Potential Microbe-disease Associations Research Articles

Predicting Microbe-Disease Association by Learning Graph Representations and Rule-Based Inference on the Heterogeneous Network

More and more clinical observations have implied that microbes have great effects on human diseases. Understanding the relations between microbes and diseases are of profound significance for disease prevention and therapy. In this paper, we propose a predictive model based on the known microbe-disease associations to discover potential microbe-disease associations through integrating Learning Graph Representations and a modified Scoring mechanism on the Heterogeneous network (called LGRSH). Firstly, the similarity networks for microbe and disease are obtained based on the similarity of Gaussian interaction profile kernel. Then, we construct a heterogeneous network including these two similarity networks and microbe-disease associations’ network. After that, the embedding algorithm Node2vec is implemented to learn representations of nodes in the heterogeneous network. Finally, according to these low-dimensional vector representations, we calculate the relevance between each microbe and disease by utilizing a modified rule-based inference method. By comparison with three other methods including LRLSHMDA, KATZHMDA and BiRWHMDA, LGRSH performs better than others. Moreover, in case studies of asthma, Chronic Obstructive Pulmonary Disease and Inflammatory Bowel Disease, there are 8, 8, and 10 out of the top-10 discovered disease-related microbes were validated respectively, demonstrating that LGRSH performs well in predicting potential microbe-disease associations.

Identifying Microbe-Disease Association Based on a Novel Back-Propagation Neural Network Model.

Over the years, numerous evidences have demonstrated that microbes living in the human body are closely related to human life activities and human diseases. However, traditional biological experiments are time-consuming and expensive, so it has become a research topic in bioinformatics to predict potential microbe-disease associations by adopting computational methods. In this study, a novel calculative method called BPNNHMDA is proposed to identify potential microbe-disease associations. In BPNNHMDA, a novel neural network model is first designed to infer potential microbe-disease associations, its input signal is a matrix of known microbe-disease associations, and its output signal is matrix of potential microbe-disease associations probabilities. And moreover, in the novel neural network model, a new activation function is designed to activate the hidden layer and the output layer based on the hyperbolic tangent function, and its initial connection weights are optimized by adopting Gaussian Interaction Profile kernel (GIP) similarity for microbes, which can improve the training speed of BPNNHMDA efficiently. Finally, in order to verify the performance of our prediction model, different frameworks such as the Leave-One-Out Cross Validation (LOOCV) and k-Fold Cross Validation ( k-Fold CV) are implemented on BPNNHMDA respectively. Simulation results illustrate that BPNNHMDA can achieve reliable AUCs of 0.9242, 0.9127 ± 0.0009 and 0.8955 ± 0.0018 in LOOCV, 5-Fold CV and 2-Fold CV separately, which are superior to previous state-of-the-art methods. Furthermore, case studies of inflammatory bowel disease (IBD), asthma and obesity demonstrate that BPNNHMDA has excellent prediction ability in practical applications as well.

WMGHMDA: a novel weighted meta-graph-based model for predicting human microbe-disease association on heterogeneous information network

BackgroundAn 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.ResultsHere, 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.ConclusionsThe 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.

A Bidirectional Label Propagation Based Computational Model for Potential Microbe-Disease Association Prediction.

A growing number of clinical observations have indicated that microbes are involved in a variety of important human diseases. It is obvious that in-depth investigation of correlations between microbes and diseases will benefit the prevention, early diagnosis, and prognosis of diseases greatly. Hence, in this paper, based on known microbe-disease associations, a prediction model called NBLPIHMDA was proposed to infer potential microbe-disease associations. Specifically, two kinds of networks including the disease similarity network and the microbe similarity network were first constructed based on the Gaussian interaction profile kernel similarity. The bidirectional label propagation was then applied on these two kinds of networks to predict potential microbe-disease associations. We applied NBLPIHMDA on Human Microbe-Disease Association database (HMDAD), and compared it with 3 other recent published methods including LRLSHMDA, BiRWMP, and KATZHMDA based on the leave-one-out cross validation and 5-fold cross validation, respectively. As a result, the area under the receiver operating characteristic curves (AUCs) achieved by NBLPIHMDA were 0.8777 and 0.8958 ± 0.0027, respectively, outperforming the compared methods. In addition, in case studies of asthma, colorectal carcinoma, and Chronic obstructive pulmonary disease, simulation results illustrated that there are 10, 10, and 8 out of the top 10 predicted microbes having been confirmed by published documentary evidences, which further demonstrated that NBLPIHMDA is promising in predicting novel associations between diseases and microbes as well.

BRWMDA:Predicting Microbe-Disease Associations Based on Similarities and Bi-Random Walk on Disease and Microbe Networks.

