Biological research has found that miRNA (microRNA) plays an important role in explaining the mechanisms of diseases. Employing advanced algorithms for inferring potential miRNA-disease associations (MDA) is a good approach to the discovery of disease-related miRNAs, since traditional biological experiments are time-consuming and labor-intensive. Currently, traditional graph convolutional neural Network (GCN) has been widely applied but cannot effectively distinguish various biological relationships among the same or different types of nodes, limiting the ability of identification. Therefore, we propose a novel end-to-end model called MKLRGCN by multi-kernel learning and relational graph convolutional neural network (RGCN) to predict MDAs more effectively. First, a multi-kernel learning module is constructed to learn combined kernels of miRNAs/diseases and their initial feature representations. Then, multiple types of relations are derived by identifying high co-occurrences between miRNAs/diseases, and hub-ordinary associations between miRNAs and diseases, which feed into RGCN to learn embeddings of miRNAs/diseases from a heterogeneous network of MDAs. Experimental results demonstrate the effectiveness of distinct modules, and the good performance of our model compared to state-of-the-art models in predicting MDAs. This work provides a useful approach for computationally identifying potential MDAs.

Depression is a complex mental disorder in which genetic factors play a critical role in its onset and progression. Accurately identifying depression-related pathogenic genes is essential for understanding its underlying biological mechanisms and developing effective therapies, but current computational methods still suffer from limitations. Therefore, we propose a novel graph convolutional network-based framework, termed MDDGCN, for identifying depressionassociated pathogenic genes. MDDGCN constructs comprehensive gene representations by multi-omics data, including gene expression profile, functional annotations as well as pathway annotations. It introduces both residual and gated long-range skip connections to enhance multi-level feature propagation, and a dynamic attention mechanism is employed to adaptively capture informative neighborhood information for genes. Under multiple evaluation scenarios, the experimental results demonstrate that MDDGCN achieves superior performance in terms of AUC and AUPRC compared to existing methods. Furthermore, literature validation and enrichment analysis for predicted genes reveal that most of them have implications to be associated with depression, further confirming the reliability of MDDGCN. This work provides an effective method for identifying depression-related genes, which would be helpful for the study of the mechanisms, diagnosis, and treatment of depression. MDDGCN can be accessed for free via https://github.com/CSUBioGroup/MDDGCN.

Differential network analysis is essential for revealing patterns of network rewiring across various conditions and understanding the biological mechanisms underlying complex diseases. Existing methods often rely on limited modalities and do not adequately capture temporal dynamics in gene expression. To address these limitations, we propose a novel framework for constructing multiple dynamic differential protein interaction networks, named Multi-DPIN, which combines temporal gene expression data with protein-protein interaction topology. Initially, active proteins and their interactions are identified using the 3 -sigma rule to construct dynamic disease networks and background networks. Subsequently, common topological structures shared with the background network are eliminated from each disease network. Finally, consistent structures across all disease networks are identified to establish the multiple dynamic differential protein interaction networks. We evaluated Multi-DPIN on publicly available cancer datasets (breast cancer and acute myeloid leukemia) and compared it with five baseline methods. Experimental results demonstrate that Multi-DPIN outperforms existing methods in identifying known oncogenes.

miRNAs (microRNAs) play a significant role in the occurrence, development and treatment of diseases. Many computational algorithms for identifying disease-related miRNAs have been proposed due to high cost of biological experiments, while most of them ignore the existence of higherorder interactions in biological networks, limiting the improvement of performance. Therefore, we proposed a novel algorithm for identifying miRNA-disease associations by multiple kernel learning with higher-order interactions (HMKLMDA). First, we construct a kind of new target kernels for fusion of multiple similarity kernels for diseases and miRNAs by considering higher-order interactions of profiles, and then we design a kind of kernel-fusion strategy by integrating high-order kernel combinations. Finally, the potential miRNA-disease associations are identified based on the fused kernels for diseases and miRNAs by Laplacian regularized least squares with graph regularization and parameter constraints. By a series of experimental evaluations, we investigated the effect of different parameters and the contributions of higher-order interactions and then demonstrated superior performance of our algorithm in identifying miRNA-disease associations.

