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525
Modeling and simulation of genetic regulatory systems: A literature review
 Journal of Computational Biology
, 2002
"... In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between ..."
Abstract

Cited by 426 (9 self)
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In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between DNA, RNA, proteins, and small molecules. As most genetic regulatory networks of interest involve many components connected through interlocking positive and negative feedback loops, an intuitive understanding of their dynamics is hard to obtain. As a consequence, formal methods and computer tools for the modeling and simulation of genetic regulatory networks will be indispensable. This paper reviews formalisms that have been employed in mathematical biology and bioinformatics to describe genetic regulatory systems, in particular directed graphs, Bayesian networks, Boolean networks and their generalizations, ordinary and partial differential equations, qualitative differential equations, stochastic equations, and rulebased formalisms. In addition, the paper discusses how these formalisms have been used in the simulation of the behavior of actual regulatory systems. Key words: genetic regulatory networks, mathematical modeling, simulation, computational biology.
Probabilistic Boolean networks: a rulebased uncertainty model for gene regulatory networks
, 2002
"... Motivation: Our goal is to construct a model for genetic regulatory networks such that the model class: (i ) incorporates rulebased dependencies between genes; (ii ) allows the systematic study of global network dynamics; (iii ) is able to cope with uncertainty, both in the data and the model selec ..."
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Cited by 236 (42 self)
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Motivation: Our goal is to construct a model for genetic regulatory networks such that the model class: (i ) incorporates rulebased dependencies between genes; (ii ) allows the systematic study of global network dynamics; (iii ) is able to cope with uncertainty, both in the data and the model selection; and (iv ) permits the quantification of the relative influence and sensitivity of genes in their interactions with other genes.
Being Bayesian about network structure
 Machine Learning
, 2000
"... Abstract. In many multivariate domains, we are interested in analyzing the dependency structure of the underlying distribution, e.g., whether two variables are in direct interaction. We can represent dependency structures using Bayesian network models. To analyze a given data set, Bayesian model sel ..."
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Cited by 203 (5 self)
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Abstract. In many multivariate domains, we are interested in analyzing the dependency structure of the underlying distribution, e.g., whether two variables are in direct interaction. We can represent dependency structures using Bayesian network models. To analyze a given data set, Bayesian model selection attempts to find the most likely (MAP) model, and uses its structure to answer these questions. However, when the amount of available data is modest, there might be many models that have nonnegligible posterior. Thus, we want compute the Bayesian posterior of a feature, i.e., the total posterior probability of all models that contain it. In this paper, we propose a new approach for this task. We first show how to efficiently compute a sum over the exponential number of networks that are consistent with a fixed order over network variables. This allows us to compute, for a given order, both the marginal probability of the data and the posterior of a feature. We then use this result as the basis for an algorithm that approximates the Bayesian posterior of a feature. Our approach uses a Markov Chain Monte Carlo (MCMC) method, but over orders rather than over network structures. The space of orders is smaller and more regular than the space of structures, and has much a smoother posterior “landscape”. We present empirical results on synthetic and reallife datasets that compare our approach to full model averaging (when possible), to MCMC over network structures, and to a nonBayesian bootstrap approach.
Inferring Subnetworks from Perturbed Expression Profiles
, 2001
"... Genomewide expression profiles of genetic mutants provide a wide variety of measurements of cellular responses to perturbations. Typical analysis of such data identifies genes affected by perturbation and uses clustering to group genes of similar function. In this paper we discover a finer structur ..."
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Cited by 159 (12 self)
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Genomewide expression profiles of genetic mutants provide a wide variety of measurements of cellular responses to perturbations. Typical analysis of such data identifies genes affected by perturbation and uses clustering to group genes of similar function. In this paper we discover a finer structure of interactions between genes, such as causality, mediation, activation, and inhibition by using a Bayesian network framework. We extend this framework to correctly handle perturbations, and to identify significant subnetworks of interacting genes. We apply this method to expression data of S. cerevisiae mutants and uncover a variety of structured metabolic, signaling and regulatory pathways. Contact: danab@cs.huji.ac.il
Sensitivity and specificity of inferring genetic regulatory interactions from microarray experiments with dynamic Bayesian networks
 Bioinformatics
, 2003
"... Motivation: Bayesian networks have been applied to infer genetic regulatory interactions from microarray gene expression data. This inference problem is particularly hard in that interactions between hundreds of genes have to be learned from very small data sets, typically containing only a few doze ..."