Many current studies have evidenced that microbes play important roles in human diseases. Therefore, discovering the associations between microbes and diseases is beneficial to systematically understanding the mechanisms of diseases, diagnosing, and treating complex diseases. It is well known that finding new potential microbe-disease associations via biological experiments is a time-consuming and expensive process. However, the computation methods can provide an opportunity to effectively predict microbe-disease associations. In recent years, efforts toward predicting microbe-disease associations are not in proportional to the importance of microbes to human diseases. In this study, we develop a method (called BRWMDA) to predict new microbe-disease associations based on similarity and improving bi-random walk on the disease and microbe networks. BRWMDA integrates microbe network, disease network, and known microbe-disease associations into a single network. After calculating the Gaussian Interaction Profile (GIP) kernel similarity of microbes based on known microbe-disease associations, the microbe network is obtained by adjusting the similarity with the logistics function. In addition, the disease network is computed by the similarity network fusion (SNF) method with the symptom-based similarity and the GIP kernel similarity based on known microbe-disease associations. Then, these two networks of microbe and disease are connected by known microbe-disease associations. Based on the assumption that similar microbes are normally associated with similar diseases and vice versa, BRWMDA is employed to predict new potential microbe-disease associations via random walk with different steps on microbe and disease networks, which reasonably uses the similarity of microbe network and disease network. The 5-fold cross validation and Leave One Out Cross Validation (LOOCV) are adopted to assess the prediction performance of our BRWMDA algorithm, as well as other competing methods for comparison. 5-fold cross validation experiments show that BRWMDA obtained the maximum AUC value of 0.9087, which is again superior to other methods of 0.9025(NGRHMDA), 0.8797 (LRLSHMDA), 0.8571 (KATZHMDA), 0.7782 (HGBI), and 0.5629 (NBI). In addition, BRWMDA also outperforms other methods in terms of LOOCV, whose AUC value is 0.9397, which is superior to other methods of 0.9111(NGRHMDA), 0.8909 (LRLSHMDA), 0.8644 (KATZHMDA), 0.7866 (HGBI), and 0.5553 (NBI). Case studies also illustrate that BRWMDA is an effective method to predict microbe-disease associations.

MHMDA: Human Microbe-Disease Association Prediction by Matrix Completion and Multi-Source Information

Microbes are vital in human health. It is helpful to promote diagnostic and treatment of human disease and drug development by identifying microbe-disease associations. However, knowledge in this area still needs to be further improved. In this paper, a new computational model using matrix completion to predict human microbe-disease associations (mHMDA, Fig. 1) is developed. First, we extract the disease feature by Gaussian kernel-based similarity and symptom-based similarity. Meanwhile, the microbe feature is computed by Gaussian kernel-based similarity. As treating potential association as the missing elements of a matrix, the matrix completion is adopted to get the potential microbe-disease associations. Leave-one-out cross-validation (LOOCV) is carried out which get the AUC (The area under ROC curve) of 0.928 showing the effectiveness of mHMDA. Furthermore, 5-fold CV get the AUCs of 0.8838 ± 0.0044 (mean ± standard deviation). Moreover, through the four case studies (asthma, inflammatory bowel disease (IBD), type 2 diabetes (T2D), and type 1 diabetes (T1D)), we find that nine, ten, nine, and eight of top-ten inferred microorganisms for the four diseases are previously verified by experiments. All these results indicate the effectiveness of mHMDA. mHMDA might be helpful to infer the disease-related microorganisms.

Predicting the associations between microbes and diseases by integrating multiple data sources and path-based HeteSim scores

Abstract A variety of microbial communities are renowned as “a forgotten organ” throughout human body, which have significant impacts on the human health and disease. Identifying the associations between microbes and diseases can provide us with valuable insights for understand the complex disease pathogenesis as well as the diagnosis and therapy, prevention, prognosis drug discovery. Because the experiment-based methods need a long and sampled time series to identify the microbe-disease associations, computational methods provide a valuable insight into understanding complex diseases. However, discovering novel and effective microbial candidates for complex diseases with computational prediction models is still limited. Here, we developed a new method to predict the potential microbe-disease associations by integrating Multiple Data sources and Path-based HeteSim scores for Human Microbe-Disease Associations (MDPH_HMDA). First of all, a heterogeneous network was constructed, in which microbe similarity was measured by the microbe-microbe functional similarity and Gaussian interaction profile kernel similarity for microbes, disease similarity was measured by the symptom-based human disease similarity and Gaussian interaction profile kernel similarity for diseases. Then, normalized HeteSim measure was employed to weight the known microbe-disease pairs, and the HeteSim scores of microbe-disease-disease path and microbe-microbe-disease path were integrated to calculate the relatedness scores for potential microbe-disease associations. Additionally, MDPH_HMDA achieved a reliable prediction performance with AUCs (the area under the ROC curve) of 0.9015 in the leave-one-out cross validation, and the results showed that our method could be effective to find the potential associations between microbes and microbes. Furthermore, representative diseases including type 2 diabetes, colorectal carcinoma, asthma and inflammatory bowel disease (IBD), in which the potential microbes associated with these diseases were ranked as candidate disease-causing microbes, respectively. The reliable performance showed that our proposed method could serve as a powerful computational tool to identify more microbe-disease associations and benefit to medical scientific progress in terms of the human medical improvement.

Prediction of Microbe-Disease Associations by Graph Regularized Non-Negative Matrix Factorization.

