Fast hybrid Bayesian integrative learning of multiple gene regulatory networks for type 1 diabetes.
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ABSTRACT:
SUBMITTER: Jia B
PROVIDER: S-EPMC8035990 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGenome-wide time-series data provide a rich set of information for discovering gene regulatory relationships. As genome-wide data for mammalian systems are being generated, it is critical to develop network inference methods that can handle tens of thousands of genes efficiently, provide a systematic framework for the integration of multiple data sources, and yield robust, accurate and compact gene-to-gene relationships.ResultsWe developed and applied ScanBMA, a Bayesian inference method that incorporates external information to improve the accuracy of the inferred network. In particular, we developed a new strategy to efficiently search the model space, applied data transformations to reduce the effect of spurious relationships, and adopted the g-prior to guide the search for candidate regulators. Our method is highly computationally efficient, thus addressing the scalability issue with network inference. The method is implemented as the ScanBMA function in the networkBMA Bioconductor software package.ConclusionsWe compared ScanBMA to other popular methods using time series yeast data as well as time-series simulated data from the DREAM competition. We found that ScanBMA produced more compact networks with a greater proportion of true positives than the competing methods. Specifically, ScanBMA generally produced more favorable areas under the Receiver-Operating Characteristic and Precision-Recall curves than other regression-based methods and mutual-information based methods. In addition, ScanBMA is competitive with other network inference methods in terms of running time.
| S-EPMC4006459 | biostudies-literature
Project description:Oscillations lie at the core of many biological processes, from the cell cycle, to circadian oscillations and developmental processes. Time-keeping mechanisms are essential to enable organisms to adapt to varying conditions in environmental cycles, from day/night to seasonal. Transcriptional regulatory networks are one of the mechanisms behind these biological oscillations. However, while identifying cyclically expressed genes from time series measurements is relatively easy, determining the structure of the interaction network underpinning the oscillation is a far more challenging problem.Here, we explicitly leverage the oscillatory nature of the transcriptional signals and present a method for reconstructing network interactions tailored to this special but important class of genetic circuits. Our method is based on projecting the signal onto a set of oscillatory basis functions using a Discrete Fourier Transform. We build a Bayesian Hierarchical model within a frequency domain linear model in order to enforce sparsity and incorporate prior knowledge about the network structure. Experiments on real and simulated data show that the method can lead to substantial improvements over competing approaches if the oscillatory assumption is met, and remains competitive also in cases it is not.DSS, experiment scripts and data are available at http://homepages.inf.ed.ac.uk/gsanguin/DSS.zip.d.trejo-banos@sms.ed.ac.ukSupplementary data are available at Bioinformatics online.
| S-EPMC4817140 | biostudies-other
Project description:Dynamic Bayesian networks (DBNs) can be used for the discovery of gene regulatory networks (GRNs) from time series gene expression data. Here, we suggest a strategy for learning DBNs from gene expression data by employing a Bayesian approach that is scalable to large networks and is targeted at learning models with high predictive accuracy. Our framework can be used to learn DBNs for multiple groups of samples and highlight differences and similarities in their GRNs. We learn these DBN models based on different structural and parametric assumptions and select the optimal model based on the cross-validated predictive accuracy. We show in simulation studies that our approach is better equipped to prevent overfitting than techniques used in previous studies. We applied the proposed DBN-based approach to two time series transcriptomic datasets from the Gene Expression Omnibus database, each comprising data from distinct phenotypic groups of the same tissue type. In the first case, we used DBNs to characterize responders and non-responders to anti-cancer therapy. In the second case, we compared normal to tumor cells of colorectal tissue. The classification accuracy reached by the DBN-based classifier for both datasets was higher than reported previously. For the colorectal cancer dataset, our analysis suggested that GRNs for cancer and normal tissues have a lot of differences, which are most pronounced in the neighborhoods of oncogenes and known cancer tissue markers. The identified differences in gene networks of cancer and normal cells may be used for the discovery of targeted therapies.
