The proliferation of single-cell RNA-seq data has greatly enhanced our ability to comprehend the intricate nature of diverse tissues. However, accurately annotating cell types in such data, especially when handling multiple reference datasets and identifying novel cell types, remains a significant challenge. To address these issues, we introduce Single Cell annotation based on Distance metric learning and Optimal Transport (scDOT), an innovative cell-type annotation method adept at integrating multiple reference datasets and uncovering previously unseen cell types. scDOT introduces two key innovations. First, by incorporating distance metric learning and optimal transport, it presents a novel optimization framework. This framework effectively learns the predictive power of each reference dataset for new query data and simultaneously establishes a probabilistic mapping between cells in the query data and reference-defined cell types. Secondly, scDOT develops an interpretable scoring system based on the acquired probabilistic mapping, enabling the precise identification of previously unseen cell types within the data. To rigorously assess scDOT's capabilities, we systematically evaluate its performance using two diverse collections of benchmark datasets encompassing various tissues, sequencing technologies and diverse cell types. Our experimental results consistently affirm the superior performance of scDOT in cell-type annotation and the identification of previously unseen cell types. These advancements provide researchers with a potent tool for precise cell-type annotation, ultimately enriching our understanding of complex biological tissues.

MOTIVATION: Spatially resolved gene expression profiles are the key to exploring the cell type spatial distributions and understanding the architecture of tissues. Many spatially resolved transcriptomics (SRT) techniques do not provide single-cell resolutions, but they measure gene expression profiles on captured locations (spots) instead, which are mixtures of potentially heterogeneous cell types. Currently, several cell-type deconvolution methods have been proposed to deconvolute SRT data. Due to the different model strategies of these methods, their deconvolution results also vary. RESULTS: Leveraging the strengths of multiple deconvolution methods, we introduce a new weighted ensemble learning deconvolution method, EnDecon, to predict cell-type compositions on SRT data in this work. EnDecon integrates multiple base deconvolution results using a weighted optimization model to generate a more accurate result. Simulation studies demonstrate that EnDecon outperforms the competing methods and the learned weights assigned to base deconvolution methods have high positive correlations with the performances of these base methods. Applied to real datasets from different spatial techniques, EnDecon identifies multiple cell types on spots, localizes these cell types to specific spatial regions and distinguishes distinct spatial colocalization and enrichment patterns, providing valuable insights into spatial heterogeneity and regionalization of tissues. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/Zhangxf-ccnu/EnDecon. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The recent advances in single-cell RNA sequencing (scRNA-seq) techniques have stimulated efforts to identify and characterize the cellular composition of complex tissues. With the advent of various sequencing techniques, automated cell-type annotation using a well-annotated scRNA-seq reference becomes popular. But it relies on the diversity of cell types in the reference, which may not capture all the cell types present in the query data of interest. There are generally unseen cell types in the query data of interest because most data atlases are obtained for different purposes and techniques. Identifying previously unseen cell types is essential for improving annotation accuracy and uncovering novel biological discoveries. To address this challenge, we propose mtANN (multiple-reference-based scRNA-seq data annotation), a new method to automatically annotate query data while accurately identifying unseen cell types with the aid of multiple references. Key innovations of mtANN include the integration of deep learning and ensemble learning to improve prediction accuracy, and the introduction of a new metric that considers three complementary aspects to distinguish between unseen cell types and shared cell types. Additionally, we provide a data-driven method to adaptively select a threshold for identifying previously unseen cell types. We demonstrate the advantages of mtANN over state-of-the-art methods for unseen cell-type identification and cell-type annotation on two benchmark dataset collections, as well as its predictive power on a collection of COVID-19 datasets. The source code and tutorial are available at https://github.com/Zhangxf-ccnu/mtANN.

The single-cell RNA sequencing (scRNA-seq) technique begins a new era by revealing gene expression patterns at single-cell resolution, enabling studies of heterogeneity and transcriptome dynamics of complex tissues at single-cell resolution. However, existing large proportion of dropout events may hinder downstream analyses. Thus imputation of dropout events is an important step in analyzing scRNA-seq data. We develop scTSSR2, a new imputation method that combines matrix decomposition with the previously developed two-side sparse self-representation, leading to fast two-side sparse self-representation to impute dropout events in scRNA-seq data. The comparisons of computational speed and memory usage among different imputation methods show that scTSSR2 has distinct advantages in terms of computational speed and memory usage. Comprehensive downstream experiments show that scTSSR2 outperforms the state-of-the-art imputation methods. A user-friendly R package scTSSR2 is developed to denoise the scRNA-seq data to improve the data quality.

The identification of differentially expressed genes between different cell groups is a crucial step in analyzing single-cell RNA-sequencing (scRNA-seq) data. Even though various differential expression analysis methods for scRNA-seq data have been proposed based on different model assumptions and strategies recently, the differentially expressed genes identified by them are quite different from each other, and the performances of them depend on the underlying data structures. In this paper, we propose a new ensemble learning-based differential expression analysis method, scDEA, to produce a more stable and accurate result. scDEA integrates the P-values obtained from 12 individual differential expression analysis methods for each gene using a P-value combination method. Comprehensive experiments show that scDEA outperforms the state-of-the-art individual methods with different experimental settings and evaluation metrics. We expect that scDEA will serve a wide range of users, including biologists, bioinformaticians and data scientists, who need to detect differentially expressed genes in scRNA-seq data.

