A multiple genomic data fused SF2 prediction model, signature identification, and gene regulatory network inference for personalized radiotherapy.
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ABSTRACT:
SUBMITTER: He QE
PROVIDER: S-EPMC7225787 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Understanding gene regulatory networks is critical to understanding cellular differentiation and response to external stimuli. Methods for global network inference have been developed and applied to a variety of species. Most approaches consider the problem of network inference independently in each species, despite evidence that gene regulation can be conserved even in distantly related species. Further, network inference is often confined to single data-types (single platforms) and single cell types. We introduce a method for multi-source network inference that allows simultaneous estimation of gene regulatory networks in multiple species or biological processes through the introduction of priors based on known gene relationships such as orthology incorporated using fused regression. This approach improves network inference performance even when orthology mapping and conservation are incomplete. We refine this method by presenting an algorithm that extracts the true conserved subnetwork from a larger set of potentially conserved interactions and demonstrate the utility of our method in cross species network inference. Last, we demonstrate our method's utility in learning from data collected on different experimental platforms.
| S-EPMC5140053 | biostudies-literature
Project description:Devising computational methods to accurately reconstruct gene regulatory networks given gene expression data is key to systems biology applications. Here we propose a method for reconstructing gene regulatory networks by simultaneous consideration of data sets from different perturbation experiments and corresponding controls. The method imposes three biologically meaningful constraints: (1) expression levels of each gene should be explained by the expression levels of a small number of transcription factor coding genes, (2) networks inferred from different data sets should be similar with respect to the type and number of regulatory interactions, and (3) relationships between genes which exhibit similar differential behavior over the considered perturbations should be favored. We demonstrate that these constraints can be transformed in a fused LASSO formulation for the proposed method. The comparative analysis on transcriptomics time-series data from prokaryotic species, Escherichia coli and Mycobacterium tuberculosis, as well as a eukaryotic species, mouse, demonstrated that the proposed method has the advantages of the most recent approaches for regulatory network inference, while obtaining better performance and assigning higher scores to the true regulatory links. The study indicates that the combination of sparse regression techniques with other biologically meaningful constraints is a promising framework for gene regulatory network reconstructions.
| S-EPMC4750075 | biostudies-literature
Project description:BackgroundInferring gene regulatory networks (GRNs) from gene expression data remains a challenge in system biology. In past decade, numerous methods have been developed for the inference of GRNs. It remains a challenge due to the fact that the data is noisy and high dimensional, and there exists a large number of potential interactions.ResultsWe present a novel method, namely priori-fused boosting network inference method (PFBNet), to infer GRNs from time-series expression data by using the non-linear model of Boosting and the prior information (e.g., the knockout data) fusion scheme. Specifically, PFBNet first calculates the confidences of the regulation relationships using the boosting-based model, where the information about the accumulation impact of the gene expressions at previous time points is taken into account. Then, a newly defined strategy is applied to fuse the information from the prior data by elevating the confidences of the regulation relationships from the corresponding regulators.ConclusionsThe experiments on the benchmark datasets from DREAM challenge as well as the E.coli datasets show that PFBNet achieves significantly better performance than other state-of-the-art methods (Jump3, GEINE3-lag, HiDi, iRafNet and BiXGBoost).
