MOTIVATION: The increasing prevalence of antibiotic-resistant bacteria has intensified the demand for novel antimicrobial agents. Antimicrobial peptides (AMPs) have emerged as promising alternatives, yet their identification or classification remains challenging due to the lack of multi-perspective information, insufficient feature representation learning, and monocular data modalities. RESULTS: In this paper, we propose a dual diffusion model-based representation learning framework for classifying AMPs, which effectively integrates both peptide sequence and structure information to address existing issues for the task. Specifically, our approach utilizes a multi-view feature construction module, which encodes peptide sequences and structures from distinctive perspectives, deriving initial feature representations with enriched biological semantics. To enhance representation learning, the proposed framework leverages both diffusion models for sequence and structure information respectively to effectively capture complex semantics from dual modalities. In addition, both single-modal and dual-modal contrastive learning are used to further advance the representation learning. Results of comprehensive experiments demonstrate that our model outperforms existing methods for the task of AMPs classification, providing a feasible solution to accelerating the discovery of novel antimicrobial agents. AVAILABILITY OF IMPLEMENTATION: The data and source codes are available in GitHub at https://github.com/kww567upup/DDM.

One-shot Text-to-Image Person Re-Identification (One-shot TIReID) aims to construct a TIReID model using only a single labeled image-text pair per identity, along with a large pool of unlabeled person images. While supervised learning in text-to-image person re-identification has demonstrated high effectiveness, the requirement for extensive annotated data, both in terms of identities and corresponding textual descriptions, makes it impractical for large-scale camera networks. One-shot TIReID presents a promising approach to reduce the annotation burden. The primary challenge in one-shot TIReID lies in establishing consistent visual-textual correspondences across diverse viewing conditions, particularly in the absence of cross-view paired data. To address this challenge, we propose a novel progressive discrepancy learning framework, termed P-CLIP, which aims to establish a shared embedding space that is robust to view-specific biases. To achieve this goal, we dynamically construct multi-view image-text pairs based on a single labeled pair and simultaneously project the multi-view data into a unified embedding space. Specifically, we propose a Progressive Multi-View Generation method (MVG) to generate multiple noisy views from a single labeled instance for training. To mitigate cross-view ambiguities, we introduce a Cross-View Discrepancy Learning module (CDL) that leverages the discrepancies among different views to guide the learning of cross-view visual-textual correspondences. This approach effectively integrates multimodal error correction into the person re-identification domain. Furthermore, to enhance the effectiveness of visual-textual correspondence learning, we propose a Compact Cross-Modal Matching Loss (CCM), which suppresses unmatched pairs while emphasizing matched ones. Extensive experiments were conducted on three benchmark datasets, and the experimental results demonstrate the effectiveness of our proposed method. The data and codes are available at https://github.com/Itachjw/P-CLIP/tree/main.

The task of nanobody paratope prediction aims to identify the residues on a nanobody that specifically bind to an antigen, which is crucial for understanding the mechanisms of an effective nanobody agent, providing significant implications for drug development accordingly. Although various methods have been proposed based on different strategies, existing methods still face several challenges: overlooking nanobody-specific structural characteristics, neglecting optimization of high-dimensional features extracted from antibody language models, and disregarding the antigen information crucial for nanobody-specific binding. To address these challenges, we propose NanoFADIL, a novel nanobody paratope prediction model that employs a fused attention mechanism combining channel attention and one-dimensional spatial attention to optimize feature representations adaptively, and uses residue-level distance supervision to guide the learning of nanobody-antigen interaction patterns. Specifically, the existing nanobody paratope dataset is augmented by incorporating the sequences of corresponding antigens, allowing the prediction of antigen-specific paratopes on nanobodies. Nanobodies are encoded by the pretrained antibody language model IgT5 to derive meaningful feature representations. High-dimensional nanobody representations are adaptively reweighted across feature channels and residue positions by our fused attention mechanism that combines channel-wise and one-dimensional spatial attention, thereby enabling the model to focus on informative features relevant to nanobody paratope prediction and contextually important residues. During training, residue-level distances between nanobodies and antigens are transformed into supervision signals, guiding the model to learn meaning-ful nanobody-antigen interaction patterns and enhancing the model's predictive capability. Experimental results demonstrate that NanoFADIL achieves superior performance compared to existing methods.

The critical role of nutrients in intervening in human diseases has made a deeper exploration of microbial metabolic processes greatly needed. Bacteriophages serve as key regulators in maintaining microecological balance. Existing studies have revealed that nutrients promote bacteriophage production in gut bacteria, subsequently affecting bacterial abundance and influencing disease development. However, current research lacks systematic integration of the relationships among bacteriophages, nutrition, gut bacteria, and diseases, which partially limits our understanding of the intervention mechanisms between nutrition and diseases. To address this, we constructed a novel knowledge graph, KGNBVD, focusing on the interconnections among dietary nutrition, gut bacteria, bacteriophages, and human diseases by harnessing large-scale biomedical literature and the promptdriven capabilities of large language models (lLMs). Additionally, to elucidate the mechanistic role of bacteriophages in linking nutrients and human diseases, we proposed a multi-view fusion approach that fully explore the features of KGNBVD. Extensive experimental results demonstrated that our method outperforms state-of-the-art methods in predicting four-entity interactions with AUC values of 96.20 % and$\mathbf{F 1}$scores of$\mathbf{8 9. 7 2 \%}$. Moreover, results of case study validated that our method can identify high-probability candidate entities for previously unseen entity interactions, effectively predicting potential interactions between nutrition and human diseases.

The prediction of protein-peptide binding residues is to identify the protein residues that can bind to peptides, which is essential for uncovering protein functions and supporting peptide-based drug development. Despite the progress made by previous methods, several challenges remain, including the neglect of protein domain information, the underutilization of protein language models, and the issue of data imbalance. In this paper, we propose PepGFD, a novel model based on a gated fusion mechanism and domain-guided feature optimization to predict protein-peptide binding residues. Specifically, PepGFD employs a gated fusion mechanism to fuse complementary features extracted from two protein language models, ESM-2 and ProtT5, to construct protein node features. Meanwhile, multiple properties are extracted from the protein structure to construct protein edge features. To guide the model in identifying key functional residues on the protein, we incorporate protein domain information to optimize protein node features. Subsequently, we employ multiple attention mechanisms to process protein features and peptide features separately, while effectively capturing the semantics among interactions between them. Additionally, a dualstrategy contrastive learning (DSCL) approach is used to address the issue of data imbalance, thereby enabling the model to better distinguish between binding and non-binding residues. Experimental results on two widely used benchmark datasets demonstrate that PepGFD achieves superior performance compared to existing models.

Identifying phage-host interactions (PHIs) is a crucial step in developing phage therapy, which is the promising solution to addressing the issue of antibiotic resistance in superbugs. However, the lifestyle of phages, which strongly depends on their host for life activities, limits their cultivability, making the study of predicting PHIs time-consuming and labor-intensive for traditional wet lab experiments. Although many deep learning (DL) approaches have been applied to PHIs prediction, most DL methods are predominantly based on sequence information, failing to comprehensively model the intricate relationships within PHIs. Moreover, most existing approaches are limited for sub-optimal performance, due to the potential risk of overfitting induced by the highly data sparsity in the task of PHIs prediction. In this study, we propose a novel approach called MI-RGC, which introduces mutual information for feature augmentation and employs regional graph convolution to learn meaningful representations. Specifically, MI-RGC treats the presence status of phages in environmental samples as random variables, and derives the mutual information between these random variables as the dependency relationships among phages. Consequently, a mutual information-based heterogeneous network is construted as feature augmentation for sequence information of phages, which is utilized for building a sequence information-based heterogeneous network. By considering the different contributions of neighboring nodes at varying distances, a regional graph convolutional model is designed, in which the neighboring nodes are segmented into different regions and a regional-level attention mechanism is employed to derive node embeddings. Finally, the embeddings learned from these two networks are aggregated through an attention mechanism, on which the prediction of PHIs is condcuted accordingly. Experimental results on three benchmark datasets demonstrate that MI-RGC derives superior performance over other methods on the task of PHIs prediction.

Bacterial resistance has emerged as one of the greatest threats to human health, and phages have shown tremendous potential in addressing the issue of drug-resistant bacteria by lysing host. The identification of phage-host interactions (PHI) is crucial for addressing bacterial infections. Some existing computational methods for predicting PHI are suboptimal in terms of prediction efficiency due to the limited types of available information. Despite the emergence of some supporting information, the generalizability of models using this information is limited by the small scale of the databases. Additionally, most existing models overlook the sparsity of association data, which severely impacts their predictive performance as well. In this study, we propose a dual-view sparse network model (DSPHI) to predict PHI, which leverages logical probability theory and network sparsification. Specifically, we first constructed similarity networks using the sequences of phages and hosts respectively, and then sparsified these networks, enabling the model to focus more on key information during the learning process, thereby improving prediction efficiency. Next, we utilize logical probability theory to compute high-order logical information between phages (hosts), which is known as mutual information. Subsequently, we connect this information in node form to the sparse phage (host) similarity network, resulting in a phage (host) heterogeneous network that better integrates the two information views, thereby reducing the complexity of model computation and enhancing information aggregation capabilities. The hidden features of phages and hosts are explored through graph learning algorithms. Experimental results demonstrate that mutual information is effective information in predicting PHI, and the sparsification procedure of similarity networks significantly improves the model's predictive performance.

It is commonly known that food nutrition is closely related to human health. The complex interactions between food nutrients and diseases, influenced by gut microbial metabolism, present challenges in systematizing and practically applying knowledge. To address this, we propose a method for extracting triples from a vast amount of literature, which is used to construct a comprehensive knowledge graph on nutrition and human health. Concurrently, we develop a query-based question answering system over our knowledge graph, proficiently addressing three types of questions. The results show that our proposed model outperforms other state-of-art methods, achieving a precision of 0.92, a recall of 0.81, and an F1 score of 0.86 in the nutrition and disease relation extraction task. Meanwhile, our question answering system achieves an accuracy of 0.68 and an F1 score of 0.61 on our benchmark dataset, showcasing competitiveness in practical scenarios. Furthermore, we design five independent experiments to assess the quality of the data structure in the knowledge graph, ensuring results characterized by high accuracy and interpretability. In conclusion, the construction of our knowledge graph shows significant promise in facilitating diet recommendations, enhancing patient care applications, and informing decision-making in clinical research.