MOTIVATION: Single-cell RNA sequencing (scRNA-seq) technologies have been testified revolutionary for their promotion on the profiling of single-cell transcriptomes at single-cell resolution. Excess zeros due to various technical noises, called dropouts, will mislead downstream analyses. Therefore, it is crucial to have accurate imputation methods to address the dropout problem. RESULTS: In this article, we develop a new dropout imputation method for scRNA-seq data based on multi-objective optimization. Our method is different from existing ones, which assume that the underlying data has a preconceived structure and impute the dropouts according to the information learned from such structure. We assume that the data combines three types of latent structures, including the horizontal structure (genes are similar to each other), the vertical structure (cells are similar to each other) and the low-rank structure. The combination weights and latent structures are learned using multi-objective optimization. And, the weighted average of the observed data and the imputation results learned from the three types of structures are considered as the final result. Comprehensive downstream experiments show the superiority of our method in terms of recovery of true gene expression profiles, differential expression analysis, cell clustering and cell trajectory inference. AVAILABILITY AND IMPLEMENTATION: The R package is available at https://github.com/Zhangxf-ccnu/scMOO and https://zenodo.org/record/5785195. The codes to reproduce the downstream analyses in this article can be found at https://github.com/Zhangxf-ccnu/scMOO_experiments_codes and https://zenodo.org/record/5786211. The detailed list of data sets used in the present study is represented in Supplementary Table S1 in the Supplementary materials. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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.

Inferring gene co-expression networks from high-throughput gene expression data is an important task in bioinformatics. Many gene networks often exhibit modular structures. Although several Gaussian graphical model-based methods have been developed to estimate gene co-expression networks by incorporating the modular structural prior, none of them takes into account the modular structures captured by the prior networks (e.g., protein interaction networks). In this study, we propose a novel prior network-dependent gene network inference (pGNI) method to estimate gene co-expression networks by integrating gene expression data and prior protein interaction network data. The underlying modular structure is learned from both sets of data. Through simulation studies, we demonstrate the feasibility and effectiveness of our method. We also apply our method to two real datasets. The modular structures in the networks estimated by our method are biological significant.

The mechanisms controlling biological process, such as the development of disease or cell differentiation, can be investigated by examining changes in the networks of gene dependencies between states in the process. High-throughput experimental methods, like microarray and RNA sequencing, have been widely used to gather gene expression data, which paves the way to infer gene dependencies based on computational methods. However, most differential network analysis methods are designed to deal with fully observed data, but missing values, such as the dropout events in single-cell RNA-sequencing data, are frequent. New methods are needed to take account of these missing values. Moreover, since the changes of gene dependencies may be driven by certain perturbed genes, considering the changes in gene expression levels may promote the identification of gene network rewiring. In this study, a novel weighted differential network estimation (WDNE) model is proposed to handle multi-platform gene expression data with missing values and take account of changes in gene expression levels. Simulation studies demonstrate that WDNE outperforms state-of-the-art differential network estimation methods. When applied WDNE to infer differential gene networks associated with drug resistance in ovarian tumors, cell differentiation and breast tumor heterogeneity, the hub genes in the estimated differential gene networks can provide important insights into the underlying mechanisms. Furthermore, a Matlab toolbox, differential network analysis toolbox, was developed to implement the WDNE model and visualize the estimated differential networks.

MOTIVATION: Differential network analysis is an important tool to investigate the rewiring of gene interactions under different conditions. Several computational methods have been developed to estimate differential networks from gene expression data, but most of them do not consider that gene network rewiring may be driven by the differential expression of individual genes. New differential network analysis methods that simultaneously take account of the changes in gene interactions and changes in expression levels are needed. RESULTS: : In this article, we propose a differential network analysis method that considers the differential expression of individual genes when identifying differential edges. First, two hypothesis test statistics are used to quantify changes in partial correlations between gene pairs and changes in expression levels for individual genes. Then, an optimization framework is proposed to combine the two test statistics so that the resulting differential network has a hierarchical property, where a differential edge can be considered only if at least one of the two involved genes is differentially expressed. Simulation results indicate that our method outperforms current state-of-the-art methods. We apply our method to identify the differential networks between the luminal A and basal-like subtypes of breast cancer and those between acute myeloid leukemia and normal samples. Hub nodes in the differential networks estimated by our method, including both differentially and nondifferentially expressed genes, have important biological functions. AVAILABILITY AND IMPLEMENTATION: All the datasets underlying this article are publicly available. Processed data and source code can be accessed through the Github repository at https://github.com/Zhangxf-ccnu/chNet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The advancements of single-cell RNA sequencing (scRNA-seq) technologies have provided us unprecedented opportunities to characterize cellular states and investigate the mechanisms of complex diseases. Due to technical issues such as dropout events, scRNA-seq data contains excess of false zero counts, which has a substantial impact on the downstream analyses. Although several computational approaches have been proposed to impute dropout events in scRNA-seq data, there is no strong consensus on which is the best approach. In this study, we propose a novel weighted ensemble learning method, named EnTSSR, to impute dropout events in scRNA-seq data. By using a multi-view two-side sparse self-representation framework, our model can exploit the consensus similarities between genes and between cells based on the imputed results of various imputation methods. Moreover, we introduce a weighted ensemble strategy to leverage the information captured by various imputation methods effectively. Down-sampling experiments, clustering analysis, differential expression analysis and cell trajectory inference are carried out to evaluate the performance of our proposed model. Experiment results demonstrate that our EnTSSR can effectively recover the true expression pattern of scRNA-seq data.

