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Dynamic disease pathways are a combination of complex dynamical processes among bio-molecules in a cell that leads to diseases. Network modeling of disease pathways considers disease-related bio-molecules (e.g. DNA, RNA, transcription factors, enzymes, proteins, and metabolites) and their interaction (e.g. DNA methylation, histone modification, alternative splicing, and protein modification) to study disease progression and predict therapeutic responses. These bio-molecules and their interactions are the basic elements in the study of the misregulation in the disease-related gene expression that lead to abnormal cellular responses. Gene regulatory networks, cell signaling networks, and metabolic networks are the three major types of intracellular networks for the study of the cellular responses elicited from extracellular signals. The disease-related cellular responses can be prevented or regulated by designing control strategies to manipulate these extracellular or other intracellular signals. The paper reviews the regulatory mechanisms, the dynamic models, and the control strategies for each intracellular network. The applications, limitations and the prospective for modeling and control are also discussed.

A major objective in genomics is to design interventions that can shift undesirable behaviors of such systems (i.e., those associated with cancers) into desirable ones. Several intervention policies have been developed in recent years, including dynamic and structural interventions. These techniques aim at making targeted changes to cell dynamics upon intervention, without considering the cell's defensive mechanisms to interventions. This simplified assumption often leads to early and short-term success of interventions, followed by partial or full recurrence of diseases. This is due to the fact that cells often have dynamic and intelligent responses to interventions through internal stimuli. This paper models gene regulatory networks (GRNs) using the Boolean network with perturbation. The dynamic and adaptive battle between intervention and the cell is modeled as a two-player zero-sum game, where intervention and the cell fight against each other with fully opposite objectives. An optimal intervention policy is obtained as a Nash equilibrium solution, through which the intervention is stochastic, ensuring the optimal solution to all potential cell responses. We analytically analyze the superiority of the proposed intervention policy against existing intervention techniques. Comprehensive numerical experiments using the p53-MDM2 negative feedback loop regulatory network and melanoma network demonstrate the high performance of the proposed method.

The complexity, scale, and uncertainty in regulatory networks (e.g., gene regulatory networks and microbial networks) regularly pose a huge uncertainty in their models. These uncertainties often cannot be entirely reduced using limited and costly data acquired from the normal condition of systems. Meanwhile, regulatory networks often suffer from the non-identifiability issue, which refers to scenarios where the true underlying network model cannot be clearly distinguished from other possible models. Perturbation or excitation is a well-known process in systems biology for acquiring targeted data to reveal the complex underlying mechanisms of regulatory networks and overcome the non-identifiability issue. We consider a general class of Boolean network models for capturing the activation and inactivation of components and their complex interactions. Assuming partial available knowledge about the interactions between components of the networks, this paper formulates the inference process through the maximum aposteriori (MAP) criterion. We develop a Bayesian lookahead policy that systematically perturbs regulatory networks to maximize the performance of MAP inference under the perturbed data. This is achieved by optimally formulating the perturbation process in a reinforcement learning context and deriving a scalable deep reinforcement learning perturbation policy to compute near-optimal Bayesian policy. The proposed method learns the perturbation policy through planning without the need for any real data. The high performance of the proposed approach is demonstrated by comprehensive numerical experiments using the well-known mammalian cell cycle and gut microbial community networks.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a positive-stranded single-stranded RNA virus with an envelope frequently altered by unstable genetic material, making it extremely difficult for vaccines, drugs, and diagnostics to work. Understanding SARS-CoV-2 infection mechanisms requires studying gene expression changes. Deep learning methods are often considered for large-scale gene expression profiling data. Data feature-oriented analysis, however, neglects the biological process nature of gene expression, making it difficult to describe gene expression behaviors accurately. In this article, we propose a novel scheme for modeling gene expression during SARS-CoV-2 infection as networks (gene expression modes, GEM), to characterize their expression behaviors. On this basis, we investigated the relationships among GEMs to determine SARS-CoV-2's core radiation mode. Our final experiments identified key COVID-19 genes by gene function enrichment, protein interaction, and module mining. Experimental results show that ATG10, ATG14, MAP1LC3B, OPTN, WDR45, and WIPI1 genes contribute to SARS-CoV-2 virus spread by affecting autophagy.

Transcription factors (TFs) regulation is required for the vast majority of biological processes in living organisms. Some diseases may be caused by improper transcriptional regulation. Identifying the target genes of TFs is thus critical for understanding cellular processes and analyzing disease molecular mechanisms. Computational approaches can be challenging to employ when attempting to predict potential interactions between TFs and target genes. In this paper, we present a novel graph model (PPRTGI) for detecting TF-target gene interactions using DNA sequence features. Feature representations of TFs and target genes are extracted from sequence embeddings and biological associations. Then, by combining the aggregated node feature with graph structure, PPRTGI uses a graph neural network with personalized PageRank to learn interaction patterns. Finally, a bilinear decoder is applied to predict interaction scores between TF and target gene nodes. We designed experiments on six datasets from different species. The experimental results show that PPRTGI is effective in regulatory interaction inference, with our proposed model achieving an area under receiver operating characteristic score of 93.87% and an area under precision-recall curves score of 88.79% on the human dataset. This paper proposes a new method for predicting TF-target gene interactions, which provides new insights into modeling molecular networks and can thus be used to gain a better understanding of complex biological systems.

Reconstructing gene regulatory networks(GRNs) is an increasingly hot topic in bioinformatics. Dynamic Bayesian network(DBN) is a stochastic graph model commonly used as a vital model for GRN reconstruction. But probabilistic characteristics of biological networks and the existence of data noise bring great challenges to GRN reconstruction and always lead to many false positive/negative edges. Score Lasso is a hybrid DBN score function combining DBN and linear regression with good performance. Its performance is, however, limited by first-order assumption and ignorance of the initial network of DBN. In this article, an integrated model based on higher-order DBN model, higher-order Lasso linear regression model and Pearson correlation model is proposed. Based on this, a hybrid higher-order DBN score function for GRN reconstruction is proposed, namely BIC-LP. BIC-LP score function is constructed by adding terms based on Lasso linear regression coefficients and Pearson correlation coefficients on classical BIC score function. Therefore, it could capture more information from dataset and curb information loss, compared with both many existing Bayesian family score functions and many state-of-the-art methods for GRN reconstruction. Experimental results show that BIC-LP can reasonably eliminate some false positive edges while retaining most true positive edges, so as to achieve better GRN reconstruction performance.