Understanding the interplay between diseases and genes is crucial for gaining deeper insights into disease mechanisms and optimizing therapeutic strategies. In recent years, various computational methods have been developed to uncover potential disease-gene associations. However, existing computational approaches for disease-gene association prediction still face two major limitations. First, most current studies focus on constructing complex heterogeneous graphs using multi-dimensional biological entity relationships, while overlooking critical latent interaction patterns, namely, disease neighbor interactions and gene neighbor interactions-which are more valuable for association prediction. Second, in self-supervised learning (SSL), the presence of noise in auxiliary tasks commonly affects the accurate modeling of diseases and genes. In this study, we propose a novel denoising method for disease-gene association prediction, termed DGSL. To address the first issue, we utilize bipartite graphs corresponding to diseases and genes to derive disease-disease and gene-gene similarities, and further construct disease and gene interaction graphs to capture the latent interaction patterns. To tackle the second challenge, we implement cross-view denoising through adaptive semantic alignment in the embedding space, while preserving useful neighbor interactions. Extensive experiments on benchmark datasets demonstrate the effectiveness of our method.

Breast cancer is a complex disease that arises from multiple factors, including genetics, age, and environmental factors. Prognosis prediction for breast cancer is a challenging task that urgently needs to be addressed. Prognostic biomarkers can aid in predicting clinical outcomes for breast cancer patients, and network-based approaches are frequently employed to identify such biomarkers. However, the accuracy of these approaches based on single source biological network is poor due to incomplete interactions of single biological network. Some network-based approaches that integrate multiple biological networks have not considered network denoising, which may lead to the accuracy of these approaches to be improved. We propose a multi-source fusion identification method named DualMarker for prognostic biomarkers of breast cancer. This method constructs a dual-layer heterogeneous network by integrating multiple biological sources. To decrease the negative effects of incomplete interactions in biological networks, we denoise the constructed network. The ranking of features is obtained by the network propagation algorithm and the initial scoring strategy. Compared with six other network-based methods, DualMarker shows the best performance in six breast cancer datasets. Moreover, we have also demonstrated that the biomarkers identified by DualMarker are of interpretability biologically and closely associated with breast cancer patients' prognosis.

Detecting protein complexes holds paramount importance in elucidating cellular organization and protein functionalities. Over the past decade, numerous approaches have centered their attention on the topological intricacies of protein-protein interaction (PPI) networks, yet these have often fallen short in harnessing the full spectrum of biological information inherent in proteins. To bridge this gap, we introduce a novel methodology, designated NE-DPC, which integrates both the topological landscape of PPI networks and the attribute profiles of proteins to facilitate the identification of protein complexes. Initially, we fuse the static PPI network with protein attributes through advanced network embedding techniques. Subsequently, we construct a cosine similarity matrix grounded on these embedded vectors, capturing the intricate relationships among proteins. Lastly, we employ a core-attachment strategy to pinpoint protein complexes. The results reveal that NE-DPC outperforms cutting-edge methods, demonstrating its effectiveness and potential in advancing protein complex detection.

Identifying disease-associated genes (DAGs) is important for the research of complex diseases, and network-based methods have been a powerful and elegant strategy for this topic. Genes and their products perform biological functions through synergy in biological networks, but mining useful information from the networks remains an open issue. Therefore, we propose a novel heterogeneous network impulsive dynamics model to identify DAGs more effectively. It inspires a heterogeneous network impulsive dynamical process by imposing impulsive signals at specific nodes, in an enhanced dual-layer heterogeneous network. Then, it extracts the impulsive dynamical signatures of responses of nodes to the impulsive signals so as to infer DAGs. A series of experiments confirm that this model has good performance of inferring DAGs under different conditions, and case studies further demonstrate its effectiveness. Furthermore, a user-friendly web platform is provided to facilitate prioritization and analysis of DAGs. It may become a useful tool for studying complex diseases and relevant genes.

Identification of protein complex is an important issue in the field of system biology, which is crucial to understanding the cellular organization and inferring protein functions. Recently, many computational methods have been proposed to detect protein complexes from protein-protein interaction (PPI) networks. However, most of these methods only focus on local information of proteins in the PPI network, which are easily affected by the noise in the PPI network. Meanwhile, it's still challenging to detect protein complexes, especially for overlapping cases. To address these issues, we propose a new method, named Dopcc, to detect overlapping protein complexes by constructing a multi-metrics network according to different strategies. First, we adopt the Jaccard coefficient to measure the neighbor similarity between proteins and denoise the PPI network. Then, we propose a new strategy, integrating hierarchical compressing with network embedding, to capture the high-order structural similarity between proteins. Further, a new co-core attachment strategy is proposed to detect overlapping protein complexes from multi-metrics. The experimental results show that our proposed method, Dopcc, outperforms the other eight state-of-the-art methods in terms of F-measure, MMR, and Composite Score on two yeast datasets.