To reveal how gene regulatory networks change over cancer development, multiple time-varying differential networks between adjacent cancer stages should be estimated simultaneously. Since the network rewiring may be driven by the perturbation of certain individual genes, there may be some hub nodes shared by these differential networks. Although several methods have been developed to estimate differential networks from gene expression data, most of them are designed for estimating a single differential network, which neglect the similarities between different differential networks. In this article, we propose a new Gaussian graphical model-based method to jointly estimate multiple time-varying differential networks for identifying network rewiring over cancer development. A D-trace loss is used to determine the differential networks. A tree-structured group Lasso penalty is designed to identify the common hub nodes shared by different differential networks and the specific hub nodes unique to individual differential networks. Simulation experiment results demonstrate that our method outperforms other state-of-the-art techniques in most cases. We also apply our method to The Cancer Genome Atlas data to explore gene network rewiring over different breast cancer stages. Hub nodes in the estimated differential networks rediscover well known genes associated with the development and progression of breast cancer.

Reconstructing gene networks from gene expression data is a long-standing challenge. In most applications, the observations can be divided into several distinct but related subpopulations and the gene expression measurements can be collected from multiple data types. Most existing methods are designed to estimate a single gene network from a single dataset. These methods may be suboptimal since they do not exploit the similarities and differences among different subpopulations and data types. In this article, we propose a joint graphical model to estimate the multiple gene networks simultaneously. Our model decomposes each subpopulation-specific gene network as a sum of common and unique components and imposes a group lasso penalty on gene networks corresponding to different data types. The gene network variations across subpopulations can be learned automatically by the decompositions of networks, and the similarities and differences among data types can be captured by the group lasso penalty. The simulation studies demonstrate that our method outperforms the state-of-the-art methods. We also apply our method to the cancer genome atlas breast cancer datasets to reconstruct subtype-specific gene networks. Hub nodes in the estimated subnetworks unique to individual cancer subtypes rediscover well-known genes associated with breast cancer subtypes and provide interesting predictions.

MOTIVATION: Single-cell RNA sequencing (scRNA-seq) methods make it possible to reveal gene expression patterns at single-cell resolution. Due to technical defects, dropout events in scRNA-seq will add noise to the gene-cell expression matrix and hinder downstream analysis. Therefore, it is important for recovering the true gene expression levels before carrying out downstream analysis. RESULTS: In this article, we develop an imputation method, called scTSSR, to recover gene expression for scRNA-seq. Unlike most existing methods that impute dropout events by borrowing information across only genes or cells, scTSSR simultaneously leverages information from both similar genes and similar cells using a two-side sparse self-representation model. We demonstrate that scTSSR can effectively capture the Gini coefficients of genes and gene-to-gene correlations observed in single-molecule RNA fluorescence in situ hybridization (smRNA FISH). Down-sampling experiments indicate that scTSSR performs better than existing methods in recovering the true gene expression levels. We also show that scTSSR has a competitive performance in differential expression analysis, cell clustering and cell trajectory inference. AVAILABILITY AND IMPLEMENTATION: The R package is available at https://github.com/Zhangxf-ccnu/scTSSR. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Reconstruction of cancer gene networks from gene expression data is important for understanding the mechanisms underlying human cancer. Due to heterogeneity, the tumor tissue samples for a single cancer type can be divided into multiple distinct subtypes (inter-tumor heterogeneity) and are composed of non-cancerous and cancerous cells (intra-tumor heterogeneity). If tumor heterogeneity is ignored when inferring gene networks, the edges specific to individual cancer subtypes and cell types cannot be characterized. However, most existing network reconstruction methods do not simultaneously take inter-tumor and intra-tumor heterogeneity into account. RESULTS: In this article, we propose a new Gaussian graphical model-based method for jointly estimating multiple cancer gene networks by simultaneously capturing inter-tumor and intra-tumor heterogeneity. Given gene expression data of heterogeneous samples for different cancer subtypes, a non-cancerous network shared across different cancer subtypes and multiple subtype-specific cancerous networks are estimated jointly. Tumor heterogeneity can be revealed by the difference in the estimated networks. The performance of our method is first evaluated using simulated data, and the results indicate that our method outperforms other state-of-the-art methods. We also apply our method to The Cancer Genome Atlas breast cancer data to reconstruct non-cancerous and subtype-specific cancerous gene networks. Hub nodes in the networks estimated by our method perform important biological functions associated with breast cancer development and subtype classification. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/Zhangxf-ccnu/NETI2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Predicting potential links in biomedical bipartite networks can provide useful insights into the diagnosis and treatment of complex diseases and the discovery of novel drug targets. Computational methods have been proposed recently to predict potential links for various biomedical bipartite networks. However, existing methods are usually rely on the coverage of known links, which may encounter difficulties when dealing with new nodes without any known link information. RESULTS: In this study, we propose a new link prediction method, named graph regularized generalized matrix factorization (GRGMF), to identify potential links in biomedical bipartite networks. First, we formulate a generalized matrix factorization model to exploit the latent patterns behind observed links. In particular, it can take into account the neighborhood information of each node when learning the latent representation for each node, and the neighborhood information of each node can be learned adaptively. Second, we introduce two graph regularization terms to draw support from affinity information of each node derived from external databases to enhance the learning of latent representations. We conduct extensive experiments on six real datasets. Experiment results show that GRGMF can achieve competitive performance on all these datasets, which demonstrate the effectiveness of GRGMF in prediction potential links in biomedical bipartite networks. AVAILABILITY AND IMPLEMENTATION: The package is available at https://github.com/happyalfred2016/GRGMF. CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The development and prognosis of complex diseases usually involves changes in regulatory relationships among biomolecules. Understanding how the regulatory relationships change with genetic alterations can help to reveal the underlying biological mechanisms for complex diseases. Although several models have been proposed to estimate the differential network between two different states, they are not suitable to deal with situations where the molecules of interest are affected by other covariates. Nor can they make use of prior information that provides insights about the structures of biomolecular networks. In this study, we introduce a novel weighted fused conditional Gaussian graphical model to jointly estimate two state-specific biomolecular regulatory networks and their difference between two different states. Unlike previous differential network estimation methods, our model can take into account the related covariates and the prior network information when inferring differential networks. The effectiveness of our proposed model is first evaluated based on simulation studies. Experiment results demonstrate that our model outperforms other state-of-the-art differential networks estimation models in all cases. We then apply our model to identify the differential gene network between two subtypes of glioblastoma based on gene expression and miRNA expression data. Our model is able to discover known mechanisms of glioblastoma and provide interesting predictions.