MiRNAs are reported to be linked to the pathogenesis of human complex diseases. Disease-related miRNAs may serve as novel bio-marks and drug targets. This work focuses on designing a multi-relational Graph Convolutional Network model to predict miRNA-disease associations (HGCNMDA) from a Heterogeneous network. HGCNMDA introduces a gene layer to construct a miRNA-gene-disease heterogeneous network. We refine the features of nodes into initial and inductive features so that the direct and indirect associations between diseases and miRNA can be considered simultaneously. Then HGCNMDA learns feature embeddings for miRNAs and disease through a multi-relational graph convolutional network model that can assign appropriate weights to different types of edges in the heterogeneous network. Finally, the miRNA-disease associations were decoded by the inner product between miRNA and disease feature embeddings. We apply our model to predict human miRNA-disease associations. The HGCNMDA is superior to the other state-of-the-art models in identifying missing miRNA-disease associations and also performs well on recommending related miRNAs/diseases to new diseases/ miRNAs. The codes are available at https://github.com/weiba/HGCNMDA.

Sepsis is among the most common causes of death in intensive care units. Septic shock is a type of circulatory shock that shows signs and symptoms that are similar to non-septic shock. Despite the impact of shock on patients and the economic burden, knowledge of the pathophysiology of septic shock is scarce. In this context, weighted gene co-expression network analysis can help to elucidate the molecular mechanisms of this condition. The gene expression dataset used in this study was downloaded from the Gene Expression Omnibus, which contains 80 patients with septic shock, 33 patients with non-septic shock, and 15 healthy controls. Our novel analysis revealed five gene modules specific for patients with septic shock and three specific gene modules for patients with non-septic shock. Interestingly, genes related to septic shock were mainly involved in the immune system and endothelial cells, while genes related to non-septic shock were primarily associated with endothelial cells. Together, the results revealed the specificity of the genes related to the immune system in septic shock. The novel approach developed here showed its potential to identify critical pathways for the occurrence and progression of these conditions while offering new treatment strategies and effective therapies.

Biomarkers associated with hepatocellular carcinoma (HCC) are of great importance to better understand biological response mechanisms to internal or external intervention. The study aimed to identify key candidate genes for HCC using machine learning (ML) and statistics-based bioinformatics models. Differentially expressed genes (DEGs) were identified using limma and then selected their common genes among DEGs identified from four datasets. After that, protein-protein interaction networks were constructed using STRING and then Cytoscape was used to determine hub genes, significant modules, and their associated genes. Simultaneously, three ML-based techniques such as support vector machine (SVM), least absolute shrinkage and selection operator-logistic regression (LASSO-LR), and partial least squares-discriminant analysis (PLS-DA) were implemented to determine the discriminative genes of HCC from common DEGs. Moreover, metadata of hub genes were formed by listing all hub genes from existing studies to incorporate other findings in our analysis. Finally, seven key candidate genes (ASPM, CCNB1, CDK1, DLGAP5, KIF20 A, MT1X, and TOP2A) were identified by intersecting common genes among hub genes, significant modules genes, discriminative genes from SVM, LASSO-LR, and PLS-DA, and meta hub genes from existing studies. Another three independent test datasets were also used to validate these seven key candidate genes using AUC, computed from ROC.

Finding network biomarkers from gene co-expression networks (GCNs) has attracted a lot of research interest. A network biomarker is a topological module, i.e., a group of densely connected nodes in a GCN, in which the gene expression values correlate with sample labels. Compared with biomarkers based on single genes, network biomarkers are not only more robust in separating samples from different categories, but are also able to better interpret the molecular mechanism of the disease. The previous network biomarker detection methods either employ distance based clustering methods or search for cliques in a GCN to detect topological modules. The first strategy assumes that the topological modules should be spherical in shape, and the second strategy requires all nodes to be fully connected. However, the relations between genes are complex, as a result, genes in the same biological process may not be directly, strongly connected. Therefore, the shapes of those modules could be oval or long strips. Hence, the shapes of gene functional modules and gene disease modules may not meet the aforementioned constraints in the previous methods. Thus, previous methods may break up the genes belonging to the same biological process into different topological modules due to those constraints. To address this issue, we propose a novel network biomarker detection method by using Gaussian mixture model clustering which allows more flexibility in the shapes of the topological modules. We have evaluated the performance of our method on a set of eight TCGA cancer datasets. The results show that our method can detect network modules that possess better discriminate power, and provide biological insights.

In this paper, we study the problem of inferring spatially-varying Gaussian Markov random fields (SV-GMRF) where the goal is to learn a network of sparse, context-specific GMRFs representing network relationships between genes. An important application of SV-GMRFs is in inference of gene regulatory networks from spatially-resolved transcriptomics datasets. The current work on inference of SV-GMRFs are based on the regularized maximum likelihood estimation (MLE) and suffer from overwhelmingly high computational cost due to their highly nonlinear nature. To alleviate this challenge, we propose a simple and efficient optimization problem in lieu of MLE that comes equipped with strong statistical and computational guarantees. Our proposed optimization problem is extremely efficient in practice: we can solve instances of SV-GMRFs with more than 2 million variables in less than 2 minutes. We apply the developed framework to study how gene regulatory networks in Glioblastoma are spatially rewired within tissue, and identify prominent activity of the transcription factor HES4 and ribosomal proteins as characterizing the gene expression network in the tumor peri-vascular niche that is known to harbor treatment resistant stem cells.