More and more evidence shows that microbes play crucial roles in human health and disease. The exploration of the relationship between microbes and diseases will help people to better understand the underlying pathogenesis and have important implications for disease diagnosis and prevention. However, the known associations between microbes and diseases are very less. We proposed a new method called non-negative matrix factorization microbe-disease associations (NMFMDA), which used Gaussian interaction profile kernel similarity measure, to calculate microbial similarity and disease similarity, and applied a logistic function to regulate disease similarity. And, based on the known microbe-disease associations, a graph-regularized non-negative matrix factorization model was utilized to simultaneously identify potential microbe-disease associations. Moreover, fivefold cross-validation was utilized to evaluate the performance of our method. It reached the reliable area under receiver operating characteristic curve (AUC) of 0.8891, higher than other state-of-the-art methods. Finally, the case studies on three complex human diseases (i.e., asthma, inflammatory bowel disease, and colon cancer) demonstrated the good performance of our method. In summary, our method can be considered as an effective computational model for predicting potential disease-microbe associations.

PRWHMDA: Human Microbe-Disease Association Prediction by Random Walk on the Heterogeneous Network with PSO.

Microorganisms resided in human body play a vital role in metabolism, immune defense, nutrition absorption, cancer control and protection against pathogen colonization. The changes of microbial communities can cause human diseases. Based on the known microbe-disease association, we presented a novel computational model employing Random Walking with Restart optimized by Particle Swarm Optimization (PSO) on the heterogeneous interlinked network of Human Microbe-Disease Associations (PRWHMDA) (see Figure 1). Based on the known human microbe-disease associations, we constructed the heterogeneous interlinked network with Cosine similarity. The extended random walk with restart (RWR) method was derived to get the potential microbe-disease associations. PSO was utilized to get the optimal parameters of RWR. To evaluate the prediction effectiveness, we performed leave one out cross validation (LOOCV) and 5-fold cross validation (CV), which got the AUC (The area under ROC curve) of 0.915 (LOOCV) and the average AUCs of 0.8875 ± 0.0046 (5-fold CV). Moreover, we carried out three case studies of asthma, inflammatory bowel disease (IBD) and type 1 diabetes (T1D) for the further evaluation. The result showed that 10, 10 and 9 of top-10 predicted microbes were verified by previously published experimental results, respectively. It is anticipated that PRWHMDA can be effective to identify the disease-related microbes and maybe helpful to disclose the relationship between microorganisms and their human host.

Novel human microbe-disease association prediction using network consistency projection

BackgroundAccumulating biological and clinical reports have indicated that imbalance of microbial community is closely associated with occurrence and development of various complex human diseases. Identifying potential microbe-disease associations, which could provide better understanding of disease pathology and further boost disease diagnostic and prognostic, has attracted more and more attention. However, hardly any computational models have been developed for large scale microbe-disease association prediction.ResultsIn this article, based on the assumption that microbes with similar functions tend to share similar association or non-association patterns with similar diseases and vice versa, we proposed the model of Network Consistency Projection for Human Microbe-Disease Association prediction (NCPHMDA) by integrating known microbe-disease associations and Gaussian interaction profile kernel similarity for microbes and diseases. NCPHMDA yielded outstanding AUCs of 0.9039, 0.7953 and average AUC of 0.8918 in global leave-one-out cross validation, local leave-one-out cross validation and 5-fold cross validation, respectively. Furthermore, colon cancer, asthma and type 2 diabetes were taken as independent case studies, where 9, 9 and 8 out of the top 10 predicted microbes were successfully confirmed by recent published clinical literature.ConclusionNCPHMDA is a non-parametric universal network-based method which can simultaneously predict associated microbes for investigated diseases but does not require negative samples. It is anticipated that NCPHMDA would become an effective biological resource for clinical experimental guidance.

A novel approach for predicting microbe-disease associations by bi-random walk on the heterogeneous network.

Since the microbiome has a significant impact on human health and disease, microbe-disease associations can be utilized as a valuable resource for understanding disease pathogenesis and promoting disease diagnosis and prognosis. Accordingly, it is necessary for researchers to achieve a comprehensive and deep understanding of the associations between microbes and diseases. Nevertheless, to date, little work has been achieved in implementing novel human microbe-disease association prediction models. In this paper, we develop a novel computational model to predict potential microbe-disease associations by bi-random walk on the heterogeneous network (BiRWHMDA). The heterogeneous network was constructed by connecting the microbe similarity network and the disease similarity network via known microbe-disease associations. Microbe similarity and disease similarity were calculated by the Gaussian interaction profile kernel similarity measure; moreover, a logistic function was applied to regulate disease similarity. Additionally, leave-one-out cross validation and 5-fold cross validation were implemented to evaluate the predictive performance of our method; both cross validation methods performed well. The leave-one-out cross validation experiment results illustrate that our method outperforms other previously proposed methods. Furthermore, case studies on asthma and inflammatory bowel disease prove the favorable performance of our method. In conclusion, our method can be considered as an effective computational model for predicting novel microbe-disease associations.