Due to the abuse of antibiotics, some pathogenic bacteria have developed resistance to most antibiotics, leading to the emergence of antibiotic-resistant superbugs. Therefore, researchers resort to phage therapy for bacterial infections. For phage therapy, the fundamental step is to accurately identify phage-host interactions. Although various methods have been proposed, the existing methods suffer from the following two shortcomings: 1) they fail to make full use of genetic information including both genome and protein sequence of phages; 2) host specificity of phages is not explicitly utilized when learning representations of phages and bacteria. In this paper, we present an efficient computational method called PHISGAE for predicting phage-host interactions, in which the host specificity is explicitly employed. Firstly, initial phage-phage connections are efficiently constructed via utilizing phage genome and protein sequence. Then, the refined heterogeneous network is derived by applying K-nearest neighbor strategy, keeping relatively more meaningful local semantics among phages and bacteria. Finally, a host specificity-aware graph autoencoder is proposed to learn high-quality representations of phages and bacteria for predicting phage-host interactions. Experimental results show that PHISGAE outperforms the state-of-the-art methods on predicting phage-host interactions at both species level and genus level (AUC values of 94.73% and 96.32%, respectively). Moreover, results of case study demonstrate that PHISGAE is able to identify candidate hosts with high probability for previously unseen phages identified from metagenomics, effectively predicting potential phage-host interactions in real-world applications.

Antimicrobial peptides (AMPs) hold significant promise in antibacterial and anticancer research, offering a crucial solution to the escalating issue of antibiotic resistance and paving the way for developing novel strategy for cancer treatments. Previously, experimental methods were used to identify AMPs. However, there is now a shift towards developing computational approaches to predict AMPs accurately, greatly reducing the time and effort required for experimental identification. Past computation methods for predicting AMPs have either focused on feature encoding and extraction or emphasized neural network design. Unfortunately, relying on a single method or feature can lead to the oversight of important information. In this study, we present AMPpred-DLFF, a novel computational method for identifying AMPs. This method initially employs ESM-2 to generate residue embedding representations, captures the spatial relationships between residues, and constructs a graph to integrate peptide data. Subsequently, a graph attention network extracts features from the graph data. Concurrently, multiple encoding techniques are used to extract residue features from sequence data, which are then processed by a convolutional neural network. Finally, the feature representations from both modules are combined, and the peptide sequence is predicted as an antimicrobial peptide through a fully connected layer. Performance assessments on several benchmark datasets demonstrate that AMPpred-DLFF outperforms current leading methods, underscoring the effectiveness of multi-view fusion in enhancing AMP prediction accuracy.

Recognizing human feelings from image and text is a core challenge of multi-modal data analysis, often applied in personalized advertising. Previous works aim at exploring the shared features, which are the matched contents between images and texts. However, the modality-dependent sentiment information (private features) in each modality is usually ignored by cross-modal interactions, the real sentiment is often reflected in one modality. In this paper, we propose a Modality-Dependent Sentiment Exploring framework (MDSE). First, to exploit the private features, we compare shared features with original image or text features, identifying previously overlooked unimodal features. Fusing the private and shared features can make the model more robust. Second, in order to obtain unified sentiment representations, we treat unimodal features and multi-modal fused features equally. We introduce a Modality-Agnostic Contrastive Loss (MACL) that performs contrastive learning between unimodal features and multi-modal fused features. The MACL can fully exploit sentiment information from multi-modal data and reduce the modality gap. Experiments on four public datasets demonstrate the effectiveness of our MDSE compared with existing methods. The full codes are available at https://github.com/royal-dargon/MDSE.

Small open reading frames (smORFs) have been acknowledged to play various roles on essential biological pathways and affect human beings from diabetes to tumorigenesis. Predicting smORFs in silico is quite a prerequisite for processing the omics data. Here, we proposed the smORF-coding-potential-predicting framework, sOCP, which provides functions to construct a model for predicting novel smORFs in some species. The sOCP model constructed in human was based on in-frame features and the nucleotide bias around the start codon, and the small feature subset was proved to be competent enough and avoid overfitting problems for complicated models. It showed more advanced prediction metrics than previous methods and could correlate closely with experimental evidence in a heterogeneous dataset. The model was applied to Rattus norvegicus and exhibited satisfactory performance. We then scanned smORFs with ATG and non-ATG start codons from the human genome and generated a database containing about a million novel smORFs with coding potential. Around 72 000 smORFs are located on the lncRNA regions of the genome. The smORF-encoded peptides may be involved in biological pathways rare for canonical proteins, including glucocorticoid catabolic process and the prokaryotic defense system. Our work provides a model and database for human smORF investigation and a convenient tool for further smORF prediction in other species.

MOTIVATION: The crisis of antibiotic resistance, which causes antibiotics used to treat bacterial infections to become less effective, has emerged as one of the foremost challenges to public health. Identifying the properties of antibiotic resistance genes (ARGs) is an essential way to mitigate this issue. Although numerous methods have been proposed for this task, most of these approaches concentrate solely on predicting antibiotic class, disregarding other important properties of ARGs. In addition, existing methods for simultaneously predicting multiple properties of ARGs fail to account for the causal relationships among these properties, limiting the predictive performance. RESULTS: In this study, we propose a causality-guided framework for annotating properties of ARGs, in which causal inference is utilized for representation learning. More specifically, the hidden biological patterns determining the properties of ARGs are described by a Gaussian Mixture Model, and procedure of causal representation learning is used to derive the hidden features. In addition, a causal graph among different properties is constructed to capture the causal relationships among properties of ARGs, which is integrated into the task of annotating properties of ARGs. The experimental results on a real-world dataset demonstrate the effectiveness of the proposed framework on the task of annotating properties of ARGs. AVAILABILITY AND IMPLEMENTATION: The data and source codes are available in GitHub at https://github.com/David-WZhao/CausalARG.

Computational drug repositioning can identify potential associations between drugs and diseases. This technology has been shown to be effective in accelerating drug development and reducing experimental costs. Although there has been plenty of research for this task, existing methods are deficient in utilizing complex relationships among biological entities, which may not be conducive to subsequent simulation of drug treatment processes. In this article, we propose a heterogeneous graph embedding method called HMLKGAT to infer novel potential drugs for diseases. More specifically, we first construct a heterogeneous information network by combining drug-disease, drug-protein and disease-protein biological networks. Then, a multi-layer graph attention model is utilized to capture the complex associations in the network to derive representations for drugs and diseases. Finally, to maintain the relationship of nodes in different feature spaces, we propose a multi-kernel learning method to transform and combine the representations. Experimental results demonstrate that HMLKGAT outperforms six state-of-the-art methods in drug-related disease prediction, and case studies of five classical drugs further demonstrate the effectiveness of HMLKGAT.

The crisis of antibiotic resistance has become a significant global threat to human health. Understanding properties of antibiotic resistance genes (ARGs) is the first step to mitigate this issue. Although many methods have been proposed for predicting properties of ARGs, most of these methods focus only on predicting antibiotic classes, while ignoring other properties of ARGs, such as resistance mechanisms and transferability. However, acquiring all of these properties of ARGs can help researchers gain a more comprehensive understanding of the essence of antibiotic resistance, which will facilitate the development of antibiotics. In this paper, the task of predicting properties of ARGs is modeled as a multi-task learning problem, and an effective subtask-aware representation learning-based framework is proposed accordingly. More specifically, property-specific expert networks and shared expert networks are utilized respectively to learn subtask-specific features for each subtask and shared features among different subtasks. In addition, a gating-controlled mechanism is employed to dynamically allocate weights to subtask-specific semantics and shared semantics obtained respectively from property-specific expert networks and shared expert networks, thus adjusting distinctive contributions of subtask-specific features and shared features to achieve optimal performance for each subtask simultaneously. Extensive experiments are conducted on publicly available data, and experimental results demonstrate the effectiveness of the proposed framework on the task of ARGs properties prediction.

The established links between nutrition and human health are widely acknowledged. Dietary nutrients play a crucial role in regulating gut microbial communities, influencing various human diseases. With a growing number of related studies, there’s a need to systematically organize these associations for coherent knowledge reasoning. However, due to the diverse and extensive nature of the knowledge landscape, significant challenges persist. To address this, we propose an approach using multimodal data and knowledge embeddings for effective knowledge reasoning in nutrition and human health. We create a comprehensive knowledge graph, KG4NH, covering dietary nutrition, gut microbiota, and human diseases. To ensure efficient knowledge representation, we employ knowledge embedding techniques to develop modality-specific encoders for structure, category, and description. Additionally, we introduce a mul-timodal fusion method to capture shared information across modalities. Our experimental results demonstrate the superiority of our approach over other state-of-the-art methods.

Despite profound impacts on human health and nature, accurately predicting microbe-metabolite interactions remains challenging due to inherent data noise. This study applies non-negative matrix factorization (NMF) and multi-view NMF to reduce noise and exploit associations across data perspectives. NMF obtains low-dimensional microbial and metabolic representations, effectively reducing noise. The dimension-reduced spectral matrices were input into the generative network model to derive conditional probabilities of individual microbe-associated metabolites and microbe-metabolite co-occurrence probabilities, the latter enabling prediction of microbe-metabolite interactions. Moreover, multi-view NMF integrates microbial and metabolic data by mapping them into a shared subspace, thereby enhancing prediction performance and validating cross-perspective correlation modeling. This study demonstrates NMF's efficacy in noise reduction through dimensionality reduction, and multiview NMF's ability to leverage cross-view associations. Both approaches demonstrate enhanced microbe-metabolite interaction prediction utilizing NMF-based and multi-view NMF-based generative network models.

Antibiotic resistance event extraction involves the automated extraction of information related to antibiotic resistance mechanisms from a vast amount of biomedical literature. This can be achieved by utilizing natural language processing techniques. However, the distinctive characteristics of the biomedical field lead to various challenges for existing antibiotic resistance event extraction methods, such as limited labeling data, complex names of biomedical entities, and nesting and overlapping event structures. These factors make it challenging to apply the current processing methods for biomedical text to the task of antibiotic resistance event extraction. To address these challenges, we propose a cascade decoding approach for antibiotic resistance event extraction based on contrastive learning (CL-MA-CasEE). This approach achieves data augmentation by constructing two contrastive learning tasks, which combines entity type embedding and POS embedding to enrich the semantic information of word representations. Furthermore, it performs event type detection, event trigger extraction, and event argument extraction through using three cascade decoders to simulate the complex event structures. Based on experiments, we demonstrate that our method can effectively extract structured antibiotic resistance event information from biomedical literature, thereby improve the efficiency of event extraction tasks as well.