Hepatocellular carcinoma (HCC) is a multifactorial and highly complex disease. Gaining a comprehensive understanding of the genetic factors associated with HCC is crucial for unraveling its intricate pathogenesis and identifying potential biomarkers. Recent advances suggest that biological network-based strategies are useful in prioritizing genes associated with diseases. However, existing network models predominantly rely on static biological networks, which to some extent hinder the modeling of dynamic biological processes and restrict the predictive capacity of disease genes. Therefore, we proposed the Dynamic Networks Random Walk (DyNRW) method to identify HCC-related genes. DyNRW overcomes the limitations of previous static network-based methods and models the dynamic regulatory relationships between genes in the biological system by constructing a time-series dynamic network based on the progression of HCC. To construct a more comprehensive biological network model, DyNRW presents an effective background-temporal multi-layer network framework to combine both static and dynamic network information. DyNRW extends the random-walk process to the multi-layer network, enabling the extraction of gene scores associated with HCC. According to the experimental results, DyNRW demonstrates better performance and stability compared to other state-of-the-art algorithms, and yields a set of promising candidate genes, many of which are confirmed by further biological validation.

Protein complexes play an essential role in living cells. Detecting protein complexes is crucial to understand protein functions and treat complex diseases. Due to high time and resource consumption of experiment approaches, many computational approaches have been proposed to detect protein complexes. However, most of them are only based on protein-protein interaction (PPI) networks, which heavily suffer from the noise in PPI networks. Therefore, we propose a novel core-attachment method, named CACO, to detect human protein complexes, by integrating the functional information from other species via protein ortholog relations. First, CACO constructs a cross-species ortholog relation matrix and transfers GO terms from other species as a reference to evaluate the confidence of PPIs. Then, a PPI filter strategy is adopted to clean the PPI network and thus a weighted clean PPI network is constructed. Finally, a new effective core-attachment algorithm is proposed to detect protein complexes from the weighted PPI network. Compared to other thirteen state-of-the-art methods, CACO outperforms all of them in terms of F-measure and Composite Score, showing that integrating ortholog information and the proposed core-attachment algorithm are effective in detecting protein complexes.

The prognosis of breast cancer is challenging, which is an urgent problem to be solved. The prognostic biomarkers for breast cancer can help us predict the clinical outcomes of patients, and network-based methods are widely introduced to find prognostic biomarkers. According to the difference of input biological data, existing network-based biomarker prediction methods are mainly classified into two types: integrating single-source network or multi-source networks. However, the interactome of single-source network remains incomplete, and biological networks are noisy, which will hamper the network-based identification accuracy of biomarkers. In this study, we introduce a multi-source fusion method, DualMarker, which integrates multiple biological information sources and constructs a dual-layer heterogeneous network by fast network embedding. Next, we introduce a network enhancement method to denoise the constructed dual-layer heterogeneous network, and we implement network propagation algorithm on the constructed dual-layer heterogeneous network to rank the features. After comparing with competitive methods, we find that DualMarker substantially outperforms these methods. In addition, we verify that the biomarkers identified by DualMarker are closely related to the prognosis of breast cancer patients.

The identification of disease-causing genes is critical for mechanistic understanding of disease etiology and clinical manipulation in disease prevention and treatment. Yet the existing approaches in tackling this question are inadequate in accuracy and efficiency, demanding computational methods with higher identification power. Here, we proposed a new method called DGHNE to identify disease-causing genes through a heterogeneous biomedical network empowered by network enhancement. First, a disease-disease association network was constructed by the cosine similarity scores between phenotype annotation vectors of diseases, and a new heterogeneous biomedical network was constructed by using disease-gene associations to connect the disease-disease network and gene-gene network. Then, the heterogeneous biomedical network was further enhanced by using network embedding based on the Gaussian random projection. Finally, network propagation was used to identify candidate genes in the enhanced network. We applied DGHNE together with five other methods into the most updated disease-gene association database termed DisGeNet. Compared with all other methods, DGHNE displayed the highest area under the receiver operating characteristic curve and the precision-recall curve, as well as the highest precision and recall, in both the global 5-fold cross-validation and predicting new disease-gene associations. We further performed DGHNE in identifying the candidate causal genes of Parkinson's disease and diabetes mellitus, and the genes connecting hyperglycemia and diabetes mellitus. In all cases, the predicted causing genes were enriched in disease-associated gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways, and the gene-disease associations were highly evidenced by independent experimental studies.

