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An Empirical Bayes Approach to Inferring LargeScale Gene Association Networks
 BIOINFORMATICS
, 2004
"... Motivation: Genetic networks are often described statistically by graphical models (e.g. Bayesian networks). However, inferring the network structure offers a serious challenge in microarray analysis where the sample size is small compared to the number of considered genes. This renders many standar ..."
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Cited by 171 (6 self)
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Motivation: Genetic networks are often described statistically by graphical models (e.g. Bayesian networks). However, inferring the network structure offers a serious challenge in microarray analysis where the sample size is small compared to the number of considered genes. This renders many standard algorithms for graphical models inapplicable, and inferring genetic networks an “illposed” inverse problem. Methods: We introduce a novel framework for smallsample inference of graphical models from gene expression data. Specifically, we focus on socalled graphical Gaussian models (GGMs) that are now frequently used to describe gene association networks and to detect conditionally dependent genes. Our new approach is based on (i) improved (regularized) smallsample point estimates of partial correlation, (ii) an exact test of edge inclusion with adaptive estimation of the degree of freedom, and (iii) a heuristic network search based on false discovery rate multiple testing. Steps (ii) and (iii) correspond to an empirical Bayes estimate of the network topology. Results: Using computer simulations we investigate the sensitivity (power) and specificity (true negative rate) of the proposed framework to estimate GGMs from microarray data. This shows that it is possible to recover the true network topology with high accuracy even for smallsample data sets. Subsequently, we analyze gene expression data from a breast cancer tumor study and illustrate our approach by inferring a corresponding largescale gene association network for 3,883 genes. Availability: The authors have implemented the approach in the R package “GeneTS ” that is freely available from
Combining microarrays and biological knowledge for estimating gene networks via Bayesian networks
 In Proceedings of the IEEE Computer Society Bioinformatics Conference (CSB 03
, 2003
"... We propose a statistical method for estimating a gene network based on Bayesian networks from microarray gene expression data together with biological knowledge including proteinprotein interactions, proteinDNA interactions, binding site information, existing literature and so on. Unfortunately, m ..."
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Cited by 64 (6 self)
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We propose a statistical method for estimating a gene network based on Bayesian networks from microarray gene expression data together with biological knowledge including proteinprotein interactions, proteinDNA interactions, binding site information, existing literature and so on. Unfortunately, microarray data do not contain enough information for constructing gene networks accurately in many cases. Our method adds biological knowledge to the estimation method of gene networks under a Bayesian statistical framework, and also controls the tradeoff between microarray information and biological knowledge automatically. We conduct Monte Carlo simulations to show the effectiveness of the proposed method. We analyze Saccharomyces cerevisiae gene expression data as an application. 1.
Dynamic Bayesian Network and Nonparametric Regression for Nonlinear Modeling of Gene Networks from Time Series Gene Expression Data
 Biosystems
, 2003
"... Abstract. We propose a dynamic Bayesian network and nonparametric regression model for constructing a gene network from time series microarray gene expression data. The proposed method can overcome a shortcoming of the Bayesian network model in the sense of the construction of cyclic regulations. Th ..."
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Cited by 56 (9 self)
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Abstract. We propose a dynamic Bayesian network and nonparametric regression model for constructing a gene network from time series microarray gene expression data. The proposed method can overcome a shortcoming of the Bayesian network model in the sense of the construction of cyclic regulations. The proposed method can analyze the microarray data as continuous data and can capture even nonlinear relations among genes. It can be expected that this model will give a deeper insight into the complicated biological systems. We also derive a new criterion for evaluating an estimated network from Bayes approach. We demonstrate the effectiveness of our method by analyzing Saccharomyces cerevisiae gene expression data. 1
Bayesian network and nonparametric heteroscedastic regression for nonlinear modeling of genetic network
 Proc. 1st IEEE Computer Society Bioinformatics Conference
, 2002
"... We propose a new statistical method for constructing a genetic network from microarray gene expression data by using a Bayesian network. An essential point of Bayesian network construction is in the estimation of the conditional distribution of each random variable. We consider fitting nonparametric ..."
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Cited by 41 (18 self)
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We propose a new statistical method for constructing a genetic network from microarray gene expression data by using a Bayesian network. An essential point of Bayesian network construction is in the estimation of the conditional distribution of each random variable. We consider fitting nonparametric regression models with heterogeneous error variances to the microarray gene expression data to capture the nonlinear structures between genes. A problem still remains to be solved in selecting an optimal graph, which gives the best representation of the system among genes. We theoretically derive a new graph selection criterion from Bayes approach in general situations. The proposed method includes previous methods based on Bayesian networks. We demonstrate the effectiveness of the proposed method through the analysis of Saccharomyces cerevisiae gene expression data newly obtained by disrupting 100 genes. 1.
Intervention in contextsensitive probabilistic Boolean networks
, 2005
"... Motivation: Intervention in a gene regulatory network is used to help it avoid undesirable states, such as those associated with a disease. Several types of intervention have been studied in the framework of a probabilistic Boolean network (PBN), which is essentially a finite collection of Boolean n ..."