Detecting drug side effects is crucial in development of drugs. As publicly available biomedical data expands, researchers have devised numerous computational methods for predicting drug-side effect associations (DSAs). Among these, network-based approaches have gained significant attention in the biomedical field. However, the challenge of data scarcity poses a significant hurdle for existing DSAs prediction models. While various data augmentation methods have been created to solve the proble, most rely on random alterations to the original networks, neglecting the causality of DSAs’ existence, thus impacting the predictive performance negatively. In this paper, we introduce a counterfactual inference-based data augmentation method to enhance performance. First,a heterogeneous information network (HIN) is construct by integrating multiple biomedical data sources. We employ community detection on the HIN to preform a counterfactual inference-based method, deriving augmented links and an augmented HIN. Subsequently, we apply a meta-path-based graph neural network to obtain high-quality representations of drugs and side effects, enabling the prediction of DSAs. Our comprehensive experiments confirm the effectiveness of this counterfactual inference-based data augmentation for DSAs prediction.

Drug repositioning is the process of identifying potential associations between approved drugs and diseases (DDAs) to unveil novel therapeutic applications. Unlike traditional drug discovery approaches, a key advantage of drug repositioning lies in its capacity to leverage the existing knowledge and safety profiles of established medications, leading to significant reductions in both the time and costs associated with drug development. While various methods have been proposed to address this challenge using diverse strategies, the conventional approach for training DDAs prediction models typically relies on random sampling of unknown drug-disease pairs to construct negative samples. However, this method may inadvertently introduce unwanted noise or errors by erroneously categorizing some genuine DDAs as negative samples, thereby leaving room for improvement in current methodologies. In this paper, we introduce a novel negative sample selection algorithm for DDAs prediction that explicitly incorporates causal knowledge inherent in DDAs. To accomplish this, we first construct a heterogeneous information network (HIN) that encompasses various biological entities associated with DDAs and their interconnections. Subsequently, we utilize the outcomes of community detection within the HIN as a form of counterfactual inference, resulting in the development of a negative sample selection algorithm based on a thoughtfully designed counterfactual question. By combining the known DDAs (i.e., positive samples) with the newly generated negative samples, we train a prediction model that incorporates a graph learning module to acquire representations of drugs and diseases. Comprehensive experiments confirm the effectiveness of our proposed model for DDAs prediction.

Drug-drug interaction (DDI) pertains to the occurrence where the concomitant use of two or more drugs may lead to interactions in terms of their pharmacokinetic or pharmacodynamic behavior, resulting in unexpected effects. Accurately predicting DDIs holds significant importance in ensuring drug safety. Despite the numerous approaches proposed for DDI prediction, a majority of these methods often overlook the challenge presented by cold-start scenario, consequently limiting their applicability. This paper presents a novel data augmentation approach for the prediction of DDIs in cold-start scenarios. This method leverages counterfactual inference to generate meaningful pseudo samples for drugs with limited prior information. To achieve this, a HIN relevant to DDIs is initially established by amalgamating various associations between drugs and proteins. Subsequently, the identification of drug communities within this HIN is regarded as a form of counterfactual inference treatment, facilitating the generation of counterfactual links for cold-start drugs and thereby augmenting the training dataset. Lastly, we enhance our understanding of drug characteristics through a meta-path-based fusion mechanism, ultimately improving the accuracy of DDIs prediction in cold-start scenarios. We substantiate the effectiveness of our proposed method through an extensive series of experiments.

Microbe-drug interactions, which refer to the effects of drugs on microorganisms, play a crucial role in the realm of studying antibiotic-resistant bacteria and the development of antimicrobial agents. With the rapid progress in biomedical field, numerous experimental results containing validated microbe-drug interactions have been available in scientific articles. However, since failing to employ domain knowledge, traditional natural language processing methods encounter challenges in accurately identifying microbe and drug entities. Moreover, the unstructured characteristics and semantic complexity of biomedical literature pose difficulties for conventional text mining approaches to accurately grasp the syntactic features. In this paper, we present a novel microbial-drug relation extraction model called D-GCN, in which dual graph convolutional networks are used. Specifically, the drug database Drugbank is leveraged as external domain knowledge, while the graph convolutional network-based model SemGCN is utilized to learn meaningful features from biomedical texts. In addition, the attention graph convolutional network A-GCN is introduced to capture crucial syntactic features contained in texts. The experimental results show that the proposed model achieves better performance over the selected baseline models, which means D-GCN can not only accurately recognize microbial and drug entity representations, but also effectively identify the microbe-drug interactions.

Microbes can affect the metabolism and immunity of human body incessantly, and the dysbiosis of human microbiome drives not only the occurrence but also the progression of disease (i.e. multiple statuses of disease). Recently, microbiome-based association tests have been widely developed to detect the association between the microbiome and host phenotype. However, the existing methods have not achieved satisfactory performance in testing the association between the microbiome and ordinal/nominal multicategory phenotypes (e.g. disease severity and tumor subtype). In this paper, we propose an optimal microbiome-based association test for multicategory phenotypes, namely, multiMiAT. Specifically, under the multinomial logit model framework, we first introduce a microbiome regression-based kernel association test for multicategory phenotypes (multiMiRKAT). As a data-driven optimal test, multiMiAT then integrates multiMiRKAT, score test and MiRKAT-MC to maintain excellent performance in diverse association patterns. Massive simulation experiments prove the success of our method. Furthermore, multiMiAT is also applied to real microbiome data experiments to detect the association between the gut microbiome and clinical statuses of colorectal cancer as well as for diverse statuses of Clostridium difficile infections.

Drug-drug interactions (DDIs) are compound effects when patients take two or more drugs at the same time, which may weaken the efficacy of drugs or cause unexpected side effects. Thus, accurately predicting DDIs is of great significance for the drug development and the drug safety surveillance. Although many methods have been proposed for the task, the biological knowledge related to DDIs is not fully utilized and the complex semantics among drug-related biological entities are not effectively captured in existing methods, leading to suboptimal performance. Moreover, the lack of interpretability for the predicted results also limits the wide application of existing methods for DDIs prediction. In this study, we propose a novel framework for predicting DDIs with interpretability. Specifically, we construct a heterogeneous information network (HIN) by explicitly utilizing the biological knowledge related to the procedure of inducing DDIs. To capture the complex semantics in HIN, a meta-path-based information fusion mechanism is proposed to learn high-quality representations of drugs. In addition, an attention mechanism is designed to combine semantic information obtained from meta-paths with different lengths to obtain final representations of drugs for DDIs prediction. Comprehensive experiments are conducted on 2410 approved drugs, and the results of predictive performance comparison show that our proposed framework outperforms selected representative baselines on the task of DDIs prediction. The results of ablation study and cold-start scenario indicate that the meta-path-based information fusion mechanism red is beneficial for capturing the complex semantics among drug-related biological entities. Moreover, the results of case study demonstrate that the designed attention mechanism is able to provide partial interpretability for the predicted DDIs. Therefore, the proposed method will be a feasible solution to the task of predicting DDIs.

Side effects of drugs have gained increasing attention in the biomedical field, and accurate identification of drug side effects is essential for drug development and drug safety surveillance. Although the traditional pharmacological experiments can accurately detect the side effects of drugs, the identifying process is time-consuming, costly, and may lead to incomplete identification of side effects. With the expanding of various biomedical databases, many computational methods have been developed for the task of drug-side effect associations (DSAs) prediction. However, existing methods have the following three drawbacks: 1). multiple drug-related databases are not fully used; 2). the complex semantics among drugs and side effects are not effectively captured; 3). the explainability of the predicted DSAs is missed for most existing methods. Therefore, there is an urgent need to find a more effective method for predicting DSAs. To address these issues, we propose a novel meta-path-based graph neural network model for drug-side effect associations prediction (MPGNN-DSA). In MPGNN-DSA, a heterogeneous information network is first constructed by combining multiple biological datasets. Then, a meta-path-based feature learning module is utilized for learning high-quality representations of drugs and side effects by capturing the semantics contained in meta-paths of the constructed HIN. With the learned features, the prediction module is conducted to derive the predicted side effects for drugs. In addition, the explainability of the predicted DSAs can be provided as well with the semantics contained in meta-paths. We conduct comprehensive experiments, and the results demonstrate the effectiveness of MPGNN-DSA, suggesting that the proposed method will be a feasible solution to the task of DSAs prediction.

In the treatment of bacterial infectious diseases, overuse of antibiotics may lead to not only bacterial resistance to antibiotics but also dysbiosis of beneficial bacteria which are essential for maintaining normal human life activities. Instead, phage therapy, which invades and lyses specific pathogenic bacteria without affecting beneficial bacteria, becomes more and more popular to treat bacterial infectious diseases. For the effective phage therapy, it requires to accurately predict potential phage-host interactions from heterogeneous information network consisting of bacteria and phages. Although many models have been proposed for predicting phage-host interactions, most methods fail to consider fully the sparsity and unconnectedness of phage-host heterogeneous information network, deriving the undesirable performance on phage-host interactions prediction. To address the challenge, we propose an effective model called GERMAN-PHI for predicting Phage-Host Interactions via Graph Embedding Representation learning with Multi-head Attention mechaNism. In GERMAN-PHI, the multi-head attention mechanism is utilized to learn representations of phages and hosts from multiple perspectives of phage-host associations, addressing the sparsity and unconnectedness in phage-host heterogeneous information network. More specifically, a module of GAT with talking-heads is employed to learn representations of phages and bacteria, on which neural induction matrix completion is conducted to reconstruct the phage-host association matrix. Results of comprehensive experiments demonstrate that GERMAN-PHI performs better than the state-of-the-art methods on phage-host interactions prediction. In addition, results of case study for two high-risk human pathogens show that GERMAN-PHI can predict validated phages with high accuracy, and some potential or new associated phages are provided as well.