| S-EPMC7362553 | biostudies-literature
Project description:BackgroundCell survival and development are orchestrated by complex interlocking programs of gene activation and repression. Understanding how this gene regulatory network (GRN) functions in normal states, and is altered in cancers subtypes, offers fundamental insight into oncogenesis and disease progression, and holds great promise for guiding clinical decisions. Inferring a GRN from empirical microarray gene expression data is a challenging task in cancer systems biology. In recent years, module-based approaches for GRN inference have been proposed to address this challenge. Despite the demonstrated success of module-based approaches in uncovering biologically meaningful regulatory interactions, their application remains limited a single condition, without supporting the comparison of multiple disease subtypes/conditions. Also, their use remains unnecessarily restricted to computational biologists, as accurate inference of modules and their regulators requires integration of diverse tools and heterogeneous data sources, which in turn requires scripting skills, data infrastructure and powerful computational facilities. New analytical frameworks are required to make module-based GRN inference approach more generally useful to the research community.ResultsWe present the RMaNI (Regulatory Module Network Inference) framework, which supports cancer subtype-specific or condition specific GRN inference and differential network analysis. It combines both transcriptomic as well as genomic data sources, and integrates heterogeneous knowledge resources and a set of complementary bioinformatic methods for automated inference of modules, their condition specific regulators and facilitates downstream network analyses and data visualization. To demonstrate its utility, we applied RMaNI to a hepatocellular microarray data containing normal and three disease conditions. We demonstrate that how RMaNI can be employed to understand the genetic architecture underlying three disease conditions. RMaNI is freely available at http://inspect.braembl.org.au/bi/inspect/rmaniConclusionRMaNI makes available a workflow with comprehensive set of tools that would otherwise be challenging for non-expert users to install and apply. The framework presented in this paper is flexible and can be easily extended to analyse any dataset with multiple disease conditions.
| S-EPMC3853211 | biostudies-literature
Project description:Tobacco exposure is one of the major risks for the initiation and progress of lung cancer. The exact corresponding mechanisms, however, are mainly unknown. Recently, a growing body of evidence has been collected supporting the involvement of DNA methylation in the regulation of gene expression in cancer cells. The identification of tobacco-related signature methylation probes and the analysis of their regulatory networks at different molecular levels may be of a great help for understanding tobacco-related tumorigenesis. Three independent lung adenocarcinoma (LUAD) datasets were used to train and validate the tobacco exposure pattern classification model. A deep selecting method was proposed and used to identify methylation signature probes from hundreds of thousands of the whole epigenome probes. Then, BIMC (biweight midcorrelation coefficient) algorithm, SRC (Spearman's rank correlation) analysis, and shortest path tracing method were explored to identify associated genes at gene regulation level and protein-protein interaction level, respectively. Afterwards, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and GO (Gene Ontology) enrichment analysis were used to analyze their molecular functions and associated pathways. 105 probes were identified as tobacco-related DNA methylation signatures. They belong to 95 genes which are involved in hsa04512, hsa04151, and other important pathways. At gene regulation level, 33 genes are uncovered to be highly related to signature probes by both BIMC and SRC methods. Among them, FARSB and other eight genes were uncovered as Hub genes in the gene regulatory network. Meanwhile, the PPI network about these 33 genes showed that MAGOH, FYN, and other five genes were the most connected core genes among them. These analysis results may provide clues for a clear biological interpretation in the molecular mechanism of tumorigenesis. Moreover, the identified signature probes may serve as potential drug targets for the precision medicine of LUAD.
| S-EPMC7201762 | biostudies-literature
Project description:BackgroundNetwork Component Analysis (NCA) has shown its effectiveness in discovering regulators and inferring transcription factor activities (TFAs) when both microarray data and ChIP-on-chip data are available. However, a NCA scheme is not applicable to many biological studies due to limited topology information available, such as lack of ChIP-on-chip data. We propose a new approach, motif-directed NCA (mNCA), to integrate motif information and gene expression data to infer regulatory networks.ResultsWe develop motif-directed NCA (mNCA) to incorporate motif information into NCA for regulatory network inference. While motif information is readily available from knowledge databases, it is a "noisy" source of network topology information consisting of many false positives. To overcome this problem, we develop a stability analysis procedure embedded in mNCA to resolve the inconsistency between motif information and gene expression data, and to enable the identification of stable TFAs. The mNCA approach has been applied to a time course microarray data set of muscle regeneration. The experimental results show that the inferred TFAs are not only numerically stable but also biologically relevant to muscle differentiation process. In particular, several inferred TFAs like those of MyoD, myogenin and YY1 are well supported by biological experiments.ConclusionA novel computational approach, mNCA, has been developed to integrate motif information and gene expression data for regulatory network reconstruction. Specifically, motif analysis is used to obtain initial network topology, and stability analysis is developed and applied with mNCA to extract stable TFAs. Experimental results on muscle regeneration microarray data have demonstrated that mNCA is a practical and reliable computational method for regulatory network inference and pathway discovery.
