A new framework for drug-disease association prediction combing light-gated message passing neural network and gated fusion mechanism.

With the development of research on the complex aetiology of many diseases, computational drug repositioning methodology has proven to be a shortcut to costly and inefficient traditional methods. Therefore, developing more promising computational methods is indispensable for finding new candidate diseases to treat with existing drugs. In this paper, a model integrating a new variant of message passing neural network and a novel-gated fusion mechanism called GLGMPNN is proposed for drug-disease association prediction. First, a light-gated message passing neural network (LGMPNN), including message passing, aggregation and updating, is proposed to separately extract multiple pieces of information from the similarity networks and the association network. Then, a gated fusion mechanism consisting of a forget gate and an output gate is applied to integrate the multiple pieces of information to extent. The forget gate calculated by the multiple embeddings is built to integrate the association information into the similarity information. Furthermore, the final node representations are controlled by the output gate, which fuses the topology information of the networks and the initial similarity information. Finally, a bilinear decoder is adopted to reconstruct an adjacency matrix for drug-disease associations. Evaluated by 10-fold cross-validations, GLGMPNN achieves excellent performance compared with the current models. The following studies show that our model can effectively discover novel drug-disease associations.

A weighted bilinear neural collaborative filtering approach for drug repositioning.

Drug repositioning is an efficient and promising strategy for traditional drug discovery and development. Many research efforts are focused on utilizing deep-learning approaches based on a heterogeneous network for modeling complex drug-disease associations. Similar to traditional latent factor models, which directly factorize drug-disease associations, they assume the neighbors are independent of each other in the network and thus tend to be ineffective to capture localized information. In this study, we propose a novel neighborhood and neighborhood interaction-based neural collaborative filtering approach (called DRWBNCF) to infer novel potential drugs for diseases. Specifically, we first construct three networks, including the known drug-disease association network, the drug-drug similarity and disease-disease similarity networks (using the nearest neighbors). To take the advantage of localized information in the three networks, we then design an integration component by proposing a new weighted bilinear graph convolution operation to integrate the information of the known drug-disease association, the drug's and disease's neighborhood and neighborhood interactions into a unified representation. Lastly, we introduce a prediction component, which utilizes the multi-layer perceptron optimized by the α-balanced focal loss function and graph regularization to model the complex drug-disease associations. Benchmarking comparisons on three datasets verified the effectiveness of DRWBNCF for drug repositioning. Importantly, the unknown drug-disease associations predicted by DRWBNCF were validated against clinical trials and three authoritative databases and we listed several new DRWBNCF-predicted potential drugs for breast cancer (e.g. valrubicin and teniposide) and small cell lung cancer (e.g. valrubicin and cytarabine).

A geometric deep learning framework for drug repositioning over heterogeneous information networks.

Drug repositioning (DR) is a promising strategy to discover new indicators of approved drugs with artificial intelligence techniques, thus improving traditional drug discovery and development. However, most of DR computational methods fall short of taking into account the non-Euclidean nature of biomedical network data. To overcome this problem, a deep learning framework, namely DDAGDL, is proposed to predict drug-drug associations (DDAs) by using geometric deep learning (GDL) over heterogeneous information network (HIN). Incorporating complex biological information into the topological structure of HIN, DDAGDL effectively learns the smoothed representations of drugs and diseases with an attention mechanism. Experiment results demonstrate the superior performance of DDAGDL on three real-world datasets under 10-fold cross-validation when compared with state-of-the-art DR methods in terms of several evaluation metrics. Our case studies and molecular docking experiments indicate that DDAGDL is a promising DR tool that gains new insights into exploiting the geometric prior knowledge for improved efficacy.

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

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

Drug-disease association prediction using semantic graph and function similarity representation learning over heterogeneous information networks.

Discovering new indications for existing drugs is a promising development strategy at various stages of drug research and development. However, most of them complete their tasks by constructing a variety of heterogeneous networks without considering available higher-order connectivity patterns in heterogeneous biological information networks, which are believed to be useful for improving the accuracy of new drug discovering. To this end, we propose a computational-based model, called SFRLDDA, for drug-disease association prediction by using semantic graph and function similarity representation learning. Specifically, SFRLDDA first integrates a heterogeneous information network (HIN) by drug-disease, drug-protein, protein-disease associations, and their biological knowledge. Second, different representation learning strategies are applied to obtain the feature representations of drugs and diseases from different perspectives over semantic graph and function similarity graphs constructed, respectively. At last, a Random Forest classifier is incorporated by SFRLDDA to discover potential drug-disease associations (DDAs). Experimental results demonstrate that SFRLDDA yields a best performance when compared with other state-of-the-art models on three benchmark datasets. Moreover, case studies also indicate that the simultaneous consideration of semantic graph and function similarity of drugs and diseases in the HIN allows SFRLDDA to precisely predict DDAs in a more comprehensive manner.