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Cited by 36 (15 self)
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Motivation: Intervention in a gene regulatory network is used to help it avoid undesirable states, such as those associated with a disease. Several types of intervention have been studied in the framework of a probabilistic Boolean network (PBN), which is essentially a finite collection of Boolean networks in which at any discrete time point the gene state vector transitions according to the rules of one of the constituent networks. For an instantaneously random PBN, the governing Boolean network is randomly chosen at each time point. For a contextsensitive PBN, the governing Boolean network remains fixed for an interval of time until a binary random variable determines a switch. The theory of automatic control has been previously applied to find optimal strategies for manipulating external (control) variables that affect the transition probabilities of an instantaneously random PBN to desirably affect its dynamic evolution over a finite time horizon. This paper extends the methods of external control to contextsensitive PBNs.
Stochastic dynamic modeling of short gene expression time series data
 IEEE Trans. NanoBiosci
, 2008
"... Abstract—In this paper, the expectation maximization (EM) algorithm is applied for modeling the gene regulatory network from gene timeseries data. The gene regulatory network is viewed as a stochastic dynamic model, which consists of the noisy gene measurement from microarray and the gene regulatio ..."
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Cited by 15 (9 self)
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Abstract—In this paper, the expectation maximization (EM) algorithm is applied for modeling the gene regulatory network from gene timeseries data. The gene regulatory network is viewed as a stochastic dynamic model, which consists of the noisy gene measurement from microarray and the gene regulation firstorder autoregressive (AR) stochastic dynamic process. By using the EM algorithm, both the model parameters and the actual values of the gene expression levels can be identified simultaneously. Moreover, the algorithm can deal with the sparse parameter identification and the noisy data in an efficient way. It is also shown that the EM algorithm can handle the microarrary gene expression data with large number of variables but a small number of observations. The gene expression stochastic dynamic models for four realworld gene expression data sets are constructed to demonstrate the advantages of the introduced algorithm. Several indices are proposed to evaluate the models of inferred gene regulatory networks, and the relevant biological properties are discussed. Index Terms—Clustering, DNA microarray technology, expectation maximization (EM) algorithm, gene expression, modeling, timeseries data. I.
An extended Kalman filtering approach to modelling nonlinear dynamic gene regulatory networks via short gene expression time series
 19 of Figures and Tables
, 2009
"... Abstract—In this paper, the extended Kalman filter (EKF) algorithm is applied to model the gene regulatory network from gene time series data. The gene regulatory network is considered as a nonlinear dynamic stochastic model that consists of the gene measurement equation and the gene regulation equa ..."
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Cited by 14 (5 self)
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Abstract—In this paper, the extended Kalman filter (EKF) algorithm is applied to model the gene regulatory network from gene time series data. The gene regulatory network is considered as a nonlinear dynamic stochastic model that consists of the gene measurement equation and the gene regulation equation. After specifying the model structure, we apply the EKF algorithm for identifying both the model parameters and the actual value of gene expression levels. It is shown that the EKF algorithm is an online estimation algorithm that can identify a large number of parameters (including parameters of nonlinear functions) through iterative procedure by using a small number of observations. Four realworld gene expression data sets are employed to demonstrate the effectiveness of the EKF algorithm, and the obtained models are evaluated from the viewpoint of bioinformatics. Index Terms—Modeling, clustering, DNA microarray technology, extended Kalman filtering, gene expression, time series data. Ç 1
Construction of Genetic Network Using Evolutionary Algorithm and Combined Fitness Function
 Genome Inform
, 2003
"... This paper proposes a method to capture the dynamics in gene expression data using Ssystem formalism and construct genetic network models. Our purposed method exploits the probabilistic heuristic search and divideandconquer approach to estimate the network structure. In evaluating the network ..."
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Cited by 12 (1 self)
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This paper proposes a method to capture the dynamics in gene expression data using Ssystem formalism and construct genetic network models. Our purposed method exploits the probabilistic heuristic search and divideandconquer approach to estimate the network structure. In evaluating the network structure, we attempt a primitive integration of other knowledge to the statistical criterion. The Zscore is used to analyze the robust and significant parameters from stochastic search results. We evaluated the proposed method on artificially generated data and E.coli mRNA expression data.
ODB: a database of operons accumulating known operons across multiple genomes
 Nucleic Acids Res
, 2006
"... multiple genomes ..."
2005a) Estimating timedependent gene networks from time series DNA microarray data by dynamic linear model with Markov switching
 In Proceedings of IEEE 4th Computational Systems Bioinformatics
"... In gene network estimation from time series microarray data, dynamic models such as differential equations and dynamic Bayesian networks assume that the network structure is stable through all time points, while the real network might changes its structure depending on time, affection of some shocks ..."
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Cited by 10 (2 self)
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In gene network estimation from time series microarray data, dynamic models such as differential equations and dynamic Bayesian networks assume that the network structure is stable through all time points, while the real network might changes its structure depending on time, affection of some shocks and so on. If the true network structure underlying the data changes at certain points, the fitting of the usual dynamic linear models fails to estimate the structure of gene network and we cannot obtain efficient information from data. To solve this problem, we propose a dynamic linear model with Markov switching for estimating timedependent gene network structure from time series gene expression data. Using our proposed method, the network structure between genes and its change points are automatically estimated. We demonstrate the effectiveness of the proposed method through the analysis of Saccharomyces cerevisiae cell cycle time series data. 1.