Identifying gene network rewiring under different biological conditions is important for understanding the mechanisms underlying complex diseases. Gaussian graphical models, which assume the data follow the multivariate normal distribution, are widely used to identify gene network rewiring. However, the normality assume often fails in reality since the data are contaminated by extreme outliers in general. In this study, we propose a new robust differential graphical model to identify gene network rewiring between two conditions based on the multivariate t-distribution. The multivariate t-distribution is more robust to outliers than the normal distribution since it has heavy tails and allows values far from the mean. A fused lasso penalty is used to borrow information across conditions to improve the results. We develop an expectation maximization algorithm to solve the optimization model. Experiment results on simulated data show that our method outperforms the state-of-the-art methods. Our method is also applied to identify gene network rewiring between luminal A and basal-like subtypes of breast cancer, and gene network rewiring between the proneural and mesenchymal subtypes of glioblastoma. Several key genes which drive gene network rewiring are discovered.

SUMMARY: To identify biological network rewiring under different conditions, we develop a user-friendly R package, named DiffNetFDR, to implement two methods developed for testing the difference in different Gaussian graphical models. Compared to existing tools, our methods have the following features: (i) they are based on Gaussian graphical models which can capture the changes of conditional dependencies; (ii) they determine the tuning parameters in a data-driven manner; (iii) they take a multiple testing procedure to control the overall false discovery rate; and (iv) our approach defines the differential network based on partial correlation coefficients so that the spurious differential edges caused by the variants of conditional variances can be excluded. We also develop a Shiny application to provide easier analysis and visualization. Simulation studies are conducted to evaluate the performance of our methods. We also apply our methods to two real gene expression datasets. The effectiveness of our methods is validated by the biological significance of the identified differential networks. AVAILABILITY AND IMPLEMENTATION: R package and Shiny app are available at https://github.com/Zhangxf-ccnu/DiffNetFDR. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: Imputation of dropout events that may mislead downstream analyses is a key step in analyzing single-cell RNA-sequencing (scRNA-seq) data. We develop EnImpute, an R package that introduces an ensemble learning method for imputing dropout events in scRNA-seq data. EnImpute combines the results obtained from multiple imputation methods to generate a more accurate result. A Shiny application is developed to provide easier implementation and visualization. Experiment results show that EnImpute outperforms the individual state-of-the-art methods in almost all situations. EnImpute is useful for correcting the noisy scRNA-seq data before performing downstream analysis. AVAILABILITY AND IMPLEMENTATION: The R package and Shiny application are available through Github at https://github.com/Zhangxf-ccnu/EnImpute. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gene dependency networks often undergo changes with respect to different disease states. Understanding how these networks rewire between two different disease states is an important task in genomic research. Although many computational methods have been proposed to undertake this task via differential network analysis, most of them are designed for a predefined data type. With the development of the high throughput technologies, gene activity measurements can be collected from different aspects (e.g., mRNA expression and DNA mutation). These different data types might share some common characteristics and include certain unique properties of data type. New methods are needed to explore the similarity and difference between differential networks estimated from different data types. In this study, we develop a new differential network inference model which identifies gene network rewiring by combining gene expression and gene mutation data. Similarities and differences between different data types are learned via a group bridge penalty function. Simulation studies have demonstrated that our method consistently outperforms the competing methods. We also apply our method to identify gene network rewiring associated with ovarian cancer platinum resistance from The Cancer Genome Atlas data. There are certain differential edges common to both data types and some differential edges unique to individual data types. Hub genes in the differential networks inferred by our method play important roles in ovarian cancer drug resistance.

Graphical models have been widely used to learn the conditional dependence structures among random variables. In many controlled experiments, such as the studies of disease or drug effectiveness, learning the structural changes of graphical models under two different conditions is of great importance. However, most existing graphical models are developed for estimating a single graph and based on a tacit assumption that there is no missing relevant variables, which wastes the common information provided by multiple heterogeneous data sets and underestimates the influence of latent/unobserved relevant variables. In this paper, we propose a joint differential network analysis (JDNA) model to jointly estimate multiple differential networks with latent variables from multiple data sets. The JDNA model is built on a penalized D-trace loss function, with group lasso or generalized fused lasso penalties. We implement a proximal gradient-based alternating direction method of multipliers to tackle the corresponding convex optimization problems. Extensive simulation experiments demonstrate that JDNA model outperforms state-of-the-art methods in estimating the structural changes of graphical models. Moreover, a series of experiments on several real-world data sets have been performed and experiment results consistently show that our proposed JDNA model is effective in identifying differential networks under different conditions.