MOTIVATION: Identifying disease-related genes is an important issue in computational biology. Module structure widely exists in biomolecule networks, and complex diseases are usually thought to be caused by perturbations of local neighborhoods in the networks, which can provide useful insights for the study of disease-related genes. However, the mining and effective utilization of the module structure is still challenging in such issues as a disease gene prediction. RESULTS: We propose a hybrid disease-gene prediction method integrating multiscale module structure (HyMM), which can utilize multiscale information from local to global structure to more effectively predict disease-related genes. HyMM extracts module partitions from local to global scales by multiscale modularity optimization with exponential sampling, and estimates the disease relatedness of genes in partitions by the abundance of disease-related genes within modules. Then, a probabilistic model for integration of gene rankings is designed in order to integrate multiple predictions derived from multiscale module partitions and network propagation, and a parameter estimation strategy based on functional information is proposed to further enhance HyMM's predictive power. By a series of experiments, we reveal the importance of module partitions at different scales, and verify the stable and good performance of HyMM compared with eight other state-of-the-arts and its further performance improvement derived from the parameter estimation. CONCLUSIONS: The results confirm that HyMM is an effective framework for integrating multiscale module structure to enhance the ability to predict disease-related genes, which may provide useful insights for the study of the multiscale module structure and its application in such issues as a disease-gene prediction.

In recent decades, exploring potential relationships between diseases has been an active research field. With the rapid accumulation of disease-related biomedical data, a lot of computational methods and tools/platforms have been developed to reveal intrinsic relationship between diseases, which can provide useful insights to the study of complex diseases, e.g. understanding molecular mechanisms of diseases and discovering new treatment of diseases. Human complex diseases involve both external phenotypic abnormalities and complex internal molecular mechanisms in organisms. Computational methods with different types of biomedical data from phenotype to genotype can evaluate disease-disease associations at different levels, providing a comprehensive perspective for understanding diseases. In this review, available biomedical data and databases for evaluating disease-disease associations are first summarized. Then, existing computational methods for disease-disease associations are reviewed and classified into five groups in terms of the usages of biomedical data, including disease semantic-based, phenotype-based, function-based, representation learning-based and text mining-based methods. Further, we summarize software tools/platforms for computation and analysis of disease-disease associations. Finally, we give a discussion and summary on the research of disease-disease associations. This review provides a systematic overview for current disease association research, which could promote the development and applications of computational methods and tools/platforms for disease-disease associations.

MOTIVATION: Biomarkers with prognostic ability and biological interpretability can be used to support decision-making in the survival analysis. Genes usually form functional modules to play synergistic roles, such as pathways. Predicting significant features from the functional level can effectively reduce the adverse effects of heterogeneity and obtain more reproducible and interpretable biomarkers. Personalized pathway activation inference can quantify the dysregulation of essential pathways involved in the initiation and progression of cancers, and can contribute to the development of personalized medical treatments. RESULTS: In this study, we propose a novel method to evaluate personalized pathway activation based on signaling entropy for survival analysis (SEPA), which is a new attempt to introduce the information-theoretic entropy in generating pathway representation for each patient. SEPA effectively integrates pathway-level information into gene expression data, converting the high-dimensional gene expression data into the low-dimensional biological pathway activation scores. SEPA shows its classification power on the prognostic pan-cancer genomic data, and the potential pathway markers identified based on SEPA have statistical significance in the discrimination of high- and low-risk cohorts and are likely to be associated with the initiation and progress of cancers. The results show that SEPA scores can be used as an indicator to precisely distinguish cancer patients with different clinical outcomes, and identify important pathway features with strong discriminative power and biological interpretability. AVAILABILITY AND IMPLEMENTATION: The MATLAB-package for SEPA is freely available from https://github.com/xingyili/SEPA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MicroRNA (miRNA) is a class of non-coding single-stranded RNA molecules encoded by endogenous genes with a length of about 22 nucleotides. MiRNAs have been successfully identified as differentially expressed in various cancers. There is evidence that disorders of miRNAs are associated with a variety of complex diseases. Therefore, inferring potential miRNA-disease associations (MDAs) is very important for understanding the aetiology and pathogenesis of many diseases and is useful to disease diagnosis, prognosis and treatment. First, We creatively fused multiple similarity subnetworks from multi-sources for miRNAs, genes and diseases by multiplexing technology, respectively. Then, three multiplexed biological subnetworks are connected through the extended binary association to form a tripartite complete heterogeneous multiplexed network (Tri-HM). Finally, because the constructed Tri-HM network can retain subnetworks' original topology and biological functions and expands the binary association and dependence between the three biological entities, rich neighbourhood information is obtained iteratively from neighbours by a non-equilibrium random walk. Through cross-validation, our tri-HM-RWR model obtained an AUC value of 0.8657, and an AUPR value of 0.2139 in the global 5-fold cross-validation, which shows that our model can more fully speculate disease-related miRNAs.