Predicting drug-disease associations through layer attention graph convolutional network.

BACKGROUND: Determining drug-disease associations is an integral part in the process of drug development. However, the identification of drug-disease associations through wet experiments is costly and inefficient. Hence, the development of efficient and high-accuracy computational methods for predicting drug-disease associations is of great significance. RESULTS: In this paper, we propose a novel computational method named as layer attention graph convolutional network (LAGCN) for the drug-disease association prediction. Specifically, LAGCN first integrates the known drug-disease associations, drug-drug similarities and disease-disease similarities into a heterogeneous network, and applies the graph convolution operation to the network to learn the embeddings of drugs and diseases. Second, LAGCN combines the embeddings from multiple graph convolution layers using an attention mechanism. Third, the unobserved drug-disease associations are scored based on the integrated embeddings. Evaluated by 5-fold cross-validations, LAGCN achieves an area under the precision-recall curve of 0.3168 and an area under the receiver-operating characteristic curve of 0.8750, which are better than the results of existing state-of-the-art prediction methods and baseline methods. The case study shows that LAGCN can discover novel associations that are not curated in our dataset. CONCLUSION: LAGCN is a useful tool for predicting drug-disease associations. This study reveals that embeddings from different convolution layers can reflect the proximities of different orders, and combining the embeddings by the attention mechanism can improve the prediction performances.

Drug repositioning based on the heterogeneous information fusion graph convolutional network.

In silico reuse of old drugs (also known as drug repositioning) to treat common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked drugs, with potentially lower overall development costs and shorter development timelines. Therefore, there is a pressing need for computational drug repurposing methodologies to facilitate drug discovery. In this study, we propose a new method, called DRHGCN (Drug Repositioning based on the Heterogeneous information fusion Graph Convolutional Network), to discover potential drugs for a certain disease. To make full use of different topology information in different domains (i.e. drug-drug similarity, disease-disease similarity and drug-disease association networks), we first design inter- and intra-domain feature extraction modules by applying graph convolution operations to the networks to learn the embedding of drugs and diseases, instead of simply integrating the three networks into a heterogeneous network. Afterwards, we parallelly fuse the inter- and intra-domain embeddings to obtain the more representative embeddings of drug and disease. Lastly, we introduce a layer attention mechanism to combine embeddings from multiple graph convolution layers for further improving the prediction performance. We find that DRHGCN achieves high performance (the average AUROC is 0.934 and the average AUPR is 0.539) in four benchmark datasets, outperforming the current approaches. Importantly, we conducted molecular docking experiments on DRHGCN-predicted candidate drugs, providing several novel approved drugs for Alzheimer's disease (e.g. benzatropine) and Parkinson's disease (e.g. trihexyphenidyl and haloperidol).

RLFDDA: a meta-path based graph representation learning model for drug-disease association prediction.

BACKGROUND: Drug repositioning is a very important task that provides critical information for exploring the potential efficacy of drugs. Yet developing computational models that can effectively predict drug-disease associations (DDAs) is still a challenging task. Previous studies suggest that the accuracy of DDA prediction can be improved by integrating different types of biological features. But how to conduct an effective integration remains a challenging problem for accurately discovering new indications for approved drugs. METHODS: In this paper, we propose a novel meta-path based graph representation learning model, namely RLFDDA, to predict potential DDAs on heterogeneous biological networks. RLFDDA first calculates drug-drug similarities and disease-disease similarities as the intrinsic biological features of drugs and diseases. A heterogeneous network is then constructed by integrating DDAs, disease-protein associations and drug-protein associations. With such a network, RLFDDA adopts a meta-path random walk model to learn the latent representations of drugs and diseases, which are concatenated to construct joint representations of drug-disease associations. As the last step, we employ the random forest classifier to predict potential DDAs with their joint representations. RESULTS: To demonstrate the effectiveness of RLFDDA, we have conducted a series of experiments on two benchmark datasets by following a ten-fold cross-validation scheme. The results show that RLFDDA yields the best performance in terms of AUC and F1-score when compared with several state-of-the-art DDAs prediction models. We have also conducted a case study on two common diseases, i.e., paclitaxel and lung tumors, and found that 7 out of top-10 diseases and 8 out of top-10 drugs have already been validated for paclitaxel and lung tumors respectively with literature evidence. Hence, the promising performance of RLFDDA may provide a new perspective for novel DDAs discovery over heterogeneous networks.