Inferring microbe-metabolite interactions is conducive to understand how microbes affect human health, and specific microbial metabolites can be used as biomarkers for the diagnosis and treatment. Most of the existing methods only utilize the known mechanisms between microbiome and metabolome, while ignore the intragroup biological interactions(including microbe-microbe correlations and metabolite-metabolite correlations). In this paper, we propose a microbe-metabolite heterogeneous network fusion model based on graph convolution network (MMHNF) for inferring microbe-metabolite interactions. The proposed model not only utilizes the common properties of microbe-metabolite interactions, but also applies the properties of microbe-microbe and metabolite-metabolite correlation networks. In addition, it can learn low-dimensional and effective feature representations from multisource heterogeneous networks by applying the graph convolution network. Comprehensive experiments are performed on both simulated and experimental data, and the results show that MMHNF outperforms selected baselines. Moreover, results of case studies on inflammatory bowel disease (IBD) demonstrate further the effectiveness of the proposed model.

Microbes are closely related to human diseases, and the internal interactions among microbes influence disease production and development as well. Therefore, accurately predicting the associations between microbes and diseases becomes very important. This field is being carried out by a large number of researchers. However, existing methods have two deficiencies: (i) they fail to utilize the pathogenic impact of microbial interactions; (ii) they ignore the noise effect of unknown microbe-disease associations for training the prediction model. In this paper, we propose a novel model for above the shortcomings. Results of extensive experiments show that the proposed model achieves better performance over SOTA methods. In addition, the results of a case study on Type 1 diabetes demonstrate the effectiveness of the predicted associations between microbes and diseases derived from our model.

Drug side effect is an important entity in the biomedical field, and identifying the association of the drug-side effects is a very important issue in pharmacological studies and drug risk-benefit. Traditional side effect discovery methods are mainly based on pharmacological experiments. These methods can detect the side effects of some drugs, but the identification process is time-consuming, expensive, and fails to identify some rare side effects. In recent years, with the expansion of massive biomedical data, computational-based methods are widely developed and applied for the task of drug-side effect association(DSA) prediction. However, existing methods cannot fully utilize public biomedical databases, and the complex semantic associations between drugs and side effects are not effectively captured, which leads to suboptimal model prediction performance. In this study, we develop a novel meta-path-based graph neural network model for drug-side effect association prediction. In the proposed model, we first construct a heterogeneous information network(HIN) by fusing multiple biological datasets. And then, a novel meta-path-based feature learning module is designed to learn high-quality representations of drugs and side effects. Finally, with the learned features, the prediction module utilizes a fully connected neural network to make prediction. In addition, comprehensive experiments is conducted, the results demonstrate the effectiveness of our model, indicating that the method will be a viable approach for DSA prediction tasks.

Compared with traditional methods, drug repositioning is a viable solution to drug discovery. Drug repositioning usually applies the procedure of drug-disease associations (DDAs) prediction, which can reduce the cost and time of drug development and improve the success rate of drug discovery. In this paper, we develop a new multi-task learning framework based on heterogeneous graph convolutional network (MTHGCN) to recognize potential DDAs. In MTHGCN, a heterogeneous information network is constructed by combining multiple biological datasets. And then, a module based on graph convolutional networks is utilized to learn low-dimensional representations of drugs and diseases. Finally, we design two types of auxiliary tasks to help to train the target DDAs prediction task based on the multi-task learning mechanism. We conduct comprehensive experiments on MTHGCN. The results demonstrate the effectiveness of MTHGCN for drug repositioning.

Drug-drug interactions (DDIs) refer to the compound effects that may impair the effectiveness of drugs or cause unexpected side effects when two or more drugs are taken together. Therefore, it is very important to accurately predict DDIs for the drug development and drug safety monitoring. Many methods have been proposed to accomplish this task, but the existing methods fail to make full use of the biological knowledge related to DDIs, and do not effectively capture the complex semantics between biological entities related to drugs, resulting in poor performance. In this paper, we propose a novel DDIs prediction framework based on heterogeneous information network (HIN). More specifically, we construct the HIN which combines biological knowledge related to DDIs. In order to capture the complex semantics in HIN, a meta-path-based fusion mechanism is proposed to obtain high-quality drugs’ representations. Moreover, we design a meta-path level attention to combine semantics obtained from meta-paths with different lengths to obtain the final representations of drugs for DDIs prediction. The experimental results demonstrate that the framework performs better than the selected representative baselines on 2410 approved drugs.

The association between the compositions of microbial communities and various host phenotypes is an important research topic. Microbiome association research addresses multiple domains, such as human disease and diet. Statistical methods for testing microbiome-phenotype associations have been studied recently to determine their ability to assess longitudinal microbiome data. However, existing methods fail to detect sparse association signals in longitudinal microbiome data. In this paper, we developed a novel method, namely aGEEMIHC, which is a data-driven adaptive microbiome higher criticism analysis based on generalized estimating equations to detect sparse microbial association signals from longitudinal microbiome data. aGEEMiHC adopts generalized estimating equations framework that fully considers the correlation among different observations from the same subject in longitudinal data. To be robust to diverse correlation structures for longitudinal data, aGEEMiHC integrates multiple microbiome higher criticism analyses based on generalized estimating equations with different working correlation structures. Extensive simulation experiments demonstrate that aGEEMiHC can control the type I error correctly and achieve superior performance according to a statistical power comparison. We also applied it to longitudinal microbiome data with various types of host phenotypes to demonstrate the stability of our method. aGEEMiHC is also utilized for real longitudinal microbiome data, and we found a significant association between the gut microbiome and Crohn's disease. In addition, our method ranks the significant factors associated with the host phenotype to provide potential biomarkers.

The increasing prevalence of antibiotic resistance has become a global health crisis. For the purpose of safety regulation, it is of high importance to identify antibiotic resistance genes (ARGs) in bacteria. Although culture-based methods can identify ARGs relatively more accurately, the identifying process is time-consuming and specialized knowledge is required. With the rapid development of whole genome sequencing technology, researchers attempt to identify ARGs by computing sequence similarity from public databases. However, these computational methods might fail to detect ARGs due to the low sequence identity to known ARGs. Moreover, existing methods cannot effectively address the issue of multidrug resistance prediction for ARGs, which is a great challenge to clinical treatments. To address the challenges, we propose an end-to-end multi-label learning framework for predicting ARGs. More specifically, the task of ARGs prediction is modeled as a problem of multi-label learning, and a deep neural network-based end-to-end framework is proposed, in which a specific loss function is introduced to employ the advantage of multi-label learning for ARGs prediction. In addition, a dual-view modeling mechanism is employed to make full use of the semantic associations among two views of ARGs, i.e. sequence-based information and structure-based information. Extensive experiments are conducted on publicly available data, and experimental results demonstrate the effectiveness of the proposed framework on the task of ARGs prediction.

Infectious diseases are currently the most important and widespread health problem, and identifying viral infection mechanisms is critical for controlling diseases caused by highly infectious viruses. Because of the lack of non-interactive protein pairs and serious imbalance between positive and negative sample ratios, the supervised learning algorithm is not suitable for prediction. At the same time, due to the lack of information on viral proteins and significant dissimilarity in sequence, some ensemble learning models have poor generalization ability. In this paper, we propose a Sequence-Based Ensemble Learning (Seq-BEL) method to predict the potential virus-human PPIs. Specifically, based on the amino acid sequence of proteins and the currently known virus-human PPI network, Seq-BEL calculates various features and similarities of human proteins and viral proteins, and then combines these similarities and features to score the potential of virus-human PPIs. The computational results show that Seq-BEL achieves success in predicting potential virus-human PPIs and outperforms other state-of-the-art methods. More importantly, Seq-BEL also has good predictive performance for new human proteins and new viral proteins. In addition, the model has the advantages of strong robustness and good generalization ability, and can be used as an effective tool for virus-human PPI prediction.

It is an important task to learn how gene regulatory networks change under different conditions. Several Gaussian graphical model-based methods have been proposed to deal with this task by inferring differential networks from gene expression data. However, most existing methods define the differential networks as the difference of precision matrices, which may include false differential edges caused by the change of conditional variances. In addition, prior information about the condition-specific networks and the differential networks can be obtained from other domains. It is useful to incorporate prior information into differential network analysis. In this study, we propose a new differential network analysis method to address the above challenges. Instead of using the precision matrices, we define the differential networks as the difference of partial correlations, which can exclude the spurious differential edges due to the variants of conditional variances. Furthermore, prior information from multiple hypothesis testing is incorporated using a weighted fused penalty. Simulation studies show that our method outperforms the competing methods. We also apply our method to identify the differential network between luminal A and basal-like subtypes of breast cancers and the differential network between acute myeloid leukemia tumors and normal samples. The hub genes in the differential networks identified by our method carry out important biological functions.

Over the past decades, Chemical-induced Disease (CID) relations have attracted extensive attention in biomedical community, reflecting wide applications in biomedical research and healthcare field. However, prior efforts fail to make full use of the interaction between local and global contexts in biomedical document, and the derived performance needs to be improved accordingly. In this paper, we propose a novel framework for document-level CID relation extraction. More specifically, a stacked Hypergraph Aggregation Neural Network (HANN) layers are introduced to model the complicated interaction between local and global contexts, based on which better contextualized representations are obtained for CID relation extraction. In addition, the CID Relation Heterogeneous Graph is constructed to capture the information with different granularities and improve further the performance of CID relation classification. Experiments on a real-world dataset demonstrate the effectiveness of the proposed framework.

Applying metagenomic data for disease classification and prediction is important for understanding the relation between disease phenotype and microbes. Comparing to traditional machine learning models, deep learning models like convolutional neural networks (CNNs) have their superiority on accuracy of classification. Current researches use phylogenetic tree to convert metagenomic abundance data to a two-dimensional matrix as input data for CNNs and improved the classification performances. However, the topological structure information of phylogenetic tree has not fully considered in previous studies. In this paper, we propose a method called TopoPhy by integrating three different kinds of phylogeny topological information to CNN input matrices. Three different measures were used to describe the structure information of a phylogeny tree including the number of child nodes, height of a layer and node distance in the tree. Experiments indicate that topological information can realize the potential of mining structure information of input data and improve the model performance of CNNs for host phenotype prediction.

