1,632 research outputs found

    Modeling multiple time units delayed gene regulatory network using dynamic Bayesian network.

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    Inferring Gene Regulatory Networks from Time Series Microarray Data

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    The innovations and improvements in high-throughput genomic technologies, such as DNA microarray, make it possible for biologists to simultaneously measure dependencies and regulations among genes on a genome-wide scale and provide us genetic information. An important objective of the functional genomics is to understand the controlling mechanism of the expression of these genes and encode the knowledge into gene regulatory network (GRN). To achieve this, computational and statistical algorithms are especially needed. Inference of GRN is a very challenging task for computational biologists because the degree of freedom of the parameters is redundant. Various computational approaches have been proposed for modeling gene regulatory networks, such as Boolean network, differential equations and Bayesian network. There is no so called golden method which can generally give us the best performance for any data set. The research goal is to improve inference accuracy and reduce computational complexity. One of the problems in reconstructing GRN is how to deal with the high dimensionality and short time course gene expression data. In this work, some existing inference algorithms are compared and the limitations lie in that they either suffer from low inference accuracy or computational complexity. To overcome such difficulties, a new approach based on state space model and Expectation-Maximization (EM) algorithms is proposed to model the dynamic system of gene regulation and infer gene regulatory networks. In our model, GRN is represented by a state space model that incorporates noises and has the ability to capture more various biological aspects, such as hidden or missing variables. An EM algorithm is used to estimate the parameters based on the given state space functions and the gene interaction matrix is derived by decomposing the observation matrix using singular value decomposition, and then it is used to infer GRN. The new model is validated using synthetic data sets before applying it to real biological data sets. The results reveal that the developed model can infer the gene regulatory networks from large scale gene expression data and significantly reduce the computational time complexity without losing much inference accuracy compared to dynamic Bayesian network

    Discovering time-lagged rules from microarray data using gene profile classifiers

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    Background: Gene regulatory networks have an essential role in every process of life. In this regard, the amount of genome-wide time series data is becoming increasingly available, providing the opportunity to discover the time-delayed gene regulatory networks that govern the majority of these molecular processes.Results: This paper aims at reconstructing gene regulatory networks from multiple genome-wide microarray time series datasets. In this sense, a new model-free algorithm called GRNCOP2 (Gene Regulatory Network inference by Combinatorial OPtimization 2), which is a significant evolution of the GRNCOP algorithm, was developed using combinatorial optimization of gene profile classifiers. The method is capable of inferring potential time-delay relationships with any span of time between genes from various time series datasets given as input. The proposed algorithm was applied to time series data composed of twenty yeast genes that are highly relevant for the cell-cycle study, and the results were compared against several related approaches. The outcomes have shown that GRNCOP2 outperforms the contrasted methods in terms of the proposed metrics, and that the results are consistent with previous biological knowledge. Additionally, a genome-wide study on multiple publicly available time series data was performed. In this case, the experimentation has exhibited the soundness and scalability of the new method which inferred highly-related statistically-significant gene associations.Conclusions: A novel method for inferring time-delayed gene regulatory networks from genome-wide time series datasets is proposed in this paper. The method was carefully validated with several publicly available data sets. The results have demonstrated that the algorithm constitutes a usable model-free approach capable of predicting meaningful relationships between genes, revealing the time-trends of gene regulation. © 2011 Gallo et al; licensee BioMed Central Ltd.Fil: Gallo, Cristian Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación; ArgentinaFil: Carballido, Jessica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación; ArgentinaFil: Ponzoni, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Ciencias e Ingeniería de la Computación; Argentin

    TimeDelay-ARACNE: Reverse engineering of gene networks from time-course data by an information theoretic approach

