disease associations is crucial for demystifying the causes of diseases and preventing them proactively. However, most of existing approaches are feeble to comprehensively investigate the interactive relationships between diseases and microbes by self-supervised manner, resulting in the microbe-disease associations are hard to ploughed. In this paper, we propose DNCL-MDA, a novel <underline xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">M</u> icrobe- <underline xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">D</u> isease <underline xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">A</u> ssociations prediction model based on <underline xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">D</u> ual <underline xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">N</u> etwork <underline xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">C</u> ontrastive <underline xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">L</u> earning, to demystify potential microbe-disease associations (MDAs). Particularly, DNCL-MDA first constructs a pair of microbe-disease dual networks, and designs an effective information flow projection method to obtain the individual disease and microbe networks while reserving their interdependent information. Then, DNCL-MDA proposes an optimized graph contrastive learning approach to learn the discriminative feature representations of diseases and microbes. Finally, the feature representations are contacted and fed into a fully connected neural network to predict the potential microbe-disease associations automatically. Experimental results on real-world datasets demonstrate that our proposed DNCL-MDA largely outperforms the state-of-the-art methods with more promising AUC performances.

Predicting potential microbe-disease associations with graph attention autoencoder, positive-unlabeled learning, and deep neural network.

Microbes have dense linkages with human diseases. Balanced microorganisms protect human body against physiological disorders while unbalanced ones may cause diseases. Thus, identification of potential associations between microbes and diseases can contribute to the diagnosis and therapy of various complex diseases. Biological experiments for microbe-disease association (MDA) prediction are expensive, time-consuming, and labor-intensive. We developed a computational MDA prediction method called GPUDMDA by combining graph attention autoencoder, positive-unlabeled learning, and deep neural network. First, GPUDMDA computes disease similarity and microbe similarity matrices by integrating their functional similarity and Gaussian association profile kernel similarity, respectively. Next, it learns the feature representation of each microbe-disease pair using graph attention autoencoder based on the obtained disease similarity and microbe similarity matrices. Third, it selects a few reliable negative MDAs based on positive-unlabeled learning. Finally, it takes the learned MDA features and the selected negative MDAs as inputs and designed a deep neural network to predict potential MDAs. GPUDMDA was compared with four state-of-the-art MDA identification models (i.e., MNNMDA, GATMDA, LRLSHMDA, and NTSHMDA) on the HMDAD and Disbiome databases under five-fold cross validations on microbes, diseases, and microbe-disease pairs. Under the three five-fold cross validations, GPUDMDA computed the best AUCs of 0.7121, 0.9454, and 0.9501 on the HMDAD database and 0.8372, 0.8908, and 0.8948 on the Disbiome database, respectively, outperforming the other four MDA prediction methods. Asthma is the most common chronic respiratory condition and affects ~339 million people worldwide. Inflammatory bowel disease is a class of globally chronic intestinal disease widely existed in the gut and gastrointestinal tract and extraintestinal organs of patients. Particularly, inflammatory bowel disease severely affects the growth and development of children. We used the proposed GPUDMDA method and found that Enterobacter hormaechei had potential associations with both asthma and inflammatory bowel disease and need further biological experimental validation. The proposed GPUDMDA demonstrated the powerful MDA prediction ability. We anticipate that GPUDMDA helps screen the therapeutic clues for microbe-related diseases.

Multi-View Feature Aggregation for Predicting Microbe-Disease Association.

Microbes play a crucial role in human health and disease. Figuring out the relationship between microbes and diseases leads to significant potential applications in disease treatments. It is an urgent need to devise robust and effective computational methods for identifying disease-related microbes. This work proposes a Multi-View Feature Aggregation (MVFA) scheme that integrates the linear and nonlinear features to identify disease-related microbes. We introduce a non-negative matrix tri-factorization (NMTF) model to extract linear features for diseases and microbes. Then we learn another type of linear feature by utilizing a bi-random walk model. The nonlinear feature is obtained by inputting the two kinds of linear features into a capsule neural network. These three types of features describe the associations between diseases and microbes from different views. Finally, considering the complementary of these features, we leverage a logistic regression model to combine the NMTF model predictions, bi-random walk model predictions, and the capsule neural network predictions to obtain the final microbe-disease pair scores. We apply our method to predict human microbe-disease associations on two datasets. Experimental results show that our multi-view model outperforms the state-of-the-art models in recovering missing microbe-disease associations and predicting associations for new microbes. The ablation study shows that aggregating multi-view linear and nonlinear features can improve the prediction performance. Case studies on two diseases, i.e. Type 1 diabetes and Liver cirrhosis, further validate our method effectiveness.