With the increasing resistance of bacteria to antibiotics, the problem of antibiotic resistance has become a major challenge in healthcare. Therefore, the accurate identification of antibiotic resistance genes (ARGs) in bacteria is particularly urgent and important. Although culture-based methods can accurately identify ARGs, they are limited by domain knowledge and are time-consuming. With the availability of whole genome sequence data, most existing methods rely on sequence alignment to calculate sequence similarity to predict ARGs. However, for ARGs that has low sequence identity with known sequences, the existing methods do not identify them well. To address the challenges, we propose a multiple view learning based framework for ARGs. Experimental results demonstrate that the proposed approach performs better than the selected representative baselines on the real-world dataset.

Microbial interaction network is the foundation to understand the structure and function of microbial communities. However, there is currently less a comprehensive dataset of microbial interaction network. Using text mining technology, available microbial interaction knowledges could be extracted automatically from unstructured biomedical text data. However, the existing biomedical relation extraction tasks can only identify binary relations among microorganisms without differentiating complex interaction types. In this paper, we proposes a computational framework for the task of multi-type microbial relation extraction based on transfer learning. Transfer learning models were applied on large-scale unlabeled texts from PubMed, and predicted 2,132 standardized multi-type microbial interaction relationships among 682 bacterial species.

The main goal of biomedical event extraction is to structurally extract biomedical events from texts, however, the specificity of the domain makes both text modeling and data annotation very difficult. We propose a self-supervised learning-based data augmentation method in this paper and design specific augmentation strategies for biomedical entities and event triggers in biomedical texts, which solves the problem of sparse annotation data to some extent. In addition we improve the reinforcement learning-based event extraction method to improve the training efficiency of the model. The experiments on two datasets demonstrate the effectiveness of our method.

MOTIVATION: Multiple events extraction from biomedical literature is a challenging task for biomedical community. Usually, biomedical event extraction is modeled as two sub-tasks, trigger identification and argument detection. Most existing methods perform these two sub-tasks sequentially, and fail to make full use of the interaction between them, leading to suboptimal results for multiple biomedical events extraction. RESULTS: We propose a novel framework of reinforcement learning (RL) for the task of multiple biomedical events extraction. More specifically, trigger identification and argument detection are treated as main-task and subsidiary-task, respectively. Assigning the event type of triggers (in the main-task) is viewed as the action taken in RL, and the result of corresponding argument detection (i.e. the subsidiary-task) for the identified trigger is used for computing the reward of the taken action. Moreover, the result of the subsidiary-task is modeled as part of environment information in RL to help the procedure of trigger identification. In addition, external biomedical knowledge bases are employed for representation learning of biomedical text, which can improve the performance of biomedical event extraction. Results on two widely used biomedical corpora demonstrate that the proposed framework performs better than the selected baselines on the task of multiple events extraction. The ablation test indicates the contributions of RL and external KBs to the performance improvement in the proposed method. In addition, by modeling multiple events extraction under the RL framework, the supervised information is exploited more effectively than the classical supervised learning paradigm. Availability and implementationSource codes will be available at: https://github.com/David-WZhao/BioEE-RL.

Recent years have witnessed the rapidly growing of the amount of semistructured documents in real-world applications. Due to the huge size of the real-world data, how to manage semistructured documents effectively is a big challenge for researchers. As a fundamental task in natural language processing field, document classification is a feasible way to handle the large-scale semistructured documents. However, existing methods fail to explicitly take advantage of the hierarchical semantics in semistructured documents. It's known that the contained semantics is beneficial for understanding the semistructured documents. Considering the hierarchical structure of a given semistructured document, we propose a semistructured document classification framework which explicitly utilizes the semantic hierarchical attention mechanism. More specifically, the hierarchical attention mechanism and graph neural network are employed to model semistructured documents, by which the multilevel semantic relationships and grammatical information are considered. Moreover, we propose an adaptive class cost learning method to treat the issue of data imbalance. Comprehensive experiments are conducted on two real-world data sets, and the results demonstrate that our framework performs better than selected baselines for semistructured document classification.

Virus plays an important role in the earth's ecosystem. It maintains the balance of the ecosystem. It infects host cells, causing damage or death to the host. Understanding the relationship between virus and host is the key to preventing viral diseases. There are a large number of proven relationships between viruses and hosts in the literature. Extracting the relationships between viruses and hosts in these literature and organizing them into a virus-host knowledge base is of great significance to medical and biological research. Virus named entity recognition (VNER) is the key prerequisite step of relationship extraction. The complexity of virus naming and classification makes the identification of virus named entities challenging. In this paper, we provide a labeled corpus for the task of VNER. Furthermore, we use different pre-training models to compare its performance on downstream virus entity recognition tasks. Finally, BioBERT_ BiLSTM_ CRF got best result on the task of VNER. The precision value, recall value and F1 value are 92.18%, 91.28% and 91.85%, respectively.

Biomedical event extraction aims to detect fine-grained interactions between biomedical entities in biomedical texts, and has become a research hotspot for researchers in the biomedical field. As the first step in biomedical event extraction, biomedical event trigger identification plays an important role in the whole process. Although researchers have proposed many methods, the performance of existing methods is not desirable due to the reliance on a large number of labeled training samples and the need for expert knowledge in the biomedical field. To treat this issue, we model the biomedical event trigger identification as a few-shot learning problem. Specifically, we utilize a knowledge-aware attention layer to obtain a rich informative representation for entities, and improve the derived prototypes accordingly by prototypical network. In addition, the module of relation network is introduced to train a more reasonable distance function for trigger type prediction. The results demonstrate the effectiveness of the proposed framework according to F1-score.

In recent years, Chemical-induced Disease (CID) relations are the most searched topics by PubMed users worldwide, reflecting its extensive applications in biomedical research and public health field. However, for CID relation extraction, prior methods fail to make full use of the interaction between local and global contexts in biomedical document. To better capture the complex relationships among contexts, we propose an effective framework for document-level CID relation extraction. Specifically, the stacked Hypergraph Aggregation Neural Network (HANN) layers are applied to model effectively the interaction between local and global contexts. Moreover, by constructing CID Relation Heterogeneous Graph, we can capture the different granularities of information and learn better contextualized representations for CID relation extraction. Extensive experiments on a commonly used dataset demonstrate the effectiveness of the proposed method.

Biomedical event extraction is usually modeled as two sub-tasks: trigger identification and argument detection. Most existing methods perform these two sub-tasks sequentially but ignore the interaction between them. This paper proposes a novel method for multiple biomedical events extraction, in which the task of event extraction is modeled under a framework of reinforcement learning (RL). We treat the trigger identification and argument detection as main-task and subsidiary-task, respectively. And the result of argument detection is modeled as environmental information. In this way, the proposed method can capture the interaction between two sub-tasks, and the semantic associations among multiple biomedical events are also utilized effectively. Moreover, external biomedical knowledge bases are employed for representation learning of biomedical text. Comprehensive experiments are conducted on two widely used biomedical corpora, and results demonstrate that our method gains better performance compared to existing methods, especially in multiple biomedical events extraction.

Sequence clustering is a basic bioinformatics task that is attracting renewed attention with the development of metagenomics and microbiomics. The latest sequencing techniques have decreased costs and as a result, massive amounts of DNA/RNA sequences are being produced. The challenge is to cluster the sequence data using stable, quick and accurate methods. For microbiome sequencing data, 16S ribosomal RNA operational taxonomic units are typically used. However, there is often a gap between algorithm developers and bioinformatics users. Different software tools can produce diverse results and users can find them difficult to analyze. Understanding the different clustering mechanisms is crucial to understanding the results that they produce. In this review, we selected several popular clustering tools, briefly explained the key computing principles, analyzed their characters and compared them using two independent benchmark datasets. Our aim is to assist bioinformatics users in employing suitable clustering tools effectively to analyze big sequencing data. Related data, codes and software tools were accessible at the link http://lab.malab.cn/∼lg/clustering/.

Many datasets that exists in the real world are often comprised of different representations or views which provide complementary information to each other. To integrate information from multiple views, data integration approaches such as nonnegative matrix factorization (NMF) have been developed to combine multiple heterogeneous data simultaneously to obtain a comprehensive representation. In this paper, we proposed a novel variant of symmetric nonnegative matrix factorization (SNMF), called Laplacian regularization based joint symmetric nonnegative matrix factorization (LJ-SNMF) for clustering multi-view data. We conduct extensive experiments on several realistic datasets including Human Microbiome Project data. The experimental results show that the proposed method outperforms other variants of NMF, which suggests the potential application of LJ-SNMF in clustering multi-view datasets. Additionally, we also demonstrate the capability of LJ-SNMF in community finding.

Interactions among microorganisms have been the key to understand microbial communities. As an important member of microorganisms, bacteria are closely related to human diseases. Therefore, studying the interaction between bacteria plays an important role in microbiome research. There are a large number of published medical literatures that contain small-scale data about the interactions between bacteria. These literatures often record the bacteria interactions discovered by co-cultural experiments for two or more species. Mining and organizing them into databases will provide reliable support for microbiome research. Named entity recognition (NER) is an essential step of interaction extraction (IE) by automatically identifying bacterial entities in the text. In this paper, we propose a method based on language model for identifying bacteria named entities. Using the language model to learn the semantic information between words, the F1 score reaches 96.14%, which is the best performance in bacteria NER compared with the previous experimental results.

In the past few years, most disease-related lncRNAs have been identified, but the experimental identification is cost-consuming and time-consuming. It is therefore very important to develop a reliable computational model to predict lncRNA-disease association. In this paper, we propose a method based on similarity, combining autoencoder and rotation forest to predict lncRNA-disease association (SARLDA). This method not only makes use of disease and lncRNA similarities, but also extracts latent low-dimension features and expand the gap between samples to make it easier to predict the associations. To evaluate our method, we conducted several experiments. Sufficient validations show that this method has significantly improved the prediction performance.

Microbial ecosystems are complex, by analyzing co-occurrence modules of microbial communities, we can better understand the conditions of microbial interactions in each environment, and help understand the interaction patterns that maintain the stability of microbial communities. Imbalances in human microbiome are closely related to human disease. Previous modular clustering analysis was based only on the relationship between paired microorganisms. In this paper, we propose calculating the logical relationship between microbial triplet in human body by information entropy and construct a hypergraph based on the triplet network. Based on the hypergraph clustering, we proposed a novel hypergraph clustering algorithm based on intra-class scatter matrix (HCIS) to reconstruct hyperedge similarity, and selected the optimal cluster number by maximizing modularity to analyze higher-order module of microorganisms. The clustering results verify the effectiveness and feasibility of HCIS algorithm for higher-order microbial module analysis.