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Cited by 111 (3 self)
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Motivation: Bayesian networks have been applied to infer genetic regulatory interactions from microarray gene expression data. This inference problem is particularly hard in that interactions between hundreds of genes have to be learned from very small data sets, typically containing only a few dozen time points during a cell cycle. Most previous studies have assessed the inference results on real gene expression data by comparing predicted genetic regulatory interactions with those known from the biological literature. This approach is controversial due to the absence of known gold standards, which renders the estimation of the sensitivity and specificity, that is, the true and (complementary) false detection rate, unreliable and difficult. The objective of the present study is to test the viability of the Bayesian network paradigm in a realistic simulation study. First, gene expression data are simulated from a realistic biological network involving DNAs, mRNAs, inactive protein monomers and active protein dimers. Then, interaction networks are inferred from these data in a reverse engineering approach, using Bayesian networks and Bayesian learning with Markov chain Monte Carlo.
Results: The simulation results are presented as receiver operator characteristics curves. This allows estimating the proportion of spurious gene interactions incurred for a specified target proportion of recovered true interactions. The findings demonstrate how the network inference performance varies with the training set size, the degree of inadequacy of prior assumptions, the experimental sampling strategy and the inclusion of further, sequencebased information.
Spectral biclustering of microarray data: Coclustering genes and conditions
 Genome Research
, 2003
"... service ..."
Exploring the Conditional Coregulation of Yeast Gene Expression Through Fuzzy KMeans Clustering
, 2002
"... Background: Organisms simplify the orchestration of gene expression by coregulating genes whose products function together in the cell. Many proteins serve different roles depending on the demands of the organism, and therefore the corresponding genes are often coexpressed with different groups o ..."
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Cited by 85 (0 self)
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Background: Organisms simplify the orchestration of gene expression by coregulating genes whose products function together in the cell. Many proteins serve different roles depending on the demands of the organism, and therefore the corresponding genes are often coexpressed with different groups of genes under different situations. This poses a challenge in analyzing wholegenome expression data, because many genes will be similarly expressed to multiple, distinct groups of genes. Because most commonly used analytical methods cannot appropriately represent these relationships, the connections between conditionally coregulated genes are often missed.
Genes, Themes and Microarrays  Using Information Retrieval for LargeScale Gene Analysis
, 2000
"... The immense volume of data resulting from DNA microarray experiments, accompanied byanincrease in the number of publications discussing generelated discoveries, presents a major data analysis challenge. Current methods for genomewide analysis of expression data typically rely on cluster analy ..."
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Cited by 78 (8 self)
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The immense volume of data resulting from DNA microarray experiments, accompanied byanincrease in the number of publications discussing generelated discoveries, presents a major data analysis challenge. Current methods for genomewide analysis of expression data typically rely on cluster analysis of gene expression patterns. Clustering indeed reveals potentially meaningful relationships among genes, but can not explain the underlying biological mechanisms. In an attempt to address this problem, we have developed a new approach for utilizing the literature in order to establish functional relationships among genes on a genomewide scale. Our method is based on revealing coherent themes within the literature, using a similaritybased search in document space. Contentbased relationships among abstracts are then translated into functional connections among genes. We describe preliminary experiments applying our algorithm to a database of documents discussing yeast genes...
The maxmin hillclimbing bayesian network structure learning algorithm
 Machine Learning
, 2006
"... Abstract. We present a new algorithm for Bayesian network structure learning, called MaxMin HillClimbing (MMHC). The algorithm combines ideas from local learning, constraintbased, and searchandscore techniques in a principled and effective way. It first reconstructs the skeleton of a Bayesian n ..."
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Cited by 75 (7 self)
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Abstract. We present a new algorithm for Bayesian network structure learning, called MaxMin HillClimbing (MMHC). The algorithm combines ideas from local learning, constraintbased, and searchandscore techniques in a principled and effective way. It first reconstructs the skeleton of a Bayesian network and then performs a Bayesianscoring greedy hillclimbing search to orient the edges. In our extensive empirical evaluation MMHC outperforms on average and in terms of various metrics several prototypical and stateoftheart algorithms, namely the PC, Sparse Candidate, Three Phase Dependency Analysis, Optimal Reinsertion, Greedy Equivalence Search, and Greedy Search. These are the first empirical results simultaneously comparing most of the major Bayesian network algorithms against each other. MMHC offers certain theoretical advantages, specifically over the Sparse Candidate algorithm, corroborated by our experiments. MMHC and detailed results of our study are publicly available at
Analyzing time series gene expression data
 Bioinformatics
, 2004
"... doi:10.1093/bioinformatics/bth283 ..."