Analyzing multiple networks is important to understand relevant features among different networks. Although many studies have been conducted for that purpose, not much attention has been paid to the analysis of attractors (i.e., steady states) in multiple networks. Therefore, we study common attractors and similar attractors in multiple networks to uncover hidden similarities and differences among networks using Boolean networks (BNs), where BNs have been used as a mathematical model of genetic networks and neural networks. We define three problems on detecting common attractors and similar attractors, and theoretically analyze the expected number of such objects for random BNs, where we assume that given networks have the same set of nodes (i.e., genes). We also present four methods for solving these problems. Computational experiments on randomly generated BNs are performed to demonstrate the efficiency of our proposed methods. In addition, experiments on a practical biological system, a BN model of the TGF- β signaling pathway, are performed. The result suggests that common attractors and similar attractors are useful for exploring tumor heterogeneity and homogeneity in eight cancers.

Gene regulatory networks (GRNs) participate in many biological processes, and reconstructing them plays an important role in systems biology. Although many advanced methods have been proposed for GRN reconstruction, their predictive performance is far from the ideal standard, so it is urgent to design a more effective method to reconstruct GRN. Moreover, most methods only consider the gene expression data, ignoring the network structure information contained in GRN. In this study, we propose a supervised model named CNNGRN, which infers GRN from bulk time-series expression data via convolutional neural network (CNN) model, with a more informative feature. Bulk time series gene expression data imply the intricate regulatory associations between genes, and the network structure feature of ground-truth GRN contains rich neighbor information. Hence, CNNGRN integrates the above two features as model inputs. In addition, CNN is adopted to extract intricate features of genes and infer the potential associations between regulators and target genes. Moreover, feature importance visualization experiments are implemented to seek the key features. Experimental results show that CNNGRN achieved competitive performance on benchmark datasets compared to the state-of-the-art computational methods. Finally, hub genes identified based on CNNGRN have been confirmed to be involved in biological processes through literature.

Utilizing gene expression data to infer gene regulatory networks has received great attention because gene regulation networks can reveal complex life phenomena by studying the interaction mechanism among nodes. However, the reconstruction of large-scale gene regulatory networks is often not ideal due to the curse of dimensionality and the impact of external noise. In order to solve this problem, we introduce a novel algorithms called ensemble path consistency algorithm based on conditional mutual information (EPCACMI), whose threshold of mutual information is dynamically self-adjusted. We first use principal component analysis to decompose a large-scale network into several subnetworks. Then, according to the absolute value of coefficient of each principal component, we could remove a large number of unrelated nodes in every subnetwork and infer the relationships among these selected nodes. Finally, all inferred subnetworks are integrated to form the structure of the complete network. Rather than inferring the whole network directly, the influence of a mass of redundant noise could be weakened. Compared with other related algorithms like MRNET, ARACNE, PCAPMI and PCACMI, the results show that EPCACMI is more effective and more robust when inferring gene regulatory networks with more nodes.

This paper proposes a revised version of the robust generalized maximum likelihood (GM)-type unscented KALMAN filter (GM-UKF) for the state estimation of gene regulatory networks (GRNs) in the presence of different types of deviations from assumptions. As known, the parameters and the power of the assumed noises within the GRN model may change abruptly as a result of jump behavior and bursting process in transcription and translation phases. Moreover, there may be outlying samples among genomic measurement data. Some other outliers may also occur in the model dynamics. The outliers may be misinterpreted by the filtering method if not detected and downweighted. To deal with all such deviations, a robust GM-UKF is designed that includes some modifications to address the challenges in calculating the projection statistics in GRNs such as the nonlinear behavior and the natural distance of the states. The proposed filter is compared to four Bayesian filters, i.e., the conventional UKF, the H ∞ -UKF, the downweighting UKF (DW-UKF), and a modified version of the GM-UKF, the so-called maximum-likelihood UKF(M-UKF). The outcome results demonstrate that the GM-UKF outperforms other methods for all outlier types while the H ∞ -UKF is appropriate for the changes in noise powers.

The measurement of gene functional similarity plays a critical role in numerous biological applications, such as gene clustering, the construction of gene similarity networks. However, most existing approaches still rely heavily on traditional computational strategies, which are not guaranteed to achieve satisfactory performance. In this study, we propose a novel computational approach called GOGCN to measure gene functional similarity by modeling the Gene Ontology (GO) through Graph Convolutional Network (GCN). GOGCN is a graph-based approach that performs sufficient representation learning for terms and relations in the GO graph. First, GOGCN employs the GCN-based knowledge graph embedding (KGE) model to learn vector representations (i.e., embeddings) for all entities (i.e., terms). Second, GOGCN calculates the semantic similarity between two terms based on their corresponding vector representations. Finally, GOGCN estimates gene functional similarity by making use of the pair-wise strategy. During the representation learning period, GOGCN promotes semantic interaction between terms through GCN, thereby capturing the rich structural information of the GO graph. Further experimental results on various datasets suggest that GOGCN is superior to the other state-of-the-art approaches, which shows its reliability and effectiveness.

Typically patient-specific gene networks are constructed with gene expression data only. Such networks cannot distinguish direct gene interactions from indirect interactions via others such as the effect of epigenetic events to gene activity. There is an increasing evidence of inter-individual variations not only in gene expression but also in epigenetic events such as DNA methylation. In this paper we propose a new method for constructing a cancer patient-specific gene correlation network using both gene expression and DNA methylation data. We derive a patient-specific network from differential second-order partial correlations of gene expression and DNA methylation between normal samples and the patient sample. The network represents direct interactions between genes by controlling the effect of DNA methylation. Using this method, we constructed 4,000 patient-specific networks for 10 types of cancer. The networks are highly effective in classifying different types of cancer and in deriving potential prognostic gene pairs. In particular, potential prognostic gene pairs derived from the networks were powerful in predicting the survival time of cancer patients. This approach will help identify patient-specific gene correlations and predict prognosis of cancer patients.

We study the target control of asynchronous Boolean networks, to identify interventions that can drive the dynamics of a given Boolean network from any initial state to the desired target attractor. Based on the application time, the control can be realised with three types of perturbations, including instantaneous, temporary and permanent perturbations. We develop efficient methods to compute the target control for a given target attractor with these three types of perturbations. We compare our methods with the stable motif-based control method on a variety of real-life biological networks to evaluate their performance. We show that our methods scale well for large Boolean networks and they are able to identify a rich set of solutions with a small number of perturbations.