Biomedical event extraction has wide applications in biomedicine field. As a prerequisite step in biomedical event extraction, event trigger identification has attracted growing attention in biomedical research. Although many approaches have been proposed for biomedical event trigger identification, two main challenges still remain for researchers: 1) most of the existing approaches treat each sentence separately in biomedical documents, failing to make full use of the semantics in the global document context; 2) the sparseness of event triggers leads to a serious issue of imbalanced class for trigger identification. In this paper, we propose an end-to-end framework for biomedical event trigger identification which addresses effectively the two mentioned challenges accordingly. Specifically, a hierarchical attention mechanism is used to model the global document context, including the semantic relationships both among words in the same sentence and among sentences in the same document. In addition, an adaptive class weight learning method is proposed to treat the class imbalance issue in biomedical event trigger identification. Experimental results on two commonly used datasets demonstrate the effectiveness of the proposed framework.

Microorganisms play a vital role in various ecosystems, but their complex interaction is still unclear. With the publication of a large number of microbial literatures, many experimentally verified microbial interaction is dispersed therein. Organizing them into a database or knowledge graph can facilitate the development of microbiology research. Text mining technology is able to automatically extract and integrate these microbial interactions, as well as discover implicit information in literatures. For this purpose, we manually annotate a Microbial Interaction Corpus (MICorpus) containing 1005 abstracts, which provide a useful data source for the MIE task. On this basis, we propose an automated MIE extraction system based on Max-Bi-LSTM model. The best result of the system is precision (P) 76.313%, recall (R) of 90.121%, and an F value (F) 82.476%.

Metabolic disorders play an important role in the development of many common diseases, including obesity, diabetes and coronary heart disease. Identifying key metabolites associated with disease can help us understand the mechanism of disease better and improve clinical diagnosis. Predicting diseases-related metabolites through computational approaches can provide potential biomarkers for further biological experiments. Text annotations on metabolites in existing databases provide prior information, which could provide more information about metabolites. However, current approaches haven't taken this information into consideration. In this work, we proposed a probability matrix factorization method which combined deep textual features to predict metabolite-disease associations. The deep neural network combining convolutional neural network and gated recurrent unit network is used to extract the corresponding features from text annotations of metabolites and diseases. Then, associations between metabolites and diseases are predicted through the matrix factorization based on these textual features. The main contributions in the work is that our model shows that adding textual features could help to improve the prediction of metabolite-disease associations. Case studies have indicated our model got predictive ability for diseases-related metabolites.

Biomedical document classification is a fundamental task in biomedical field. Existing methods do not make full use of the hierarchically semantic structures in biomedical documents which can be utilized to improve the performance of biomedical document classification. In this paper, according to the hierarchical structures in given biomedical documents, we propose two models for biomedical document classification, which are based on the semantically hierarchical attention mechanism. Specifically, we utilize a hierarchical attention mechanism to model biomedical documents, taking into account simultaneously multiple-level semantic relationships in documents. In addition, an adaptive cost sensitive learning method is proposed to address the data imbalance issue. Extensive experiments on two real-world datasets demonstrate the effectiveness of the proposed methods.

BACKGROUND: Microbes have been shown to play a crucial role in various ecosystems. Many human diseases have been proved to be associated with bacteria, so it is essential to extract the interaction between bacteria for medical research and application. At the same time, many bacterial interactions with certain experimental evidences have been reported in biomedical literature. Integrating this knowledge into a database or knowledge graph could accelerate the progress of biomedical research. A crucial and necessary step in interaction extraction (IE) is named entity recognition (NER). However, due to the specificity of bacterial naming, there are still challenges in bacterial named entity recognition. RESULTS: In this paper, we propose a novel method for bacterial named entity recognition, which integrates domain features into a deep learning framework combining bidirectional long short-term memory network and convolutional neural network. When domain features are not added, F1-measure of the model achieves 89.14%. After part-of-speech (POS) features and dictionary features are added, F1-measure of the model achieves 89.7%. Hence, our model achieves an advanced performance in bacterial NER with the domain features. CONCLUSIONS: We propose an efficient method for bacterial named entity recognition which combines domain features and deep learning models. Compared with the previous methods, the effect of our model has been improved. At the same time, the process of complex manual extraction and feature design are significantly reduced.

BACKGROUND: Viruses are closely related to bacteria and human diseases. It is of great significance to predict associations between viruses and hosts for understanding the dynamics and complex functional networks in microbial community. With the rapid development of the metagenomics sequencing, some methods based on sequence similarity and genomic homology have been used to predict associations between viruses and hosts. However, the known virus-host association network was ignored in these methods. RESULTS: We proposed a kernelized logistic matrix factorization with integrating different information to predict potential virus-host associations on the heterogeneous network (ILMF-VH) which is constructed by connecting a virus network with a host network based on known virus-host associations. The virus network is constructed based on oligonucleotide frequency measurement, and the host network is constructed by integrating oligonucleotide frequency similarity and Gaussian interaction profile kernel similarity through similarity network fusion. The host prediction accuracy of our method is better than other methods. In addition, case studies show that the host of crAssphage predicted by ILMF-VH is consistent with presumed host in previous studies, and another potential host Escherichia coli is also predicted. CONCLUSIONS: The proposed model is an effective computational tool for predicting interactions between viruses and hosts effectively, and it has great potential for discovering novel hosts of viruses.

BACKGROUND: The traditional methods of visualizing high-dimensional data objects in low-dimensional metric spaces are subject to the basic limitations of metric space. These limitations result in multidimensional scaling that fails to faithfully represent non-metric similarity data. RESULTS: Multiple maps t-SNE (mm-tSNE) has drawn much attention due to the construction of multiple mappings in low-dimensional space to visualize the non-metric pairwise similarity to eliminate the limitations of a single metric map. mm-tSNE regularization combines the intrinsic geometry between data points in a high-dimensional space. The weight of data points on each map is used as the regularization parameter of the manifold, so the weights of similar data points on the same map are also as close as possible. However, these methods use standard momentum methods to calculate parameters of gradient at each iteration, which may lead to erroneous gradient search directions so that the target loss function fails to achieve a better local minimum. In this article, we use a Nesterov momentum method to learn the target loss function and correct each gradient update by looking back at the previous gradient in the candidate search direction. By using indirect second-order information, the algorithm obtains faster convergence than the original algorithm. To further evaluate our approach from a comparative perspective, we conducted experiments on several datasets including social network data, phenotype similarity data, and microbiomic data. CONCLUSIONS: The experimental results show that the proposed method achieves better results than several versions of mm-tSNE based on three evaluation indicators including the neighborhood preservation ratio (NPR), error rate and time complexity.

Cyanobacteria bloom is a serious public health threat and a global challenge. Literature on the bloom prediction and forecasting has been accumulating and the emphasis appears to have been on the relation between the blooms and environmental factors, whilst the complexity of the bloom mechanism makes it difficult to reach adequate output of the models. Rapid development of next generation sequencing techniques provides a way in which comprehensive and quick examination of the microbial community can be achieved, especially for the bloom community structure. This facilitates using of merely the sequence data along with the machine learning techniques to predict and forecast the bloom occurrence. But there has been rare report on this theme in the literature. In this case study, machine learning approaches were applied with the metagenomic data as the only input (rather than with environmental data) to predict the Cyanobacteria blooms. k-NN classification, SVM classification and k-means clustering were applied and their efficiencies were evaluated using relevant indices. Feature selection was performed and the yielded sub datasets were worked on seriatim. In the predicting experiment with k-NN approach, the final year's data among the 8 years OTU time series were used as target data and various combination of the preceding years' data were used as predictor data; the output came with the best values of 1.00 and 100% for the evaluation indices F1 score and sensitivity, specificity, precision, and accuracy, for the 7 preceding years' predictor input, among the experiment results. This case study demonstrated the feasibility of using machine learning approaches in the Cyanobacteria bloom prediction with only metagenomic sequence data, and the importance of feature selection processing in obtaining better output of the machine learning approaches. The metagenomic data based machine learning approaches are efficient, economic, and faster, possessing the advantage and potential for being adopted as a promising means in the bloom prediction practice.

The human oral cavity is an important habitat of microbes in the human body. It includes the colonization of various microorganisms such as bacteria, archaea, fungi, protozoa and viruses. Although oral diseases have been studied for decades, we have limited understanding of the boundaries of a healthy oral ecosystem and ecological shift toward dysbiosis. Here, we analyzed salivary microbiomes from 268 healthy adults after overnight fasting. The microbiome data set is firstly divided into five sample clusters based on the similarity pattern of microbial abundance. For each cluster, the correlation networks among salivary bacteria are constructed based on an ensemble of six correlations and two dissimilarity measure. The stability and specificity of modularity in the five microbial networks are investigated. The existences of conserved and changing modules were found across five microbial correlation networks.

From a biological standpoint, due to the special combination of complex symptoms, some type of complex diseases is difficult to be accurately diagnosed. Known as phenotypic overlap, these sets of disease-related symptoms reveal a common pathological and physiological mechanism. Researchers attempt to visualize the phenotypic relationships between different human diseases from the perspective of machine learning, but traditional methods of visualizing high-dimensional data objects into low-dimensional would be subject to fundamental limitations of metric spaces. Our method is primarily based on the multiple maps t-SNE regularization, which is a probabilistic method for visualizing data points in multiple low-dimensional spaces. We use the Nesterov accelerated gradient method to learn the objective loss function. This method thought to counterweigh too high velocities by “peeking ahead” actual objective values in the candidate search direction, thus providing a larger and timelier correction to velocity. Experiments results on several dataset show that the proposed method outperforms the original version of mm-tSNE and mm-tSNE with regularization, as measured by the neighborhood preservation ratio. This suggests the modified mm-tSNE regularization can be applied directly in other domain including social and biological datasets.