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    <p>Abstract</p> <p>Background</p> <p>One of main aims of Molecular Biology is the gain of knowledge about how molecular components interact each other and to understand gene function regulations. Using microarray technology, it is possible to extract measurements of thousands of genes into a single analysis step having a picture of the cell gene expression. Several methods have been developed to infer gene networks from steady-state data, much less literature is produced about time-course data, so the development of algorithms to infer gene networks from time-series measurements is a current challenge into bioinformatics research area. In order to detect dependencies between genes at different time delays, we propose an approach to infer gene regulatory networks from time-series measurements starting from a well known algorithm based on information theory.</p> <p>Results</p> <p>In this paper we show how the ARACNE (Algorithm for the Reconstruction of Accurate Cellular Networks) algorithm can be used for gene regulatory network inference in the case of time-course expression profiles. The resulting method is called TimeDelay-ARACNE. It just tries to extract dependencies between two genes at different time delays, providing a measure of these dependencies in terms of mutual information. The basic idea of the proposed algorithm is to detect time-delayed dependencies between the expression profiles by assuming as underlying probabilistic model a stationary Markov Random Field. Less informative dependencies are filtered out using an auto calculated threshold, retaining most reliable connections. TimeDelay-ARACNE can infer small local networks of time regulated gene-gene interactions detecting their versus and also discovering cyclic interactions also when only a medium-small number of measurements are available. We test the algorithm both on synthetic networks and on microarray expression profiles. Microarray measurements concern <it>S. cerevisiae </it>cell cycle, <it>E. coli </it>SOS pathways and a recently developed network for in vivo assessment of reverse engineering algorithms. Our results are compared with ARACNE itself and with the ones of two previously published algorithms: Dynamic Bayesian Networks and systems of ODEs, showing that TimeDelay-ARACNE has good accuracy, recall and <it>F</it>-score for the network reconstruction task.</p> <p>Conclusions</p> <p>Here we report the adaptation of the ARACNE algorithm to infer gene regulatory networks from time-course data, so that, the resulting network is represented as a directed graph. The proposed algorithm is expected to be useful in reconstruction of small biological directed networks from time course data.</p

    Modeling Non-Linear Dynamic Phenomena in Biochemical Networks

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    Facilitated by the development of high-throughput techniques, the focus of biological research has changed in the last decades from the investigation of single cell components to a system-level approach, which aims at an understanding of interactions between these cell components. This objective requires modeling and analysis methods for these regulatory networks. In this thesis, we investigate mechanisms causing qualitative dynamic behaviors of regulatory subsystems. For this purpose, we introduce a differential equation model based on underlying molecular binding reactions, whose parameters are estimated using time series concentration data. In the first part, the model is applied to subsystems with qualitatively different dynamic behaviors: The response of the Mycobacterium tuberculosis to DNA damages is described as the relaxation of a system to its steady state after external perturbation. Specific repression of genes in Escherichia coli by the global regulator protein H-NS is explained by the interrelation of feedback mechanisms. In order to prevent overfitting, a typical problem in network inference from experimental data, we introduce an approach based on Bayesian statistics, which includes prior knowledge about the system in terms of prior probability distributions. This approach is applied to simulated data and to the regulatory network of the Saccharomyces cerevisiae cell cycle. Motivated by results on the yeast cell cycle, the second part of this thesis investigates the robustness of periodic behavior in regulatory networks. The model presented belongs to a class of differential equations whose solutions tend to converge to a steady state. Accordingly, periodic behavior is not robust with respect to parameter variations. We explain this phenomenon by applying a bifurcation analysis and investigating the stability of steady states. It is shown that large time scale differences and an inclusion of time-delays can stabilize sustained oscillations, and we postulate that they are important to maintain oscillations in biological systems

    Modelling biochemical networks with intrinsic time delays: a hybrid semi-parametric approach

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    <p>Abstract</p> <p>Background</p> <p>This paper presents a method for modelling dynamical biochemical networks with intrinsic time delays. Since the fundamental mechanisms leading to such delays are many times unknown, non conventional modelling approaches become necessary. Herein, a hybrid semi-parametric identification methodology is proposed in which discrete time series are incorporated into fundamental material balance models. This integration results in hybrid delay differential equations which can be applied to identify unknown cellular dynamics.</p> <p>Results</p> <p>The proposed hybrid modelling methodology was evaluated using two case studies. The first of these deals with dynamic modelling of transcriptional factor A in mammalian cells. The protein transport from the cytosol to the nucleus introduced a delay that was accounted for by discrete time series formulation. The second case study focused on a simple network with distributed time delays that demonstrated that the discrete time delay formalism has broad applicability to both discrete and distributed delay problems.</p> <p>Conclusions</p> <p>Significantly better prediction qualities of the novel hybrid model were obtained when compared to dynamical structures without time delays, being the more distinctive the more significant the underlying system delay is. The identification of the system delays by studies of different discrete modelling delays was enabled by the proposed structure. Further, it was shown that the hybrid discrete delay methodology is not limited to discrete delay systems. The proposed method is a powerful tool to identify time delays in ill-defined biochemical networks.</p