Summary: We develop DiffGraph, an R package that integrates four influential differential graphical models for identifying gene network rewiring under two different conditions from gene expression data. The input and output of different models are packaged in the same format, making it convenient for users to compare different models using a wide range of datasets and carry out follow-up analysis. Furthermore, the inferred differential networks can be visualized both non-interactively and interactively. The package is useful for identifying gene network rewiring from input datasets, comparing the predictions of different methods and visualizing the results. Availability and implementation: The package is available at https://github.com/Zhangxf-ccnu/DiffGraph. Contact: [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

Exploring the rewiring pattern of gene regulatory networks between different pathological states is an important task in bioinformatics. Although a number of computational approaches have been developed to infer differential networks from high-throughput data, most of them only focus on gene expression data. The valuable static gene regulatory network data accumulated in recent biomedical researches are neglected. In this study, we propose a new Gaussian graphical model-based method to infer differential networks by integrating gene expression and static gene regulatory network data. We first evaluate the empirical performance of our method by comparing with the state-of-the-art methods using simulation data. We also apply our method to The Cancer Genome Atlas data to identify gene network rewiring between ovarian cancers with different platinum responses, and rewiring between breast cancers of luminal A subtype and basal-like subtype. Hub genes in the estimated differential networks rediscover known genes associated with platinum resistance in ovarian cancer and signatures of the breast cancer intrinsic subtypes.

MOTIVATION: Understanding how gene regulatory networks change under different cellular states is important for revealing insights into network dynamics. Gaussian graphical models, which assume that the data follow a joint normal distribution, have been used recently to infer differential networks. However, the distributions of the omics data are non-normal in general. Furthermore, although much biological knowledge (or prior information) has been accumulated, most existing methods ignore the valuable prior information. Therefore, new statistical methods are needed to relax the normality assumption and make full use of prior information. RESULTS: We propose a new differential network analysis method to address the above challenges. Instead of using Gaussian graphical models, we employ a non-paranormal graphical model that can relax the normality assumption. We develop a principled model to take into account the following prior information: (i) a differential edge less likely exists between two genes that do not participate together in the same pathway; (ii) changes in the networks are driven by certain regulator genes that are perturbed across different cellular states and (iii) the differential networks estimated from multi-view gene expression data likely share common structures. Simulation studies demonstrate that our method outperforms other graphical model-based algorithms. We apply our method to identify the differential networks between platinum-sensitive and platinum-resistant ovarian tumors, and the differential networks between the proneural and mesenchymal subtypes of glioblastoma. Hub nodes in the estimated differential networks rediscover known cancer-related regulator genes and contain interesting predictions. AVAILABILITY AND IMPLEMENTATION: The source code is at https://github.com/Zhangxf-ccnu/pDNA. CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: The accurate identification of protein complexes is important for the understanding of cellular organization. Up to now, computational methods for protein complex detection are mostly focus on mining clusters from protein-protein interaction (PPI) networks. However, PPI data collected by high-throughput experimental techniques are known to be quite noisy. It is hard to achieve reliable prediction results by simply applying computational methods on PPI data. Behind protein interactions, there are protein domains that interact with each other. Therefore, based on domain-protein associations, the joint analysis of PPIs and domain-domain interactions (DDI) has the potential to obtain better performance in protein complex detection. As traditional computational methods are designed to detect protein complexes from a single PPI network, it is necessary to design a new algorithm that could effectively utilize the information inherent in multiple heterogeneous networks. RESULTS: In this paper, we introduce a novel multi-network clustering algorithm to detect protein complexes from multiple heterogeneous networks. Unlike existing protein complex identification algorithms that focus on the analysis of a single PPI network, our model can jointly exploit the information inherent in PPI and DDI data to achieve more reliable prediction results. Extensive experiment results on real-world data sets demonstrate that our method can predict protein complexes more accurately than other state-of-the-art protein complex identification algorithms. CONCLUSIONS: In this work, we demonstrate that the joint analysis of PPI network and DDI network can help to improve the accuracy of protein complex detection.

The detection of protein complexes from protein-protein interaction (PPI) networks is an important step toward understanding the functional organization within cells. A great number of graph clustering algorithms have been proposed to undertake this task. Since PPI data collected by high-throughput technologies is quite noisy, simply applying graph clustering algorithms on PPI data is generally not adequate to achieve reliable prediction results. Behind protein interactions, there are protein domains that interact with each other. Jointly exploiting protein-protein interactions and domain-domain interactions (DDI) have the potential to increase the accuracy of protein complex detection. However, traditional graph clustering algorithms focus on clustering proteins within a single PPI network, and cannot make use of information inherent in other heterogeneous networks. In this paper, we proposed a novel generative model to perform multi-network clustering. Unlike previous protein complex detection algorithms that can only utilize the information within a single PPI network, our model is a flexible framework that can take into account PPIs, DDIs and domain-protein associations to achieve more consistent and reliable clustering results. Experiment results on real data demonstrate that our method performs much better than state-of-the-art protein complex detection techniques.