The identification of gene regulatory networks (GRN) from gene expression time series data is a challenge and open problem in system biology. This paper considers the structure inference of GRN from the incomplete and noisy gene expression data, which is a not well-studied issue for GRN inference. In this paper, the dynamical behavior of the gene expression process is described by a stochastic nonlinear state-space model with unknown noise information. A variational Bayesian (VB) framework are proposed to estimate the parameters and gene expression levels simultaneously. One of the advantages of this method is that it can easily handle the missing observations by generating the prediction values. Considering the sparsity of GRN, the smoothed gene data are modeled by the extreme gradient boosting tree, and the regulatory interactions among genes are identified by the importance scores based on the tree model. The proposed method is tested on the artificial DREAM4 datasets and one real gene expression dataset of yeast. The comparative results show that the proposed method can effectively recover the regulatory interactions of GRN in the presence of missing observations and outperforms the existing methods for GRN identification.

Cancer is not only a very aggressive but also a very diverse disease. Recent advances in high-throughput omics technologies of cancer have enabled biomedical researchers to have more opportunities for studying its multi-level biological regulatory mechanism. However, there are few methods to explore the underlying mechanism of cancer by identifying its multidimensional molecular regulatory modules from the multidimensional omics data of cancer. In this paper, we propose a sparse orthogonality-regularized joint non-negative matrix factorization (SOJNMF) algorithm which can integratively analyze multidimensional omics data. This method can not only identify multidimensional molecular regulatory modules, but reduce the overlap rate of features among the multidimensional modules while ensuring the sparsity of the coefficient matrix after decomposition. Gene expression data, miRNA expression data and gene methylation data of liver cancer are integratively analyzed based on SOJNMF algorithm. Then, we obtain 238 multidimensional molecular regulatory modules. The results of permutation test indicate that different omics features within these modules are significantly correlated in statistics. Meanwhile, the results of functional enrichment analysis show that these multidimensional modules are significantly related to the underlying mechanism of the occurrence and development of liver cancer.

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.

Regulatory module mining methods divide genes into multiple gene subgroups and explore potential biological mechanisms from omics data. By transforming gene expression profile data into gene co-expression network, we transform the task of gene module detection into the problem of finding community structure in the graph, and introduce the latest network representation learning method-graph neural network to optimize this problem. In order to systematically evaluate whether the algorithm allows overlap to affect such problems, we make two variants of the output of the algorithm, Deepgmd_cluster and Deepgmd. The difference between them is whether overlap is allowed. By comparing the known modules and the modules generated by the algorithm, we can evaluate the quality of the algorithm. We use this method to compare our algorithm with some current mainstream methods. The results show that our method has greater advantages. In the end, we analyze some typical modules from the modules found by the algorithm for visualization, and use the GO database and KEGG database to perform enrichment analysis and pathway analysis on these modules.

In this paper, state observation of coupled reaction-diffusion genetic regulatory networks (GRNs) with time-varying delays is investigated under Dirichlet boundary conditions. First, the above GRNs are constructed to model gene regulatory properties, where the feedback regulation function of the GRNs is assumed to exhibit the Hill form and a novel method to deal with it is introduced. Then a time-space sampled-data state observer is designed for the mentioned networks and new criteria are established by utilizing the Lyapunov stability theory and the inequality techniques of Halanay et al. Finally, the validity of the theoretical results is proved by numerical examples.

One of the key challenges in systems biology is to derive gene regulatory networks (GRNs) from complex high-dimensional sparse data. Bayesian networks (BNs) and dynamic Bayesian networks (DBNs) have been widely applied to infer GRNs from gene expression data. GRNs are typically sparse but traditional approaches of BN structure learning to elucidate GRNs often produce many spurious (false positive) edges. We present two new BN scoring functions, which are extensions to the Bayesian Information Criterion (BIC) score, with additional penalty terms and use them in conjunction with DBN structure search methods to find a graph structure that maximises the proposed scores. Our BN scoring functions offer better solutions for inferring networks with fewer spurious edges compared to the BIC score. The proposed methods are evaluated extensively on auto regressive and DREAM4 benchmarks. We found that they significantly improve the precision of the learned graphs, relative to the BIC score. The proposed methods are also evaluated on three real time series gene expression datasets. The results demonstrate that our algorithms are able to learn sparse graphs from high-dimensional time series data. The implementation of these algorithms is open source and is available in form of an R package on GitHub at https://github.com/HamdaBinteAjmal/DBN4GRN, along with the documentation and tutorials.

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 accumulated omic data provides an opportunity to exploit the mechanisms of cancers and poses a challenge for their integrative analysis. Although extensive efforts have been devoted to address this issue, the current algorithms result in undesirable performance because of the complexity of patterns and heterogeneity of data. In this study, the ultimate goal is to propose an effective and efficient algorithm (called NMF-DEC) to identify clusters by integrating the interactome and transcriptome data. By treating the expression profiles of genes as attributes of vertices in the gene interaction networks, we transform the integrative analysis of omic data into clustering of attributed networks. To circumvent the heterogeneity, we construct a similarity network for the attributes of genes and cast it into the common module detection problem in multi-layer networks. The NMF-DEC explores the relation between attributes and topological structure of networks by jointly factorizing the similarity and interaction networks with the same basis. In this optimization, the interaction network is dynamically updated and the information of attributes is dynamically incorporated, providing a better strategy to characterize the structure of modules in attributed networks. Extensive experiments indicate that compared with state-of-the-art baselines, NMF-DEC is more accurate on social network, and show better performance on cancer attributed networks, implying the superiority of the proposed methods for the integrative analysis of omic data.