There are intensive computational efforts to discover large-scale microbial interactions from metagenomic abundance data, however, it is often difficult to validate such inferred interactions without a manually curated dataset. There are also a number of small-scale microbial interactions reported in massive literature with experimental confidence. Text mining can be employed to extract such microbial interactions from biomedical literature which could be a significant complement to abundance-based method. The key tasks of text mining include named entity recognition and relation extraction. Named entity recognition identifies the name of the specified type from the text. We manually annotated a corpus with 1344 abstracts from microbial literature for the task of bacterial named entity recognition. Six new features were added in addition to the general features of the biomedical field. Based on a bacterial dictionary and conditional random field (CRF), the bacterial named entity recognition model was trained and it achieved a performance with precision 89.118%, recall 81.598 % and F-measure 85.192%. The system and template are available at https://github.com/bluelilywxy/BacNER-V1.0.git.

Gene (microRNA) identification is a key step in understanding the cellular mechanisms. Compared with biological experiments, computational prediction of disease genes is cheaper and more effortless. In this study, we analyzed the properties of tumor-associated microRNA in mouse and found that tumor-associated genes display 8distinguishingfeatures when compared with genes not yet known to be involved in tumor. The features of tumor-associated genes tend to located at network center and interact with each other were found by analyze the network characteristics. In addition, the features of the tumor-associated genes tend to be involved in certain biological processes and show certain phenotypes also were found through enrichment analysis. Based on these features, a machine-learning algorithm SVM were developed to predict new tumor-associated genes in mouse. Using the machine-learning algorithm, 120 tumor-associated genes were predicted with a posterior probability more than 0.9. We verified the accuracy of the identification framework with the data set of tumor-associated genes, and the result shows that this method is feasible.

Genome-wide association studies (GWAS) of T2D have discovered a number of loci that contribute to susceptibility to the disease. In this paper, we classified and identified the suspected risky Loci of T2D with computational method based on the known T2D GWAS-associated SNPs. The framework includes two parts: we first classified the SNPs based on their features of position and function through a simplified classification decision tree which was constructed by C4.5 decision tree algorithm; we then identified whether the genes associated with the suspected risky SNPs are associated with T2D by using random walk algorithm with Restart Model on the PPI network of T2D GWAS-associated genes among proteins and interactors. Based on the classification of SNP associated with T2D, we analyzed molecular pathogenesis of T2D. We verified the accuracy and reliability of the classification and identification framework with the data set of GWAS-associated SNPs. The result shows that this method is reliable. It provides a significant way to identify and classify the suspected risky Loci associated with T2D and further insights into the molecular pathogenesis of T2D.

Known as phenotypic overlapping, some disease-rel ated symptoms share a common pathologi cal and physiological mechanism. Researchers attempt to visualize the phenotypic relationships between different human diseases from the perspective of machine learning, but traditional visualization methods may be subject to fundamental limitations of metric spaces. Multiple maps t-SNE regularization method, a probabilistic method for visualizing data points in multiple low-dimensional spaces has been proposed to address the limitation. However, the convergence speed is low when apply on the scale dataset. We use the RMSProp with Nesterov momentum method to learn the objective loss function. This method normalize the gradients by applying an exponential moving average of gradient magnitude for each iteration parameter and use Nesterov momentum to counterweigh too high velocities by “peeking ahead” actual objective values in the candidate search direction. This method convergent faster than the original method of convergence speed. Experiments results on several dataset shows that the proposed method outperforms the several version of mm-tSNE with or without regularization, as measured by the neighborhood preservation ratio and error rate. This suggests the modified mm-tSNE regularization can be applied directly in other domain including social, biological and microbiomic datasets.

Microbiome datasets are often comprised of different representations or views which provide complementary information to understand microbial communities, such as metabolic pathways, taxonomic assignments, and gene families. Data integration methods including approaches based on nonnegative matrix factorization (NMF) combine multi-view data to create a comprehensive view of a given microbiome study by integrating multi-view information. In this paper, we proposed a novel variant of NMF which called Laplacian regularized joint non-negative matrix factorization (LJ-NMF) for integrating functional and phylogenetic profiles from HMP. We compare the performance of this method to other variants of NMF. The experimental results indicate that the proposed method offers an efficient framework for microbiome data analysis.

Microbiome datasets are often comprised of different representations or views which provide complementary information, such as genes, functions, and taxonomic assignments. Integration of multi-view information for clustering microbiome samples could create a comprehensive view of a given microbiome study. Similarity network fusion (SNF) can efficiently integrate similarities built from each view of data into a unique network that represents the full spectrum of the underlying data. Based on this method, we develop a Robust Similarity Network Fusion (RSNF) approach which combines the strength of random forest and the advantage of SNF at data aggregation. The experimental results indicate the strength of the proposed strategy. The method substantially improves the clustering performance significantly comparing to several state-of-the-art methods in several datasets.

Many datasets existed in the real world are often comprised of different representations or views which provide complementary information to each other. For example, microbiome datasets can be represented by metabolic paths, taxonomic assignment or gene families. To integrate information from multiple views, data integration approaches such as methods based on nonnegative matrix factorization (NMF) have been developed to combine multi-view information simultaneously to obtain a comprehensive view which reveals the underlying data structure shared by multiple views. In this paper, we proposed a novel variant of symmetric nonnegative matrix factorization (SNMF), called Laplacian regularized joint symmetric nonnegative matrix factorization (LJ-SNMF) for clustering multi-view data. We conduct extensive experiments on several realistic datasets including Human Microbiome Project (HMP) data. The experimental results show that the proposed method outperforms other variants of NMF, which suggests the potential application of LJ-SNMF in clustering multi-view datasets.

The microbiota living in the human body plays a very important role in our health and disease, so the identification of microbes associated with diseases will contribute to improving medical care and to better understanding of microbe functions, interactions. However, the known associations between the diseases and microbes are very less. We proposed a new method for prioritization of candidate microbes to predict disease-microbe relationships that based on the random walking on the heterogeneous network. Here, we first constructed a heterogeneous network by connecting the disease network and microbe network using the disease-microbe relationship information, then extended the random walk to the heterogeneous network, finally we used leave-one-out cross-validation to evaluate the method and ranked the candidate disease-causing microbes. We used the algorithm to disclose some potential association between disease and microbe that cannot be found by microbe network or disease network alone. Furthermore, we studied three representative diseases, Type 2 diabetes, Asthma and Psoriasis, and presented the potential microbes associated with these diseases, respectively. We confirmed that the discovery of the associations will be a good clinical solution for disease mechanism understanding, diagnosis and therapy.

Detection of protein complexes and functional modules plays a crucial role for strengthening the comprehension of cellular organization and biological functions on the dynamic protein-protein interaction network. In this article, we put forward a new strategy to identify temporal protein complexes. Integrating time-course gene expression data into static protein interaction data, a series of time-sequenced subnetworks were constructed. Then we combined the network topology and gene ontology information for defining the distance between proteins in PPI network. A novel method to find the cluster centers and then form initial clusters was based on the idea that cluster centers are usually recognized as nodes with higher densities than their neighbors and with a relatively larger distance from other cluster centers. Finally, inspired by the brainstorming discussion process, two ways are introduced to update the initial clusters for achieving the optimal results. After the filtering and merging procedure, experimental results demonstrated that the proposed strategy had a good performance comparing with the other four advanced algorithms - MCODE, FAG-EC, HC-PIN, and CNC.

While much progress has been made on the genetic analysis of osteoporosis in the past 20 years, there are a lot of genes and SNPs that are associated with osteoporosis through GWAS. In this paper, we aim to identify the risky SNPs associated with osteoporosis by algorithms based on the known osteoporosis GWAS-associated SNPs. The whole framework of our prediction method includes two steps: Firstly, we identify whether the associated genes of the suspected risky SNPs is osteoporosis GWAS-associated genes by the method of random walk algorithm on the PPI network of osteoporosis GWAS-associated genes. Then, we classify the positive result SNPs based on their features of position and function through ID3 decision tree algorithm. We verify the accuracy of the prediction framework with the data set of GWAS-associated SNPs, and the result shows that the method is feasible. It provides a more convenient way to identify the risky SNPs of osteoporosis associated.

Visualization is an important method in microbiome data analysis, and dimensionality reduction is a necessary procedure to achieve it. Multidimensional Scaling (MDS) is a popular method, which is necessary to compute the distance matrix. The Unifrac distance is very reasonable and biologically meaningful in the analysis of microbiome data. Due to the complexity of the phylogenetic tree and the high dimensionality of data, MDS needs a large amount of calculations to determine all the distances between pairs. In this paper, we proposed a novel dimensionality reduction algorithm based on Laplace matrix (DRLM) for the analysis of microbiome data. The experimental results indicate that both on synthesized and microbiome data, our algorithm DRLM can not only cluster the data more clearly, but also can significantly reduce the computational cost.

Microbial abundance dynamics along time axis can be used to explore complex interactions among microorganisms. This is very important to use time series data for understanding the structure and function of a microbial community and its dynamic characteristics with the purturbations of external environment and physiology. Species with Time Delay regulatory network of relationships will be more suitable for microbial interactions, because the regulation between microorganisms is often a slow process with delay, rather than an instantaneous process. In this study, a novel local linear manifold-constrained Vector Autoregression (LVAR) model that considered the time delay among microbial interactions is developed for analyzing microbiomics data in the application. The experimental results indicate that the new approach has better performance than several other VAR-based models and demonstrate its capability of extracting relevant microbial interactions.

The detection of temporal protein complexes would be a great aid in furthering our knowledge of the dynamic features and molecular mechanism in cell life activities. Inspired by the idea of that the tighter a protein's neighbors inside a module connect, the greater the possibility that the protein belongs to the module, we propose a novel clustering algorithm CNC (Clustering based on Neighbor Closeness) and apply it to the time course protein interaction networks (TCPINs) to detect temporal protein complexes. Our novel algorithm has better performance on identifying protein complexes than five state-of-the-art algorithms—Hunter, MCODE, CFinder, SPICI, and ClusterONE—in terms of matching degree and accuracy metric, meanwhile it obtains many protein complexes with strong biological significance.

Network is an exceptional way of depicting biological information. In biology, many different biological processes are represented by network, such as regulatory network, metabolic network and food web. In biology, network is a powerful supplement to the standard numerical data such as profile or count data. By absorbing network information, Vector autoregressive (VAR) model was proved to be an efficient approach to infer dynamic interactions in biological systems. Variants of network-regularized VAR with different penalties or regularization can avoid the problem of over-fitting and provide great potential in high-dimensional time series analysis. In this paper, we develop a novel regularization method for multivariate VAR which incorporates not only network topology but the signs of the network connections. By virtue of coordinate descent, we present a fast implementation for estimating model parameters. We then apply the proposed approach on several time series data sets especially a time series dataset of human gut microbiomes. The experimental results indicate that the new approach has better performance than other VAR-based models.