    Sparse machine learning models in bioinformatics

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    The meaning of parsimony is twofold in machine learning: either the structure or (and) the parameter of a model can be sparse. Sparse models have many strengths. First, sparsity is an important regularization principle to reduce model complexity and therefore avoid overfitting. Second, in many fields, for example bioinformatics, many high-dimensional data may be generated by a very few number of hidden factors, thus it is more reasonable to use a proper sparse model than a dense model. Third, a sparse model is often easy to interpret. In this dissertation, we investigate the sparse machine learning models and their applications in high-dimensional biological data analysis. We focus our research on five types of sparse models as follows. First, sparse representation is a parsimonious principle that a sample can be approximated by a sparse linear combination of basis vectors. We explore existing sparse representation models and propose our own sparse representation methods for high dimensional biological data analysis. We derive different sparse representation models from a Bayesian perspective. Two generic dictionary learning frameworks are proposed. Also, kernel and supervised dictionary learning approaches are devised. Furthermore, we propose fast active-set and decomposition methods for the optimization of sparse coding models. Second, gene-sample-time data are promising in clinical study, but challenging in computation. We propose sparse tensor decomposition methods and kernel methods for the dimensionality reduction and classification of such data. As the extensions of matrix factorization, tensor decomposition techniques can reduce the dimensionality of the gene-sample-time data dramatically, and the kernel methods can run very efficiently on such data. Third, we explore two sparse regularized linear models for multi-class problems in bioinformatics. Our first method is called the nearest-border classification technique for data with many classes. Our second method is a hierarchical model. It can simultaneously select features and classify samples. Our experiment, on breast tumor subtyping, shows that this model outperforms the one-versus-all strategy in some cases. Fourth, we propose to use spectral clustering approaches for clustering microarray time-series data. The approaches are based on two transformations that have been recently introduced, especially for gene expression time-series data, namely, alignment-based and variation-based transformations. Both transformations have been devised in order to take into account temporal relationships in the data, and have been shown to increase the ability of a clustering method in detecting co-expressed genes. We investigate the performances of these transformations methods, when combined with spectral clustering on two microarray time-series datasets, and discuss their strengths and weaknesses. Our experiments on two well known real-life datasets show the superiority of the alignment-based over the variation-based transformation for finding meaningful groups of co-expressed genes. Fifth, we propose the max-min high-order dynamic Bayesian network (MMHO-DBN) learning algorithm, in order to reconstruct time-delayed gene regulatory networks. Due to the small sample size of the training data and the power-low nature of gene regulatory networks, the structure of the network is restricted by sparsity. We also apply the qualitative probabilistic networks (QPNs) to interpret the interactions learned. Our experiments on both synthetic and real gene expression time-series data show that, MMHO-DBN can obtain better precision than some existing methods, and perform very fast. The QPN analysis can accurately predict types of influences and synergies. Additionally, since many high dimensional biological data are subject to missing values, we survey various strategies for learning models from incomplete data. We extend the existing imputation methods, originally for two-way data, to methods for gene-sample-time data. We also propose a pair-wise weighting method for computing kernel matrices from incomplete data. Computational evaluations show that both approaches work very robustly

    Microarray Data Mining and Gene Regulatory Network Analysis

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    The novel molecular biological technology, microarray, makes it feasible to obtain quantitative measurements of expression of thousands of genes present in a biological sample simultaneously. Genome-wide expression data generated from this technology are promising to uncover the implicit, previously unknown biological knowledge. In this study, several problems about microarray data mining techniques were investigated, including feature(gene) selection, classifier genes identification, generation of reference genetic interaction network for non-model organisms and gene regulatory network reconstruction using time-series gene expression data. The limitations of most of the existing computational models employed to infer gene regulatory network lie in that they either suffer from low accuracy or computational complexity. To overcome such limitations, the following strategies were proposed to integrate bioinformatics data mining techniques with existing GRN inference algorithms, which enables the discovery of novel biological knowledge. An integrated statistical and machine learning (ISML) pipeline was developed for feature selection and classifier genes identification to solve the challenges of the curse of dimensionality problem as well as the huge search space. Using the selected classifier genes as seeds, a scale-up technique is applied to search through major databases of genetic interaction networks, metabolic pathways, etc. By curating relevant genes and blasting genomic sequences of non-model organisms against well-studied genetic model organisms, a reference gene regulatory network for less-studied organisms was built and used both as prior knowledge and model validation for GRN reconstructions. Networks of gene interactions were inferred using a Dynamic Bayesian Network (DBN) approach and were analyzed for elucidating the dynamics caused by perturbations. Our proposed pipelines were applied to investigate molecular mechanisms for chemical-induced reversible neurotoxicity

    A Survey on Evolutionary Algorithm Based Hybrid Intelligence in Bioinformatics

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