Uncovering genotype-phenotype relationships is a fundamental challenge in genomics. Gene prioritization is an important step for this endeavor to make a short manageable list from a list of thousands of genes coming from high-throughput studies. Network propagation methods are promising and state of the art methods for gene prioritization based on the premise that functionally related genes tend to be close to each other in the biological networks. Recently, we introduced PhenoGeneRanker, a network-propagation algorithm for multiplex heterogeneous networks. PhenoGeneRanker allows multi-layer gene and phenotype networks. It also calculates empirical p values of gene and phenotype ranks using random stratified sampling of seeds of genes and phenotypes based on their connectivity degree in the network. In this study, we introduce the PhenoGeneRanker Bioconductor package and its application to multi-omics rat genome datasets to rank hypertension disease-related genes and strains. We showed that PhenoGeneRanker performed better to rank hypertension disease-related genes using multiplex gene networks than aggregated gene networks. We also showed that PhenoGeneRanker performed better to rank hypertension disease-related strains using multiplex phenotype network than single or aggregated phenotype networks. We performed a rigorous hyperparameter analysis and, finally showed that Gene Ontology (GO) enrichment of statistically significant top-ranked genes resulted in hypertension disease-related GO terms.

Gene co-expression network (GCN) becomes an increasingly important tool in omics data analysis. A great challenge for GCN construction is that the sample size is far lower than the number of genes. Traditional methods rely on considerable samples. Moreover, association signals are likely weak, nonlinear and stochastic, which are difficult to be identified among thousands of candidates. In this paper, the gray correlation coefficient (GCC) is introduced, and a novel method to construct gene differential co-expression networks (GDCNs) is proposed. Based on the GDCNs, three measures are proposed to explore informative genes. The proposed method can make full use of the information provided by a handful of samples and overcome the shortages of GCNs, which can evaluate the changes of co-expression relationships that are possibly triggered by treatments. Based on RNA-seq data of Brassica napus, GDCNs under multiple experimental conditions are constructed and investigated. It is found that the GCC-based method is very robust to data processing. The GDCNs facilitate the inference of gene functions and the identification of informative genes that are responsible for stress responsiveness. The GDCN-based approaches integrate the 'guilt by association' and the 'guilt by rewiring' rules, which provide alternative tools for omics data analysis.

Tracking the dynamic modules (modules change over time) during cancer progression is essential for studying cancer pathogenesis, diagnosis, and therapy. However, current algorithms only focus on detecting dynamic modules from temporal cancer networks without integrating the heterogeneous genomic data, thereby resulting in undesirable performance. To attack this issue, we propose a novel algorithm (aka TANMF) to detect dynamic modules in cancer temporal attributed networks, which integrates the temporal networks and gene attributes. To obtain the dynamic modules, the temporality and gene attributed are incorporated into an overall objective function, which transforms the dynamic module detection into an optimization problem. TANMF jointly decomposes the snapshots at two subsequent time steps to obtain the latent features of dynamic modules, where the attributes are fused via regulations. Furthermore, the L 1 constraint is imposed to improve the robustness. Experimental results demonstrate that TANMF is more accurate than state-of-the-art methods in terms of accuracy. By applying TANMF to breast cancer data, the obtained dynamic modules are more enriched by the known pathways and associated with patients' survival time. The proposed model and algorithm provide an effective way for the integrative analysis of heterogeneous omics.

With the advances in gene sequencing technologies, millions of somatic mutations have been reported in the past decades, but mining cancer driver genes with oncogenic mutations from these data remains a critical and challenging area of research. In this study, we proposed a network-based classification method for identifying cancer driver genes with merging the multi-biological information. In this method, we construct a cancer specific genetic network from the human protein-protein interactome (PPI) to mine the network structure attributes, and combine biological information such as mutation frequency and differential expression of genes to achieve accurate prediction of cancer driver genes. Across seven different cancer types, the proposed algorithm always achieves high prediction accuracy, which is superior to the existing advanced methods. In the analysis of the predicted results, about 40 percent of the top 10 candidate genes overlap with the Cancer Gene Census database. Interestingly, the feature comparison indicates that the network based features are still more important than the biological features, including the mutation frequency and genetic differential expression. Further analyses also show that the integration of network structure attributes and biological information is valuable for predicting new cancer driver genes.

Deterministic asynchronous Boolean networks play a crucial role in modeling and analysis of gene regulatory networks. In this paper, we focus on a typical type of deterministic asynchronous Boolean networks called deterministic generalized asynchronous random Boolean networks (DGARBNs). We first formulate the extended state transition graph, which captures the whole dynamics of a DGARBN and paves potential ways to analyze this DGARBN. We then propose two SMT-based methods for attractor detection and optimal control of DGARBNs. These methods are implemented in a JAVA tool called DABoolNet. Two experiments are designed to highlight the scalability of the proposed methods. We also formally state and prove several relations between DGARBNs and other models including deterministic asynchronous models, block-sequential Boolean networks, generalized asynchronous random Boolean networks, and mixed-context random Boolean networks. Several case studies are presented to show the applications of our methods.

Gene regulatory networks are biologically robust, which imparts resilience to living systems against most external perturbations affecting them. However, there is a limit to this and disturbances beyond this limit can impart unwanted signalling on one or more master regulators in a network. Certain disturbances may affect the functioning of other constituent genes of the same network. In most cases, this phenomenon can have some effect on the functioning of the living organism. In this investigation, we have proposed a methodology to mitigate the effects of external perturbations on a genetic network using a proportional-integral-derivative controller. The proposed controller has been used to perturb one or more of the other unaffected master regulators such that the most affected gene/s of the network revert to their normal state. The only required condition of such type of manoeuvring is that there should be multiple master regulators in a network. The proposed technique has been experimented on a 10-gene DREAM4 benchmark network and also on a larger 20-gene network, where only downregulation has been considered due to data constraints. Simulation results indicate that the most vulnerable genes can be reverted to their normal expression levels in 10 out of the 16 simulations performed.