Integration of Neighbor Topologies Based on Meta-Paths and Node Attributes for Predicting Drug-Related Diseases.

Identifying new disease indications for existing drugs can help facilitate drug development and reduce development cost. The previous drug-disease association prediction methods focused on data about drugs and diseases from multiple sources. However, they did not deeply integrate the neighbor topological information of drug and disease nodes from various meta-path perspectives. We propose a prediction method called NAPred to encode and integrate meta-path-level neighbor topologies, multiple kinds of drug attributes, and drug-related and disease-related similarities and associations. The multiple kinds of similarities between drugs reflect the degrees of similarity between two drugs from different perspectives. Therefore, we constructed three drug-disease heterogeneous networks according to these drug similarities, respectively. A learning framework based on fully connected neural networks and a convolutional neural network with an attention mechanism is proposed to learn information of the neighbor nodes of a pair of drug and disease nodes. The multiple neighbor sets composed of different kinds of nodes were formed respectively based on meta-paths with different semantics and different scales. We established the attention mechanisms at the neighbor-scale level and at the neighbor topology level to learn enhanced neighbor feature representations and enhanced neighbor topological representations. A convolutional-autoencoder-based module is proposed to encode the attributes of the drug-disease pair in three heterogeneous networks. Extensive experimental results indicated that NAPred outperformed several state-of-the-art methods for drug-disease association prediction, and the improved recall rates demonstrated that NAPred was able to retrieve more actual drug-disease associations from the top-ranked candidates. Case studies on five drugs further demonstrated the ability of NAPred to identify potential drug-related disease candidates.

Inferring Drug-Related Diseases Based on Convolutional Neural Network and Gated Recurrent Unit.

Predicting novel uses for drugs using their chemical, pharmacological, and indication information contributes to minimizing costs and development periods. Most previous prediction methods focused on integrating the similarity and association information of drugs and diseases. However, they tended to construct shallow prediction models to predict drug-associated diseases, which make deeply integrating the information difficult. Further, path information between drugs and diseases is important auxiliary information for association prediction, while it is not deeply integrated. We present a deep learning-based method, CGARDP, for predicting drug-related candidate disease indications. CGARDP establishes a feature matrix by exploiting a variety of biological premises related to drugs and diseases. A novel model based on convolutional neural network (CNN) and gated recurrent unit (GRU) is constructed to learn the local and path representations for a drug-disease pair. The CNN-based framework on the left of the model learns the local representation of the drug-disease pair from their feature matrix. As the different paths have discriminative contributions to the drug-disease association prediction, we construct an attention mechanism at the path level to learn the informative paths. In the right part, a GRU-based framework learns the path representation based on path information between the drug and the disease. Cross-validation results indicate that CGARDP performs better than several state-of-the-art methods. Further, CGARDP retrieves more real drug-disease associations in the top part of the prediction result that are of concern to biologists. Case studies on five drugs demonstrate that CGARDP can discover potential drug-related disease indications.

Prediction of drug-disease associations based on reinforcement symmetric metric learning and graph convolution network.

Accurately identifying novel indications for drugs is crucial in drug research and discovery. Traditional drug discovery is costly and time-consuming. Computational drug repositioning can provide an effective strategy for discovering potential drug-disease associations. However, the known experimentally verified drug-disease associations is relatively sparse, which may affect the prediction performance of the computational drug repositioning methods. Moreover, while the existing drug-disease prediction method based on metric learning algorithm has achieved better performance, it simply learns features of drugs and diseases only from the drug-centered perspective, and cannot comprehensively model the latent features of drugs and diseases. In this study, we propose a novel drug repositioning method named RSML-GCN, which applies graph convolutional network and reinforcement symmetric metric learning to predict potential drug-disease associations. RSML-GCN first constructs a drug-disease heterogeneous network by integrating the association and feature information of drugs and diseases. Then, the graph convolutional network (GCN) is applied to complement the drug-disease association information. Finally, reinforcement symmetric metric learning with adaptive margin is designed to learn the latent vector representation of drugs and diseases. Based on the learned latent vector representation, the novel drug-disease associations can be identified by the metric function. Comprehensive experiments on benchmark datasets demonstrated the superior prediction performance of RSML-GCN for drug repositioning.