| S-EPMC2259422 | biostudies-literature
Project description:Glioblastoma (GBM) is a highly invasive brain tumor, whose cells infiltrate surrounding normal brain tissue beyond the lesion outlines visible in the current medical scans. These infiltrative cells are treated mainly by radiotherapy. Existing radiotherapy plans for brain tumors derive from population studies and scarcely account for patient-specific conditions. Here, we provide a Bayesian machine learning framework for the rational design of improved, personalized radiotherapy plans using mathematical modeling and patient multimodal medical scans. Our method, for the first time, integrates complementary information from high-resolution MRI scans and highly specific FET-PET metabolic maps to infer tumor cell density in GBM patients. The Bayesian framework quantifies imaging and modeling uncertainties and predicts patient-specific tumor cell density with credible intervals. The proposed methodology relies only on data acquired at a single time point and, thus, is applicable to standard clinical settings. An initial clinical population study shows that the radiotherapy plans generated from the inferred tumor cell infiltration maps spare more healthy tissue thereby reducing radiation toxicity while yielding comparable accuracy with standard radiotherapy protocols. Moreover, the inferred regions of high tumor cell densities coincide with the tumor radioresistant areas, providing guidance for personalized dose-escalation. The proposed integration of multimodal scans and mathematical modeling provides a robust, non-invasive tool to assist personalized radiotherapy design.
| S-EPMC7170051 | biostudies-literature
Project description:MotivationGene regulatory network (GRN) inference based on genomic data is one of the most actively pursued computational biological problems. Because different types of biological data usually provide complementary information regarding the underlying GRN, a model that integrates big data of diverse types is expected to increase both the power and accuracy of GRN inference. Towards this goal, we propose a novel algorithm named iRafNet: integrative random forest for gene regulatory network inference.ResultsiRafNet is a flexible, unified integrative framework that allows information from heterogeneous data, such as protein-protein interactions, transcription factor (TF)-DNA-binding, gene knock-down, to be jointly considered for GRN inference. Using test data from the DREAM4 and DREAM5 challenges, we demonstrate that iRafNet outperforms the original random forest based network inference algorithm (GENIE3), and is highly comparable to the community learning approach. We apply iRafNet to construct GRN in Saccharomyces cerevisiae and demonstrate that it improves the performance in predicting TF-target gene regulations and provides additional functional insights to the predicted gene regulations.Availability and implementationThe R code of iRafNet implementation and a tutorial are available at: http://research.mssm.edu/tulab/software/irafnet.html
| S-EPMC4542785 | biostudies-literature
Project description:We present SCENIC, a computational method for simultaneous gene regulatory network reconstruction and cell-state identification from single-cell RNA-seq data (http://scenic.aertslab.org). On a compendium of single-cell data from tumors and brain, we demonstrate that cis-regulatory analysis can be exploited to guide the identification of transcription factors and cell states. SCENIC provides critical biological insights into the mechanisms driving cellular heterogeneity.
| S-EPMC5937676 | biostudies-literature
Project description:Bipartite network inference is a ubiquitous problem across disciplines. One important example in the field molecular biology is gene regulatory network inference. Gene regulatory networks are an instrumental tool aiding in the discovery of the molecular mechanisms driving diverse diseases, including cancer. However, only noisy observations of the projections of these regulatory networks are typically assayed. In an effort to better estimate regulatory networks from their noisy projections, we formulate a non-convex but analytically tractable optimization problem called OTTER. This problem can be interpreted as relaxed graph matching between the two projections of the bipartite network. OTTER's solutions can be derived explicitly and inspire a spectral algorithm, for which we provide network recovery guarantees. We also provide an alternative approach based on gradient descent that is more robust to noise compared to the spectral algorithm. Interestingly, this gradient descent approach resembles the message passing equations of an established gene regulatory network inference method, PANDA. Using three cancer-related data sets, we show that OTTER outperforms state-of-the-art inference methods in predicting transcription factor binding to gene regulatory regions. To encourage new graph matching applications to this problem, we have made all networks and validation data publicly available.
| S-EPMC8546743 | biostudies-literature