Predicting disease genes in PPI network has attracted a lot of attention over the years. Based on the assumption that the phenotypes of the genes in the same complex where candidate gene located in are more similar to disease, the candidate gene is more possible to be disease gene, we propose a new disease gene identification method based on protein complex phenotype similarity. First, our method mines protein complexes in PPI network by resolution-limit-free clustering algorithm and maps the candidate genes to complexes. Second, we define phenotype similarity according to phenotype ontology, and calculate phenotype similarity value between gene and disease. Third, we add up the phenotype similarity value of whole genes in the complex as weight of candidate gene and rank the candidate gene according to the sum of phenotype similarity value. Finally, we test our method by leave-one-out cross validation. The results show that our method is effective and outperforms other methods such as NetRank, NetScore, NetZcore, Flow, RWR and NDRC. Importantly, we predict the disease gene of Prader-Willi syndrome (MIM: 176270) and Renal tubular dysgenesis (MIM: 267430) successfully, which do not exist in our disease-gene datasets but exists in online databases and scientific publications.

Microbial interactions play important roles on the structure and function of complex microbial communities. With the rapid accumulation of high-throughput metagenomic or 16S rRNA sequencing data, it is possible to infer complex microbial interactions. Co-occurrence patterns of microbial species among multiple samples are often utilized to infer interactions. There are few methods to consider the temporally interacting patterns among microbial species. In this paper, we present a Graph-regularized Vector Autoregressive (GVAR) model to infer causal relationships among microbial entities. The new model has advantage comparing to the original vector autoregressive (VAR) model. Specifically, GVAR can incorporate similarity information for microbial interaction inference--i.e., GVAR assumed that if two species are similar in the previous stage, they tend to have similar influence on the other species in the next stage. We apply the model on a time series dataset of human gut microbiome which was treated with repeated antibiotics. The experimental results indicate that the new approach has better performance than several other VAR-based models and demonstrate its capability of extracting relevant microbial interactions.

Microbiome datasets are often comprised of different representations or views which provide complementary information, such as metabolic pathways, taxonomic assignments and gene families. Computational methods for integration of multi-view information combine these data to create a comprehensive view of a given microbiome study. Similarity network fusion (SNF) provides a candidate to solve this problem by efficiently fusing similarity networks built from each data view into one network that represents the full spectrum of the underlying data. Based on this method, we propose a Robust Similarity Network Fusion (RSNF) approach which combines the strength of random forest to construct robust affine graph and the advantage of SNF at data aggregation. The experimental results indicate that the proposed strategy not only substantially outperforms single data type analysis but improve the clustering performance significantly comparing to several state-of-the-art methods in various datasets. The application on human microbiome data suggests that we can cluster microbiome samples in high accuracy.

Dimensionality reduction and visualization are two important procedures in microbiome data analysis. With the intrinsic high dimensionality of the feature space in raw microbiome sequencing data, such as 16S rRNA, it requires proper simplification for possible further analysis. The explosively increasing size of data from large-scale microbiome studies inevitably and exponentially raises the computational complexity of existing algorithms, which is an urgent issue standing in the way requires addressing. This study proposed a new approach for dimensionality reduction and visualization on microbiome sequencing data associated with the very issue. This method not only greatly improves the efficiency of computing on microbiomic big data analysis by spectral interpolation technique but also preserves as much information as possible from original data with decent visualization results. With this adaptive method introduced to the large-scale studies of microbiome, we can better facilitate the revealing of patterns and insights of microbial communities.

In recent years, there are growing interests in developing novel approaches for inferring dynamic interactions in biological systems including gene transcription network and microbial interaction networks. Multivariate Vector Autoregression (MVAR) model is one of these efficient methods. Variants of MVAR with different penalties or regularizations can avoid the problem of over-fitting and provide great potential in high-dimensional data analysis. In this paper, we developed a novel regularization methods for MVAR via weighted fusion which consider the correlation among variables. The weighted fusion can potentially incorporate information redundancy among correlated variables for estimation and variable selection. Weighted fusion is also useful when the number of predictors p is larger than the number of observations n. In theory, we discuss the grouping effect of weighted fusion regularization for linear models. We then apply the proposed model on several time series data sets especially a time series dataset of human gut microbiomes. The experimental results indicate that the new approach has better performance that several other VAR-based models and we demonstrate its capability of extracting relevant microbial interactions.

Visualization of large-scale data is the first step to acquire preliminary insight into complex biological data. In recent years, many statistical visualization methods have been designed to support data visualization. Stochastic Neighbor Embedding (SNE) is one of these efficient approaches, which uses the probabilistic distance to model differences among data points within the data space. SNE and its variants (e.g. t-SNE) have demonstrated superiority over other methods in exploring complex data. By using these methods, however, similar data points tend to group together, which prevents the identification of subtle differences. A good visualization method should not only present clear data structure, but distinguish subtle differences. In this paper, we propose a novel extension of SNE. The approach has three innovations: (1) we replaced the Gaussian distribution in SNE with a Laplacian distribution on both high dimensional space and low dimensional space. The Laplace distribution has wider tails than the Gaussian distribution, and thus it can be used to overcome the over-crowding problem noted in SNE and its variants. (2) We used a symmetric modification of Kullback-Leibler divergence measure as the objective function which provides more flexibility to the model. (3) We add a graph Laplacian regularization terms to the objective function which have an advantage to preserve the manifold structure among data points. Experiments on simulation data and human microbiome data indicate that it has better visualization performance than other methods in distinguishing crowding data points.

Microbial interaction, such as species competition and symbiotic relationships, plays important role to enable microorganisms to survive by establishing a homeostasis between microbial neighbors and local environments. Thanks to the recent accumulation of large-scale high-throughput sequencing data of complex microbial communities, there are increasing interests in identifying microbial interactions. Computational methods for microbial interactions inference are currently focused on the similarity among microbial individuals (i.e. cooccurrence and correlation patterns), however, less methods considered the dynamics of a single complex community over time. In this paper, we propose to use a multivariate statistical method - Multivariate Vector Autoregression (MVAR) to infer dynamic microbial interactions from the time series of human gut microbiomes. Specifically, we apply MVAR model on a time series data of human gut microbiomes which were treated with repeated antibiotics. The referred microbial interactions identify novel interactions which may provide a novel complementary to similarity or correlation-based methods.

Current data mining and statistical methods to extract patterns and relationships in microbiomic data are often based on several assumptions such as Euclidean, linear, continuous and metric space which may not be the true space of microbiomic data. For example, the microbial profiles (functional and taxonomic classifications) are often correlated in a hierarchical style. These assumptions prevent discovering the true relationships in microbiomic data analysis. Thus, it is urgent to develop new computational methods to overcome these assumptions and consider the microbiomic data properties in the analysis procedure. In this study, we will propose novel variable selection method based on manifold-constrained regularization (McRe). Considering the nonlinear and correlation structure of data, McRe get improved results in simulation data. The method is also applied to a microbiomic dataset.

In recent years, a huge number of microbiomic data provide a great opportunity for investigation of microbe-related questions. We find that nonmetric property is a prevalent property in microbiomic data and this property should be considered as a factor in development of computational methods for visualization and dimension reduction of microbiomic data.

The study of Bioinformatics has been growing rapidly over the past few years, it is mainly focused on DNAs and proteins. Proteins are the main body of performing complex physiological functions of organisms, and protein-protein interactions are the basis of maintaining the structure of cells and realizing functions, so studying protein interaction networks is of great importance. By aligning and analyzing the protein interaction networks from different species, we can predict proteins' functions, mine conserved functional modules and so on. To this end, this paper presents a method of mining the maximum conserved functional module from the alignment of pairwise protein interaction networks. In this method, the protein interaction networks are abstracted as graphical models. Considering that the alignment of networks may result in combinatorial explosion and other issues, this paper introduces a scoring system and a pruning strategy, and thus the complexity of the algorithm is reduced. In order to verify the effectiveness and robustness of our method, we experiment with the S. cerevisiae and D. melanogaster protein-protein interaction networks, and the experimental results show that our method is effective.

Discovering the global structures of microbial community using large-scale metagenomes is a significant challenge in the era of post-genomics. Data-driven methods such as dimension reduction have shown to be useful when they applied on a metagenomics profile matrix which summarize the abundance of functional or taxonomic categorizations in metagenomic samples. Analogously, model-driven method such as probability topic model (PTM) has been used to build a generative model to simulate the generating of a microbial community based on metagenomic profiles. Data-driven methods are direct and simple, they provide intuitive visualization and understanding of metagenomic profiles. Model-driven methods are often complicated but give a generative mechanism of microbial community which is helpful in understanding the generating process of complex microbial ecology. However, results from model-driven methods are usually hard to visualize and there is less an intuitive understanding of them. We developed a new computational framework to incorporate the strength of data-driven methods into model-based methods and applied the framework to discover and interpret enterotype in human microbiome.

Using metagenomics to detect the global structure of microbial community remains a significant challenge. The structure of a microbial community and its functions are complicated not only because of the complex interactions among microbes but also their complicate interacting with confounding environmental factors. Recently dimension reduction methods such as Principle component analysis, Non-negative matrix factorization and Canonical correlation analysis have been employed extensively to investigate the complex structure embedded in metagenomic profiles which summarize the abundance of functional or taxonomic categorizations in metagenomic studies. However, metagenomic profiles are not necessary to meet the "Assumption of Linearity" behind these methods. Therefore it is worth to investigate how nonlinear methods can be utilized in metagenomic studies. In this paper, a nonlinear manifold learning method- Isomap is used to visualize and analyze large-scale metagenomic profiles. Isomap was applied on a large-scale Pfam profile which are derived from 45 metagenomes in Global Ocean Sampling expedition. In our result, a novel nonlinear structure of protein families is identified and the relationships among the identified nonlinear components and environmental factors of global ocean are explored. The results indicate the strength of nonlinear methods in learning the complex microbial structure. With the coming of the huge number of new sequenced metagenomes, nonlinear methods like Isomap could be necessary complementary tools to current widely used methods.