Identifying biomarkers of heterogeneous complex diseases has always been one of the focuses in medical research. In previous studies, the powerful network propagation methods have been applied to finding marker genes related to specific diseases, but existing methods are mostly based on a single network, which may be greatly affected by the incompleteness of the network and the ignorance of a large amount of information about physical and functional interactions between biological components. Other methods that directly integrate multiple types of interactions into an aggregate network have the risks that different types of data may conflict with each other and the characteristics and topologies of each individual network are lost. Meanwhile, biomarkers used in clinical trials should have the characteristics of small quantity and strong discriminate ability. In this study, we developed a multiplex network-based dual ranking framework (DualRank) for heterogeneous complex disease analysis. We applied the proposed method to heterogeneous complex diseases for diagnosis, prognosis, and classification. The results showed that DualRank outperformed competing methods and could identify biomarkers with the small quantity, great prediction performance (average AUC = 0.818) and biological interpretability.

Biological functions of a cell are typically carried out through protein complexes. The detection of protein complexes is therefore of great significance for understanding the cellular organizations and protein functions. In the past decades, many computational methods have been proposed to detect protein complexes. However, most of the existing methods just search the local topological information to mine dense subgraphs as protein complexes, ignoring the global topological information. To tackle this issue, we propose the DPCMNE method to detect protein complexes via multi-level network embedding. It can preserve both the local and global topological information of biological networks. First, DPCMNE employs a hierarchical compressing strategy to recursively compress the input protein-protein interaction (PPI) network into multi-level smaller PPI networks. Then, a network embedding method is applied on these smaller PPI networks to learn protein embeddings of different levels of granularity. The embeddings learned from all the compressed PPI networks are concatenated to represent the final protein embeddings of the original input PPI network. Finally, a core-attachment based strategy is adopted to detect protein complexes in the weighted PPI network constructed by the pairwise similarity of protein embeddings. To assess the efficiency of our proposed method, DPCMNE is compared with other eight clustering algorithms on two yeast datasets. The experimental results show that the performance of DPCMNE outperforms those state-of-the-art complex detection methods in terms of F1 and F1+Acc. Furthermore, the results of functional enrichment analysis indicate that protein complexes detected by DPCMNE are more biologically significant in terms of P-score.

The prediction of genes related to diseases is important to the study of the diseases due to high cost and time consumption of biological experiments. Network propagation is a popular strategy for disease-gene prediction. However, existing methods focus on the stable solution of dynamics while ignoring the useful information hidden in the dynamical process, and it is still a challenge to make use of multiple types of physical/functional relationships between proteins/genes to effectively predict disease-related genes. Therefore, we proposed a framework of network impulsive dynamics on multiplex biological network (NIDM) to predict disease-related genes, along with four variants of NIDM models and four kinds of impulsive dynamical signatures (IDSs). NIDM is to identify disease-related genes by mining the dynamical responses of nodes to impulsive signals being exerted at specific nodes. By a series of experimental evaluations in various types of biological networks, we confirmed the advantage of multiplex network and the important roles of functional associations in disease-gene prediction, demonstrated superior performance of NIDM compared with four types of network-based algorithms and then gave the effective recommendations of NIDM models and IDS signatures. To facilitate the prioritization and analysis of (candidate) genes associated to specific diseases, we developed a user-friendly web server, which provides three kinds of filtering patterns for genes, network visualization, enrichment analysis and a wealth of external links (http://bioinformatics.csu.edu.cn/DGP/NID.jsp). NIDM is a protocol for disease-gene prediction integrating different types of biological networks, which may become a very useful computational tool for the study of disease-related genes.