BACKGROUND: Protein complexes carry out nearly all signaling and functional processes within cells. The study of protein complexes is an effective strategy to analyze cellular functions and biological processes. With the increasing availability of proteomics data, various computational methods have recently been developed to predict protein complexes. However, different computational methods are based on their own assumptions and designed to work on different data sources, and various biological screening methods have their unique experiment conditions, and are often different in scale and noise level. Therefore, a single computational method on a specific data source is generally not able to generate comprehensive and reliable prediction results. RESULTS: In this paper, we develop a novel Two-layer INtegrative Complex Detection (TINCD) model to detect protein complexes, leveraging the information from both clustering results and raw data sources. In particular, we first integrate various clustering results to construct consensus matrices for proteins to measure their overall co-complex propensity. Second, we combine these consensus matrices with the co-complex score matrix derived from Tandem Affinity Purification/Mass Spectrometry (TAP) data and obtain an integrated co-complex similarity network via an unsupervised metric fusion method. Finally, a novel graph regularized doubly stochastic matrix decomposition model is proposed to detect overlapping protein complexes from the integrated similarity network. CONCLUSIONS: Extensive experimental results demonstrate that TINCD performs much better than 21 state-of-the-art complex detection techniques, including ensemble clustering and data integration techniques.

BACKGROUND: Protein complexes are the key molecular entities to perform many essential biological functions. In recent years, high-throughput experimental techniques have generated a large amount of protein interaction data. As a consequence, computational analysis of such data for protein complex detection has received increased attention in the literature. However, most existing works focus on predicting protein complexes from a single type of data, either physical interaction data or co-complex interaction data. These two types of data provide compatible and complementary information, so it is necessary to integrate them to discover the underlying structures and obtain better performance in complex detection. RESULTS: In this study, we propose a novel multi-view clustering algorithm, called the Partially Shared Multi-View Clustering model (PSMVC), to carry out such an integrated analysis. Unlike traditional multi-view learning algorithms that focus on mining either consistent or complementary information embedded in the multi-view data, PSMVC can jointly explore the shared and specific information inherent in different views. In our experiments, we compare the complexes detected by PSMVC from single data source with those detected from multiple data sources. We observe that jointly analyzing multi-view data benefits the detection of protein complexes. Furthermore, extensive experiment results demonstrate that PSMVC performs much better than 16 state-of-the-art complex detection techniques, including ensemble clustering and data integration techniques. CONCLUSIONS: In this work, we demonstrate that when integrating multiple data sources, using partially shared multi-view clustering model can help to identify protein complexes which are not readily identifiable by conventional single-view-based methods and other integrative analysis methods. All the results and source codes are available on https://github.com/Oyl-CityU/PSMVC .

BACKGROUND: To facilitate advances in personalized medicine, it is important to detect predictive, stable and interpretable biomarkers related with different clinical characteristics. These clinical characteristics may be heterogeneous with respect to underlying interactions between genes. Usually, traditional methods just focus on detection of differentially expressed genes without taking the interactions between genes into account. Moreover, due to the typical low reproducibility of the selected biomarkers, it is difficult to give a clear biological interpretation for a specific disease. Therefore, it is necessary to design a robust biomarker identification method that can predict disease-associated interactions with high reproducibility. RESULTS: In this article, we propose a regularized logistic regression model. Different from previous methods which focus on individual genes or modules, our model takes gene pairs, which are connected in a protein-protein interaction network, into account. A line graph is constructed to represent the adjacencies between pairwise interactions. Based on this line graph, we incorporate the degree information in the model via an adaptive elastic net, which makes our model less dependent on the expression data. Experimental results on six publicly available breast cancer datasets show that our method can not only achieve competitive performance in classification, but also retain great stability in variable selection. Therefore, our model is able to identify the diagnostic and prognostic biomarkers in a more robust way. Moreover, most of the biomarkers discovered by our model have been verified in biochemical or biomedical researches. CONCLUSIONS: The proposed method shows promise in the diagnosis of disease pathogenesis with different clinical characteristics. These advances lead to more accurate and stable biomarker discovery, which can monitor the functional changes that are perturbed by diseases. Based on these predictions, researchers may be able to provide suggestions for new therapeutic approaches.

BACKGROUND: Several recent studies have used the Minimum Dominating Set (MDS) model to identify driver nodes, which provide the control of the underlying networks, in protein interaction networks. There may exist multiple MDS configurations in a given network, thus it is difficult to determine which one represents the real set of driver nodes. Because these previous studies only focus on static networks and ignore the contextual information on particular tissues, their findings could be insufficient or even be misleading. RESULTS: In this study, we develop a Collective-Influence-corrected Minimum Dominating Set (CI-MDS) model which takes into account the collective influence of proteins. By integrating molecular expression profiles and static protein interactions, 16 tissue-specific networks are established as well. We then apply the CI-MDS model to each tissue-specific network to detect MDS proteins. It generates almost the same MDSs when it is solved using different optimization algorithms. In addition, we classify MDS proteins into Tissue-Specific MDS (TS-MDS) proteins and HouseKeeping MDS (HK-MDS) proteins based on the number of tissues in which they are expressed and identified as MDS proteins. Notably, we find that TS-MDS proteins and HK-MDS proteins have significantly different topological and functional properties. HK-MDS proteins are more central in protein interaction networks, associated with more functions, evolving more slowly and subjected to a greater number of post-translational modifications than TS-MDS proteins. Unlike TS-MDS proteins, HK-MDS proteins significantly correspond to essential genes, ageing genes, virus-targeted proteins, transcription factors and protein kinases. Moreover, we find that besides HK-MDS proteins, many TS-MDS proteins are also linked to disease related genes, suggesting the tissue specificity of human diseases. Furthermore, functional enrichment analysis reveals that HK-MDS proteins carry out universally necessary biological processes and TS-MDS proteins usually involve in tissue-dependent functions. CONCLUSIONS: Our study uncovers key features of TS-MDS proteins and HK-MDS proteins, and is a step forward towards a better understanding of the controllability of human interactomes.