Many of the known prognostic gene signatures for cancer are individual genes or combination of genes, found by the analysis of microarray data. However, many of the known cancer signatures are less predictive than random gene expression signatures, and such random signatures are significantly associated with proliferation genes. With the availability of RNA-seq gene expression data for thousands of human cancer patients, we have analyzed RNA-seq and clinical data of cancer patients and constructed gene correlation networks specific to individual cancer patients. From the patient-specific gene correlation networks, we derived prognostic gene pairs for three types of cancer. In this paper, we propose a new method for inferring prognostic gene pairs from patient-specific gene correlation networks. The main difference of our method from previous ones includes (1) it is focused on finding prognostic gene pairs rather than prognostic genes, (2) it can identify prognostic gene pairs from RNA-seq data even when no significant prognostic genes exist, and (3) prognostic gene pairs can serve as robust prognostic biomarkers in the sense that most prognostic gene pairs show little association with proliferation genes, the major boosting factor of the predictive power of random gene signatures. Evaluation of our method with extensive data of three types of cancer (liver cancer, pancreatic cancer, and stomach cancer) showed that our approach is general and that gene pairs can serve as more reliable prognostic signatures for cancer than genes. Analysis of patient-specific gene networks suggests that prognosis of individual cancer patients is affected by the existence of prognostic gene pairs in the patient-specific network and by the size of the patient-specific network. Although preliminary, our approach will be useful for finding gene pairs to predict survival time of patients and to tailor treatments to individual characteristics. The program for dynamically constructing patient-specific gene networks and for finding prognostic gene pairs is available at http://bclab.inha.ac.kr/LPS.

This article is concerned with the problem of finite-time H ∞ state estimation for switched genetic regulatory networks with randomly occurring uncertainties. The persistent dwell-time switching rule, as a more versatile class of switching rules, is considered in this paper. Besides, several random variables that obey the Bernoulli distribution are used to represent randomly occurring uncertainties. The overriding purpose of this article is to design an estimator to ensure that the estimation error system is stochastically finite-time bounded and satisfies the H ∞ performance. Based on this, sufficient conditions for the explicit form of the estimator gains can be obtained by the Lyapunov method. Finally, a numerical example is given to verify the correctness and feasibility of the proposed method.

Motivation: Laboratory gene regulatory data for a species are sporadic. Despite the abundance of gene regulatory network algorithms that employ single data sets, few algorithms can combine the vast but disperse sources of data and extract the potential information. With a motivation to compensate for this shortage, we developed an algorithm called GENEREF that can accumulate information from multiple types of data sets in an iterative manner, with each iteration boosting the performance of the prediction results., Results: The algorithm is examined extensively on data extracted from the quintuple DREAM4 networks and DREAM5's Escherichia coli and Saccharomyces cerevisiae networks and sub-networks. Many single-dataset and multi-dataset algorithms were compared to test the performance of the algorithm. Results show that GENEREF surpasses non-ensemble state-of-the-art multi-perturbation algorithms on the selected networks and is competitive to present multiple-dataset algorithms. Specifically, it outperforms dynGENIE3 and is on par with iRafNet. Also, we argued that a scoring method solely based on the AUPR criterion would be more trustworthy than the traditional score., Availability: The Python implementation along with the data sets and results can be downloaded from github.com/msaremi/GENEREF.

Previous efforts in gene network reconstruction have mainly focused on data-driven modeling, with little attention paid to knowledge-based approaches. Leveraging prior knowledge, however, is a promising paradigm that has been gaining momentum in network reconstruction and computational biology research communities. This paper proposes two new algorithms for reconstructing a gene network from expression profiles with and without prior knowledge in small sample and high-dimensional settings. First, using tools from the statistical estimation theory, particularly the empirical Bayesian approach, the current research estimates a covariance matrix via the shrinkage method. Second, estimated covariance matrix is employed in the penalized normal likelihood method to select the Gaussian graphical model. This formulation allows the application of prior knowledge in the covariance estimation, as well as in the Gaussian graphical model selection. Experimental results on simulated and real datasets show that, compared to state-of-the-art methods, the proposed algorithms achieve better results in terms of both PR and ROC curves. Finally, the present work applies its method on the RNA-seq data of human gastric atrophy patients, which was obtained from the EMBL-EBI database. The source codes and relevant data can be downloaded from: https://github.com/AbbaszadehO/DKGN.

We present PALLAS, a practical method for gene regulatory network (GRN) inference from time series data, which employs penalized maximum likelihood and particle swarms for optimization. PALLAS is based on the Partially-Observable Boolean Dynamical System (POBDS) model and thus does not require ad-hoc binarization of the data. The penalty in the likelihood is a LASSO regularization term, which encourages the resulting network to be sparse. PALLAS is able to scale to networks of realistic size under no prior knowledge, by virtue of a novel continuous-discrete Fish School Search particle swarm algorithm for efficient simultaneous maximization of the penalized likelihood over the discrete space of networks and the continuous space of observational parameters. The performance of PALLAS is demonstrated by a comprehensive set of experiments using synthetic data generated from real and artificial networks, as well as real time series microarray and RNA-seq data, where it is compared to several other well-known methods for gene regulatory network inference. The results show that PALLAS can infer GRNs more accurately than other methods, while being capable of working directly on gene expression data, without need of ad-hoc binarization. PALLAS is a fully-fledged program, written in python, and available on GitHub (https://github.com/yukuntan92/PALLAS).

The inference of Boolean networks is crucial for analyzing the topology and dynamics of gene regulatory networks. Many data-driven approaches using evolutionary algorithms have been proposed based on time-series data. However, the ability to infer both network topology and dynamics is restricted by their inflexible encoding schemes. To address this problem, we propose a novel Boolean network inference algorithm for inferring both network topology and dynamics simultaneously. The main idea is that, we use a marker-based genetic algorithm to encode both regulatory nodes and logical operators in a chromosome. By using the markers and introducing more logical operators, the proposed algorithm can infer more diverse candidate Boolean functions. The proposed algorithm is applied to five networks, including two artificial Boolean networks and three real-world gene regulatory networks. Compared with other algorithms, the experimental results demonstrate that our proposed algorithm infers more accurate topology and dynamics.