Breast cancer is a heterogeneous disease with many clinically distinguishable molecular subtypes each corresponding to a cluster of patients. Identification of prognostic and heterogeneous biomarkers for breast cancer is to detect cluster-specific gene biomarkers which can be used for accurate survival prediction of breast cancer outcomes. In this study, we proposed a FUsion Network-based method (FUNMarker) to identify prognostic and heterogeneous breast cancer biomarkers by considering the heterogeneity of patient samples and biological information from multiple sources. To reduce the affect of heterogeneity of patients, samples were first clustered using the K-means algorithm based on the principal components of gene expression. For each cluster, to comprehensively evaluate the influence of genes on breast cancer, genes were weighted from three aspects: biological function, prognostic ability and correlation with known disease genes. Then they were ranked via a label propagation model on a fusion network that combined physical protein interactions from seven types of networks and thus could reduce the impact of incompleteness of interactome. We compared FUNMarker with three state-of-the-art methods and the results showed that biomarkers identified by FUNMarker were biological interpretable and had stronger discriminative power than the existing methods in differentiating patients with different prognostic outcomes.

Complex diseases are affected by many factors, and their pathogenic mechanism is complicated, which brings difficulties to the analysis and treatment of diseases. AUC, the area under the ROC curve, is often used as a gold standard to evaluate the performance of a binary classifier. The existing methods of constructing classifier by optimizing AUC are easy to fall into local optimum, and have high time complexity, which is not suitable for real-time analysis of high-dimensional gene expression data. With the rapid development of high-throughput sequencing technology, feature selection and model estimation become the necessary means to reduce the dimension and complexity of data, and the selected important features have the potential as biomarkers to reveal the pathogenesis of diseases. In this paper, we proposed a topological AUC-based biomarker ensemble method for the complex disease analysis, which uses gene expression data and the topological information derived from the protein-protein interaction network to identify biomarkers. The main contribution is to optimize two objectives simultaneously: maximizing the AUC score and minimizing the number of selected features. We applied the proposed method to analyze two types of problems: 1) prognosis of breast cancer, 2) classification of similar diseases. The results show that our method can effectively identify a small set of biomarkers with the powerful classification ability and the biological interpretability.

BACKGROUND: Drug discovery is known for the large amount of money and time it consumes and the high risk it takes. Drug repositioning has, therefore, become a popular approach to save time and cost by finding novel indications for approved drugs. In order to distinguish these novel indications accurately in a great many of latent associations between drugs and diseases, it is necessary to exploit abundant heterogeneous information about drugs and diseases. RESULTS: In this article, we propose a meta-path-based computational method called NEDD to predict novel associations between drugs and diseases using heterogeneous information. First, we construct a heterogeneous network as an undirected graph by integrating drug-drug similarity, disease-disease similarity, and known drug-disease associations. NEDD uses meta paths of different lengths to explicitly capture the indirect relationships, or high order proximity, within drugs and diseases, by which the low dimensional representation vectors of drugs and diseases are obtained. NEDD then uses a random forest classifier to predict novel associations between drugs and diseases. CONCLUSIONS: The experiments on a gold standard dataset which contains 1933 validated drug-disease associations show that NEDD produces superior prediction results compared with the state-of-the-art approaches.

Analysis of heterogeneous complex diseases based on the expression of biomarkers has always been the focus of medical research. In the past studies, the powerful network propagation has been applied in finding marker genes related to specific diseases. However, the network propagation model largely depends on the reliability and integrity of the network data, current networks may cause some problems due to the incompleteness of the networks. In this study, we developed a multiplex network-based dual ranking framework (DualRank) for heterogeneous complex disease analysis. We applied the proposed method to heterogeneous complex diseases for disease diagnosis, cancer prognosis, and similar disease classification. The results showed that DualRank outperformed current methods and could identify biomarkers with small quantity, strong prediction accuracy and biological interpretability.