BACKGROUND: Recently, several studies have drawn attention to the determination of a minimum set of driver proteins that are important for the control of the underlying protein-protein interaction (PPI) networks. In general, the minimum dominating set (MDS) model is widely adopted. However, because the MDS model does not generate a unique MDS configuration, multiple different MDSs would be generated when using different optimization algorithms. Therefore, among these MDSs, it is difficult to find out the one that represents the true driver set of proteins. RESULTS: To address this problem, we develop a centrality-corrected minimum dominating set (CC-MDS) model which includes heterogeneity in degree and betweenness centralities of proteins. Both the MDS model and the CC-MDS model are applied on three human PPI networks. Unlike the MDS model, the CC-MDS model generates almost the same sets of driver proteins when we implement it using different optimization algorithms. The CC-MDS model targets more high-degree and high-betweenness proteins than the uncorrected counterpart. The more central position allows CC-MDS proteins to be more important in maintaining the overall network connectivity than MDS proteins. To indicate the functional significance, we find that CC-MDS proteins are involved in, on average, more protein complexes and GO annotations than MDS proteins. We also find that more essential genes, aging genes, disease-associated genes and virus-targeted genes appear in CC-MDS proteins than in MDS proteins. As for the involvement in regulatory functions, the sets of CC-MDS proteins show much stronger enrichment of transcription factors and protein kinases. The results about topological and functional significance demonstrate that the CC-MDS model can capture more driver proteins than the MDS model. CONCLUSIONS: Based on the results obtained, the CC-MDS model presents to be a powerful tool for the determination of driver proteins that can control the underlying PPI networks. The software described in this paper and the datasets used are available at https://github.com/Zhangxf-ccnu/CC-MDS .

Identification of protein complexes is fundamental for understanding the cellular functional organization. With the accumulation of physical protein-protein interaction (PPI) data, computational detection of protein complexes from available PPI networks has drawn a lot of attentions. While most of the existing protein complex detection algorithms focus on analyzing the physical protein-protein interaction network, none of them take into account the "signs" (i.e., activation-inhibition relationships) of physical interactions. As the "signs" of interactions reflect the way proteins communicate, considering the "signs" of interactions can not only increase the accuracy of protein complex identification, but also deepen our understanding of the mechanisms of cell functions. In this study, we proposed a novel Signed Graph regularized Nonnegative Matrix Factorization (SGNMF) model to identify protein complexes from signed PPI networks. In our experiments, we compared the results collected by our model on signed PPI networks with those predicted by the state-of-the-art complex detection techniques on the original unsigned PPI networks. We observed that considering the "signs" of interactions significantly benefits the detection of protein complexes. Furthermore, based on the predicted complexes, we predicted a set of signed complex-complex interactions for each dataset, which provides a novel insight of the higher level organization of the cell. All the experimental results and codes can be downloaded from http://mail.sysu.edu.cn/home/[email protected]/dai/others/SGNMF.zip.

BACKGROUND: Proteins dynamically interact with each other to perform their biological functions. The dynamic operations of protein interaction networks (PPI) are also reflected in the dynamic formations of protein complexes. Existing protein complex detection algorithms usually overlook the inherent temporal nature of protein interactions within PPI networks. Systematically analyzing the temporal protein complexes can not only improve the accuracy of protein complex detection, but also strengthen our biological knowledge on the dynamic protein assembly processes for cellular organization. RESULTS: In this study, we propose a novel computational method to predict temporal protein complexes. Particularly, we first construct a series of dynamic PPI networks by joint analysis of time-course gene expression data and protein interaction data. Then a Time Smooth Overlapping Complex Detection model (TS-OCD) has been proposed to detect temporal protein complexes from these dynamic PPI networks. TS-OCD can naturally capture the smoothness of networks between consecutive time points and detect overlapping protein complexes at each time point. Finally, a nonnegative matrix factorization based algorithm is introduced to merge those very similar temporal complexes across different time points. CONCLUSIONS: Extensive experimental results demonstrate the proposed method is very effective in detecting temporal protein complexes than the state-of-the-art complex detection techniques.

BACKGROUND: Identification of protein complexes can help us get a better understanding of cellular mechanism. With the increasing availability of large-scale protein-protein interaction (PPI) data, numerous computational approaches have been proposed to detect complexes from the PPI networks. However, most of the current approaches do not consider overlaps among complexes or functional annotation information of individual proteins. Therefore, they might not be able to reflect the biological reality faithfully or make full use of the available domain-specific knowledge. RESULTS: In this paper, we develop a Generative Model with Functional and Topological Properties (GMFTP) to describe the generative processes of the PPI network and the functional profile. The model provides a working mechanism for capturing the interaction structures and the functional patterns of proteins. By combining the functional and topological properties, we formulate the problem of identifying protein complexes as that of detecting a group of proteins which frequently interact with each other in the PPI network and have similar annotation patterns in the functional profile. Using the idea of link communities, our method naturally deals with overlaps among complexes. The benefits brought by the functional properties are demonstrated by real data analysis. The results evaluated using four criteria with respect to two gold standards show that GMFTP has a competitive performance over the state-of-the-art approaches. The effectiveness of detecting overlapping complexes is also demonstrated by analyzing the topological and functional features of multi- and mono-group proteins. CONCLUSIONS: Based on the results obtained in this study, GMFTP presents to be a powerful approach for the identification of overlapping protein complexes using both the PPI network and the functional profile. The software can be downloaded from http://mail.sysu.edu.cn/home/[email protected]/dai/others/GMFTP.zip.