| S-EPMC9294428 | biostudies-literature
Project description:We present the Fast Greedy Equivalence Search (FGES)-Merge, a new method for learning the structure of gene regulatory networks via merging locally learned Bayesian networks, based on the fast greedy equivalent search algorithm. The method is competitive with the state of the art in terms of the Matthews correlation coefficient, which takes into account both precision and recall, while also improving upon it in terms of speed, scaling up to tens of thousands of variables and being able to use empirical knowledge about the topological structure of gene regulatory networks. To showcase the ability of our method to scale to massive networks, we apply it to learning the gene regulatory network for the full human genome using data from samples of different brain structures (from the Allen Human Brain Atlas). Furthermore, this Bayesian network model should predict interactions between genes in a way that is clear to experts, following the current trends in explainable artificial intelligence. To achieve this, we also present a new open-access visualization tool that facilitates the exploration of massive networks and can aid in finding nodes of interest for experimental tests.
| S-EPMC10745139 | biostudies-literature
Project description:BACKGROUND:Reverse engineering of transcriptional regulatory networks (TRN) from genomics data has always represented a computational challenge in System Biology. The major issue is modeling the complex crosstalk among transcription factors (TFs) and their target genes, with a method able to handle both the high number of interacting variables and the noise in the available heterogeneous experimental sources of information. RESULTS:In this work, we propose a data fusion approach that exploits the integration of complementary omics-data as prior knowledge within a Bayesian framework, in order to learn and model large-scale transcriptional networks. We develop a hybrid structure-learning algorithm able to jointly combine TFs ChIP-Sequencing data and gene expression compendia to reconstruct TRNs in a genome-wide perspective. Applying our method to high-throughput data, we verified its ability to deal with the complexity of a genomic TRN, providing a snapshot of the synergistic TFs regulatory activity. Given the noisy nature of data-driven prior knowledge, which potentially contains incorrect information, we also tested the method's robustness to false priors on a benchmark dataset, comparing the proposed approach to other regulatory network reconstruction algorithms. We demonstrated the effectiveness of our framework by evaluating structural commonalities of our learned genomic network with other existing networks inferred by different DNA binding information-based methods. CONCLUSIONS:This Bayesian omics-data fusion based methodology allows to gain a genome-wide picture of the transcriptional interplay, helping to unravel key hierarchical transcriptional interactions, which could be subsequently investigated, and it represents a promising learning approach suitable for multi-layered genomic data integration, given its robustness to noisy sources and its tailored framework for handling high dimensional data.
| S-EPMC7257163 | biostudies-literature
Project description:Susceptibility to immune-mediated diabetes (IMD) in humans and NOD mice involves their inherently defective T cell immunoregulatory abilities. We have followed natural killer (NK) T cell numbers in patients with IMD, both by flow cytometry using mAbs to the characteristic junctions found in the T cell receptors of this cell subtype, and by semiquantitative RT-PCR for the corresponding transcripts. Both before and after clinical onset, the representation of these cells in patients' PBMCs is reduced. We also report low numbers of resting CD4(+) CD25(+) T cells in IMD patients, a subset of T cells shown to have important immunoregulatory functions in abrogating autoimmunities in 3-day thymectomized experimental mice. Whereas a biased Th1 to Th2 cytokine profile has been suggested to underlie the pathogenesis of IMD in both species, we found defective production of IFN-gamma in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-gamma and IL-4 deficiencies in V(alpha)24(+) NK T-enriched cells. These data suggest that multiple immunoregulatory T (Treg) cell defects underlie islet cell autoimmunity leading to IMD in humans and that these lesions may be part of a broad T cell defect.