Gene regulatory networks (GRNs)are involved in various biological processes, such as cell cycle, differentiation and apoptosis. The existing large amount of expression data, especially the time-series expression data, provide a chance to infer GRNs by computational methods. These data can reveal the dynamics of gene expression and imply the regulatory relationships among genes. However, identify the indirect regulatory links is still a big challenge as most studies treat time points as independent observations, while ignoring the influences of time delays. In this study, we propose a GRN inference method based on information-theory measure, called NIMCE. NIMCE incorporates the transfer entropy to measure the regulatory links between each pair of genes, then applies the causation entropy to filter indirect relationships. In addition, NIMCE applies multi time delays to identify indirect regulatory relationships from candidate genes. Experiments on simulated and colorectal cancer data show NIMCE outperforms than other competing methods. All data and codes used in this study are publicly available at https://github.com/CSUBioGroup/NIMCE.

Computational and mathematical models are a must for the in silico analysis or design of Gene Regulatory Networks (GRN)as they offer a theoretical context to deeply address biological regulation. We have proposed a framework where models of network dynamics are expressed through a class of nonlinear and temporal multiscale Ordinary Differential Equations (ODE). To find out models that disclose network structures underlying an observed or desired network behavior, and parameter values that enable the candidate models to reproduce such behavior, we follow a reasoning cycle that alternates procedures for model selection and parameter refinement. Plausible network models are first selected via qualitative simulation, and next their parameters are given quantitative values such that the ODE model solution reproduces the specified behavior. This paper gives algorithms to tackle the parameter refinement problem formulated as an optimization problem. We search, within the parameter space symbolically expressed, for the largest hypersphere whose points correspond to parameter values such that the ODE solution gives an instance of the given qualitative trajectory. Our approach overcomes the limitation of a previously proposed stochastic approach, namely computational load and very reduced scalability. Its applicability and effectiveness are demonstrated through two benchmark synthetic networks with different complexity.

Motivation: In bioinformatics, complex cellular modeling and behavior simulation to identify significant molecular interactions is considered a relevant problem. Traditional methods model such complex systems using single and binary network. However, this model is inadequate to represent biological networks as different sets of interactions can simultaneously take place for different interaction constraints (such as transcription regulation and protein interaction). Furthermore, biological systems may exhibit varying interaction topologies even for the same interaction type under different developmental stages or stress conditions. Therefore, models which consider biological systems as solitary interactions are inaccurate as they fail to capture the complex behavior of cellular interactions within organisms. Identification and counting of recurrent motifs within a network is one of the fundamental problems in biological network analysis. Existing methods for motif counting on single network topologies are inadequate to capture patterns of molecular interactions that have significant changes in biological expression when identified across different organisms that are similar, or even time-varying networks within the same organism. That is, they fail to identify recurrent interactions as they consider a single snapshot of a network among a set of multiple networks. Therefore, we need methods geared towards studying multiple network topologies and the pattern conservation among them. Contributions: In this paper, we consider the problem of counting the number of instances of a user supplied motif topology in a given multilayer network. We model interactions among a set of entities (e.g., genes)describing various conditions or temporal variation as multilayer networks. Thus a separate network as each layer shows the connectivity of the nodes under a unique network state. Existing motif counting and identification methods are limited to single network topologies, and thus cannot be directly applied on multilayer networks. We apply our model and algorithm to study frequent patterns in cellular networks that are common in varying cellular states under different stress conditions, where the cellular network topology under each stress condition describes a unique network layer., Results: We develop a methodology and corresponding algorithm based on the proposed model for motif counting in multilayer networks. We performed experiments on both real and synthetic datasets. We modeled the synthetic datasets under a wide spectrum of parameters, such as network size, density, motif frequency. Results on synthetic datasets demonstrate that our algorithm finds motif embeddings with very high accuracy compared to existing state-of-the-art methods such as G-tries, ESU (FANMODE)and mfinder. Furthermore, we observe that our method runs from several times to several orders of magnitude faster than existing methods. For experiments on real dataset, we consider Escherichia coli (E. coli)transcription regulatory network under different experimental conditions. We observe that the genes selected by our method conserves functional characteristics under various stress conditions with very low false discovery rates. Moreover, the method is scalable to real networks in terms of both network size and number of layers.

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.

Identification of common molecular mechanisms in interrelated diseases is essential for better prognoses and targeted therapies. However, complexity of metabolic pathways makes it difficult to discover common disease genes underlying metabolic disorders; and it requires more sophisticated bioinformatics models that combine different types of biological data and computational methods. Accordingly, we built an integrative network analysis model to identify shared disease genes in metabolic syndrome (MS), type 2 diabetes (T2D), and coronary artery disease (CAD). We constructed weighted gene co-expression networks by combining gene expression, protein-protein interaction, and gene ontology data from multiple sources. For 90 different configurations of disease networks, we detected the significant modules by using MCL, SPICi, and Linkcomm graph clustering algorithms. We also performed a comparative evaluation on disease modules to determine the best method providing the highest biological validity. By overlapping the disease modules, we identified 22 shared genes for MS-CAD and T2D-CAD. Moreover, 19 out of these genes were directly or indirectly associated with relevant diseases in the previous medical studies. This study does not only demonstrate the performance of different biological data sources and computational methods in disease-gene discovery, but also offers potential insights into common genetic mechanisms of the metabolic disorders.

A key objective of studying biological systems is to design therapeutic intervention strategies for beneficially altering cell dynamics. Derivation of control policies is hindered by the high-dimensional state spaces associated with gene regulatory networks. Hence, it is critical to reduce the network complexity and the paper aims to address this issue by focusing on the distribution of the canalizing power (CP) of the genes in the model. Canalizing genes enforce broad corrective actions on cellular processes and play a crucial role in producing optimal reactions to external stimuli. Therefore, it is critical to reduce the network while preserving the canalizing power of genes. We reduce Boolean networks with perturbation by removing genes with the smallest canalizing power consecutively, and evaluate the stability of canalizing power. A systematic empirical study demonstrates that there are two classes of networks, reducible and irreducible with respect to the preservation of canalizing power of the genes. Based on these observations, we introduce the definition of reducible networks and proceed with the problem of selecting the relevant network features that allow for discriminating networks from the two different classes. We demonstrate the efficacy of the selected features on synthetic and real gene regulatory networks.