REDDA: Integrating multiple biological relations to heterogeneous graph neural network for drug-disease association prediction.

Computational drug repositioning is an effective way to find new indications for existing drugs, thus can accelerate drug development and reduce experimental costs. Recently, various deep learning-based repurposing methods have been established to identify the potential drug-disease associations (DDA). However, effective utilization of the relations of biological entities to capture the biological interactions to enhance the drug-disease association prediction is still challenging. To resolve the above problem, we proposed a heterogeneous graph neural network called REDDA (Relations-Enhanced Drug-Disease Association prediction). Assembled with three attention mechanisms, REDDA can sequentially learn drug/disease representations by a general heterogeneous graph convolutional network-based node embedding block, a topological subnet embedding block, a graph attention block, and a layer attention block. Performance comparisons on our proposed benchmark dataset show that REDDA outperforms 8 advanced drug-disease association prediction methods, achieving relative improvements of 0.76% on the area under the receiver operating characteristic curve (AUC) score and 13.92% on the precision-recall curve (AUPR) score compared to the suboptimal method. On the other benchmark dataset, REDDA also obtains relative improvements of 2.48% on the AUC score and 4.93% on the AUPR score. Specifically, case studies also indicate that REDDA can give valid predictions for the discovery of -new indications for drugs and new therapies for diseases. The overall results provide an inspiring potential for REDDA in the in silico drug development. The proposed benchmark dataset and source code are available in https://github.com/gu-yaowen/REDDA.

A model for predicting drug-disease associations based on dense convolutional attention network.

The development of new drugs is a time-consuming and labor-intensive process. Therefore, researchers use computational methods to explore other therapeutic effects of existing drugs, and drug-disease association prediction is an important branch of it. The existing drug-disease association prediction method ignored the prior knowledge contained in the drug-disease association data, which provided a strong basis for the research. Moreover, the previous methods only paid attention to the high-level features in the network when extracting features, and directly fused or connected them in series, resulting in the loss of information. Therefore, we propose a novel deep learning model for drug-disease association prediction, called DCNN. The model introduces the Gaussian interaction profile kernel similarity for drugs and diseases, and combines them with the structural similarity of drugs and the semantic similarity of diseases to construct the feature space jointly. Then dense convolutional neural network (DenseCNN) is used to capture the feature information of drugs and diseases, and introduces a convolutional block attention module (CBAM) to weight features from the channel and space levels to achieve adaptive optimization of features. The ten-fold cross-validation results of the model DCNN and the experimental results of the case study show that it is superior to the existing drug-disease association predictors and effectively predicts the drug-disease associations.

HeteroDualNet: A Dual Convolutional Neural Network With Heterogeneous Layers for Drug-Disease Association Prediction via Chou's Five-Step Rule.

Identifying new treatments for existing drugs can help reduce drug development costs and explore novel indications of drugs. The prediction of associations between drugs and diseases is challenging because their similarities and relations are complicated and non-linear. We propose a HeteroDualNet model to address this issue. Firstly, three types of matrices are extracted to represent intra-drug similarities, intra-disease similarity and drug-disease associations. The intra-drug similarities consider three drug features and a newly introduced drug-related disease correlation. Secondly, an embedding mechanism is proposed to integrate these matrices in a heterogenous drug-disease association layer (hetero-layer). Further, a neighbouring heterogeneous layer (hetero-layer-N) is constructed to incorporate the biological premise that similar drugs can often treat related diseases. Finally, a dual convolutional neural network is built with hetero-layer and hetero-layer-N as two branches to learn from characteristics of drug-disease and the relations of their neighbours simultaneously. HeteroDualNet outperformed the other four methods in comparison over a public dataset of 763 drugs and 681 diseases in terms of Areas Under the Curves of Receiver Operating Characteristics and Precision-Recall, and recall rate at top k. Case study of five drugs further proved the capacity of HeteroDualNet in finding reliable disease candidates of drugs as validated by database records or literature. Our findings show that the embedded heterogenous layers of original and neighbouring drug-disease representations in a dual neural network improved the association prediction performance.