| S-EPMC150819 | biostudies-literature
Project description:The availability of cross-platform, large-scale genomic data has enabled the investigation of complex biological relationships for many cancers. Identification of reliable cancer-related biomarkers requires the characterization of multiple interactions across complex genetic networks. MicroRNAs are small non-coding RNAs that regulate gene expression; however, the direct relationship between a microRNA and its target gene is difficult to measure. We propose a novel Bayesian model to identify microRNAs and their target genes that are associated with survival time by incorporating the microRNA regulatory network through prior distributions. We assume that biomarkers involved in regulatory networks are likely associated with survival time. We employ non-local prior distributions and a stochastic search method for the selection of biomarkers associated with the survival outcome. We use KEGG pathway information to incorporate correlated gene effects within regulatory networks. Using simulation studies, we assess the performance of our method, and apply it to experimental data of kidney renal cell carcinoma (KIRC) obtained from The Cancer Genome Atlas. Our novel method validates previously identified cancer biomarkers and identifies biomarkers specific to KIRC progression that were not previously discovered. Using the KIRC data, we confirm that biomarkers involved in regulatory networks are more likely to be associated with survival time, showing connections in one regulatory network for five out of six such genes we identified.
| S-EPMC4499566 | biostudies-literature
Project description:Significant advances in biotechnology have allowed for simultaneous measurement of molecular data across multiple genomic, epigenomic and transcriptomic levels from a single tumor/patient sample. This has motivated systematic data-driven approaches to integrate multi-dimensional structured datasets, since cancer development and progression is driven by numerous co-ordinated molecular alterations and the interactions between them. We propose a novel multi-scale Bayesian approach that combines integrative graphical structure learning from multiple sources of data with a variable selection framework-to determine the key genomic drivers of cancer progression. The integrative structure learning is first accomplished through novel joint graphical models for heterogeneous (mixed scale) data, allowing for flexible and interpretable incorporation of prior existing knowledge. This subsequently informs a variable selection step to identify groups of co-ordinated molecular features within and across platforms associated with clinical outcomes of cancer progression, while according appropriate adjustments for multicollinearity and multiplicities. We evaluate our methods through rigorous simulations to establish superiority over existing methods that do not take the network and/or prior information into account. Our methods are motivated by and applied to a glioblastoma multiforme (GBM) dataset from The Cancer Genome Atlas to predict patient survival times integrating gene expression, copy number and methylation data. We find a high concordance between our selected prognostic gene network modules with known associations with GBM. In addition, our model discovers several novel cross-platform network interactions (both cis and trans acting) between gene expression, copy number variation associated gene dosing and epigenetic regulation through promoter methylation, some with known implications in the etiology of GBM. Our framework provides a useful tool for biomedical researchers, since clinical prediction using multi-platform genomic information is an important step towards personalized treatment of many cancers.
| S-EPMC6066211 | biostudies-other
Project description:Bayesian networks are probabilistic models that represent complex distributions in a modular way and have become very popular in many fields. There are many methods to build Bayesian networks from a random sample of independent and identically distributed observations. However, many observational studies are designed using some form of clustered sampling that introduces correlations between observations within the same cluster and ignoring this correlation typically inflates the rate of false positive associations. We describe a novel parameterization of Bayesian networks that uses random effects to model the correlation within sample units and can be used for structure and parameter learning from correlated data without inflating the Type I error rate. We compare different learning metrics using simulations and illustrate the method in two real examples: an analysis of genetic and non-genetic factors associated with human longevity from a family-based study, and an example of risk factors for complications of sickle cell anemia from a longitudinal study with repeated measures.
| S-EPMC4857179 | biostudies-literature
Project description:BackgroundUnderstanding gene interactions in complex living systems can be seen as the ultimate goal of the systems biology revolution. Hence, to elucidate disease ontology fully and to reduce the cost of drug development, gene regulatory networks (GRNs) have to be constructed. During the last decade, many GRN inference algorithms based on genome-wide data have been developed to unravel the complexity of gene regulation. Time series transcriptomic data measured by genome-wide DNA microarrays are traditionally used for GRN modelling. One of the major problems with microarrays is that a dataset consists of relatively few time points with respect to the large number of genes. Dimensionality is one of the interesting problems in GRN modelling.ResultsIn this paper, we develop a biclustering function enrichment analysis toolbox (BicAT-plus) to study the effect of biclustering in reducing data dimensions. The network generated from our system was validated via available interaction databases and was compared with previous methods. The results revealed the performance of our proposed method.ConclusionsBecause of the sparse nature of GRNs, the results of biclustering techniques differ significantly from those of previous methods.
| S-EPMC3231811 | biostudies-literature