Cancer progression is dynamic, and tracking dynamic modules is promising for cancer diagnosis and therapy. Accumulated genomic data provide us an opportunity to investigate the underlying mechanisms of cancers. However, as far as we know, no algorithm has been designed for dynamic modules by integrating heterogeneous omics data. To address this issue, we propose an integrative framework for dynamic module detection based on regularized nonnegative matrix factorization method (DrNMF) by integrating the gene expression and protein interaction network. To remove the heterogeneity of genomic data, we divide the samples of expression profiles into groups to construct gene co-expression networks. To characterize the dynamics of modules, the temporal smoothness framework is adopted, in which the gene co-expression network at the previous stage and protein interaction network are incorporated into the objective function of DrNMF via regularization. The experimental results demonstrate that DrNMF is superior to state-of-the-art methods in terms of accuracy. For breast cancer data, the obtained dynamic modules are more enriched by the known pathways, and can be used to predict the stages of cancers and survival time of patients. The proposed model and algorithm provide an effective integrative analysis of heterogeneous genomic data for cancer progression.

Searching for active modules, i.e., regions showing striking changes in molecular activity in biological networks is important to reveal regulatory and signaling mechanisms of biological systems. Most existing active modules identification methods are based on protein-protein interaction networks or metabolic networks, which require comprehensive and accurate prior knowledge. On the other hand, weighted gene co-expression networks (WGCNs) are purely constructed from gene expression profiles. However, existing WGCN analysis methods are designed for identifying functional modules but not capable of identifying active modules. There is an urgent need to develop an active module identification algorithm for WGCNs to discover regulatory and signaling mechanism associating with a given cellular response. To address this urgent need, we propose a novel algorithm called active modules on the multi-layer weighted (co-expression gene) network, based on a continuous optimization approach (AMOUNTAIN). The algorithm is capable of identifying active modules not only from single-layer WGCNs but also from multilayer WGCNs such as cross-species and dynamic WGCNs. We first validate AMOUNTAIN on a synthetic benchmark dataset. We then apply AMOUNTAIN to WGCNs constructed from Th17 differentiation gene expression datasets of human and mouse, which include a single layer, a cross-species two-layer and a multilayer dynamic WGCNs. The identified active modules from WGCNs are enriched by known protein-protein interactions, and more importantly, they reveal some interesting and important regulatory and signaling mechanisms of Th17 cell differentiation.

Gene Regulatory Network (GRN) is formed due to mutual transcriptional regulation within a set of protein coding genes in cellular context of an organism. Computational inference of GRN is important to understand the behavior of each gene in terms of change in its protein production rate (expression level). As Recurrent Neural Network (RNN) is efficient in GRN modeling, a bi-objective RNN formulation has been applied here. Based on Archived Multi Objective Simulated Annealing (AMOSA), four algorithms, namely, AMOSA Revised (AMOSAR), Modified Freezing based AMOSA (AMOFSA), Tabu based AMOSA (AMOTSA) and Modified Freezing and Tabu based AMOSA (AMOFTSA) have been proposed and applied to RNN (treated as GRN) for parameter learning taking four gene expression time series datasets. Comparative studies on the performance of the algorithms (based on each dataset) have been made in terms of the number of GRNs obtained in the final non-dominated front and the performance metrics, namely, recall, precision and f1 score. Two proposed variants, namely, AMOFSA and AMOTSA have been found competitive in performance. Experimental observations and statistical analysis show that, modified algorithms are better than AMOSAR and the state-of-the-art algorithms in respect of the above-mentioned metrics.

Controlling the dynamics of gene regulatory networks is a challenging problem. In recent years, a number of control methods have been proposed, but most of these approaches do not address the problem of how they could be implemented in practice. In this paper, we consider the idea of using a synthetic regulatory network as a closed-loop controller that can control and respond to the dynamics of a cell's native regulatory network in situ. We explore this idea using a computational model in which both native and synthetic regulatory networks are represented by Boolean networks. We then use an evolutionary algorithm to optimise both the structure and parameters of the synthetic Boolean network. To test this approach, we look at whether controllers can be optimised to target specific steady states in five different Boolean regulatory circuit models. Our results show that in most cases the controllers are able to drive the dynamics of the target system to a specified steady state, often using few interventions, and further experiments using random Boolean networks show that the approach scales well to larger controlled networks.

Boolean networks are a notable model of gene regulatory networks and, particularly, prominent theories discuss how they can capture cellular differentiation processes. One frequent motif in gene regulatory networks, especially in those circuits involved in cell differentiation, is autoregulation. In spite of this, the impact of autoregulation on Boolean network attractor landscape has not yet been extensively discussed in literature. In this paper we propose to model autoregulation as self-loops, and analyse how the number of attractors and their robustness may change once they are introduced in a well-known and widely used Boolean networks model, namely random Boolean networks. Results show that self-loops provide an evolutionary advantage in dynamic mechanisms of cells, by increasing both number and maximal robustness of attractors. These results provide evidence to the hypothesis that autoregulation is a straightforward functional component to consolidate cell dynamics, mainly in differentiation processes.

Identifying essential genes in comparison states (EGS) is vital to understanding cell differentiation, performing drug discovery, and identifying disease causes. Here, we present a machine learning method termed Prediction of Essential Genes in Comparison States (PreEGS). To capture the alteration of the network in comparison states, PreEGS extracts topological and gene expression features of each gene in a five-dimensional vector. PreEGS also recruits a positive sample expansion method to address the problem of unbalanced positive and negative samples, which is often encountered in practical applications. Different classifiers are applied to the simulated datasets, and the PreEGS based on the random forests model (PreEGSRF) was chosen for optimal performance. PreEGSRF was then compared with six other methods, including three machine learning methods, to predict EGS in a specific state. On real datasets with four gene regulatory networks, PreEGSRF predicted five essential genes related to leukemia and five enriched KEGG pathways. Four of the predicted essential genes and all predicted pathways were consistent with previous studies and highly correlated with leukemia. With high prediction accuracy and generalization ability, PreEGSRF is broadly applicable for the discovery of disease-causing genes, driver genes for cell fate decisions, and complex biomarkers of biological systems.