With the rapid development of high-throughput experiment techniques for protein-protein interaction (PPI) detection, a large amount of PPI network data are becoming available. However, the data produced by these techniques have high levels of spurious and missing interactions. This study assigns a new reliably indication for each protein pairs via the new generative network model (RIGNM) where the scale-free property of the PPI network is considered to reliably identify both spurious and missing interactions in the observed high-throughput PPI network. The experimental results show that the RIGNM is more effective and interpretable than the compared methods, which demonstrate that this approach has the potential to better describe the PPI networks and drive new discoveries.

Face recognition with occlusion is common in the real world. Inspired by the works of structured sparse representation, we try to explore the structure of the error incurred by occlusion from two aspects: the error morphology and the error distribution. Since human beings recognize the occlusion mainly according to its region shape or profile without knowing accurately what the occlusion is, we argue that the shape of the occlusion is also an important feature. We propose a morphological graph model to describe the morphological structure of the error. Due to the uncertainty of the occlusion, the distribution of the error incurred by occlusion is also uncertain. However, we observe that the unoccluded part and the occluded part of the error measured by the correntropy induced metric follow the exponential distribution, respectively. Incorporating the two aspects of the error structure, we propose the structured sparse error coding for face recognition with occlusion. Our extensive experiments demonstrate that the proposed method is more stable and has higher breakdown point in dealing with the occlusion problems in face recognition as compared to the related state-of-the-art methods, especially for the extreme situation, such as the high level occlusion and the low feature dimension.

Biomarker identification and cancer classification are two closely related problems. In gene expression data sets, the correlation between genes can be high when they share the same biological pathway. Moreover, the gene expression data sets may contain outliers due to either chemical or electrical reasons. A good gene selection method should take group effects into account and be robust to outliers. In this paper, we propose a Laplace naive Bayes model with mean shrinkage (LNB-MS). The Laplace distribution instead of the normal distribution is used as the conditional distribution of the samples for the reasons that it is less sensitive to outliers and has been applied in many fields. The key technique is the L1 penalty imposed on the mean of each class to achieve automatic feature selection. The objective function of the proposed model is a piecewise linear function with respect to the mean of each class, of which the optimal value can be evaluated at the breakpoints simply. An efficient algorithm is designed to estimate the parameters in the model. A new strategy that uses the number of selected features to control the regularization parameter is introduced. Experimental results on simulated data sets and 17 publicly available cancer data sets attest to the accuracy, sparsity, efficiency, and robustness of the proposed algorithm. Many biomarkers identified with our method have been verified in biochemical or biomedical research. The analysis of biological and functional correlation of the genes based on Gene Ontology (GO) terms shows that the proposed method guarantees the selection of highly correlated genes simultaneously

The functional annotation of proteins is one of the most important tasks in the post-genomic era. Although many computational approaches have been developed in recent years to predict protein function, most of these traditional algorithms do not take interrelationships among functional terms into account, such as different GO terms usually coannotate with some common proteins. In this study, we propose a new functional similarity measure in the form of Jaccard coefficient to quantify these interrelationships and also develop a framework for incorporating GO term similarity into protein function prediction process. The experimental results of cross-validation on S. cerevisiae and Homo sapiens data sets demonstrate that our method is able to improve the performance of protein function prediction. In addition, we find that small size terms associated with a few of proteins obtain more benefit than the large size ones when considering functional interrelationships. We also compare our similarity measure with other two widely used measures, and results indicate that when incorporated into function prediction algorithms, our proposed measure is more effective. Experiment results also illustrate that our algorithms outperform two previous competing algorithms, which also take functional interrelationships into account, in prediction accuracy. Finally, we show that our method is robust to annotations in the database which are not complete at present. These results give new insights about the importance of functional interrelationships in protein function prediction.

Detecting protein complexes from protein interaction networks is one major task in the postgenome era. Previous developed computational algorithms identifying complexes mainly focus on graph partition or dense region finding. Most of these traditional algorithms cannot discover overlapping complexes which really exist in the protein-protein interaction (PPI) networks. Even if some density-based methods have been developed to identify overlapping complexes, they are not able to discover complexes that include peripheral proteins. In this study, motivated by recent successful application of generative network model to describe the generation process of PPI networks and to detect communities from social networks, we develop a regularized sparse generative network model (RSGNM), by adding another process that generates propensities using exponential distribution and incorporating Laplacian regularizer into an existing generative network model, for protein complexes identification. By assuming that the propensities are generated using exponential distribution, the estimators of propensities will be sparse, which not only has good biological interpretation but also helps to control the overlapping rate among detected complexes. And the Laplacian regularizer will lead to the estimators of propensities more smooth on interaction networks. Experimental results on three yeast PPI networks show that RSGNM outperforms six previous competing algorithms in terms of the quality of detected complexes. In addition, RSGNM is able to detect overlapping complexes and complexes including peripheral proteins simultaneously. These results give new insights about the importance of generative network models in protein complexes identification.