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From network to pathway: integrative network analysis of genomic dataWang, Chen 25 August 2011 (has links)
The advent of various types of high-throughput genomic data has enabled researchers to investigate complex biological systems in a systemic way and started to shed light on the underlying molecular mechanisms in cancers. To analyze huge amounts of genomic data, effective statistical and machine learning tools are clearly needed; more importantly, integrative approaches are especially needed to combine different types of genomic data for a network or pathway view of biological systems. Motivated by such needs, we make efforts in this dissertation to develop integrative framework for pathway analysis. Specifically, we dissect the molecular pathway into two parts: protein-DNA interaction network and protein-protein interaction network. Several novel approaches are proposed to integrate gene expression data with various forms of biological knowledge, such as protein-DNA interaction and protein-protein interaction for reliable molecular network identification.
The first part of this dissertation seeks to infer condition-specific transcriptional regulatory network by integrating gene expression data and protein-DNA binding information. Protein-DNA binding information provides initial relationships between transcription factors (TFs) and their target genes, and this information is essential to derive biologically meaningful integrative algorithms. Based on the availability of this information, we discuss the inference task based on two different situations:
(a) if protein-DNA binding information of multiple TFs is available:
based on the protein-DNA data of multiple TFs, which are derived from sequence analysis between DNA motifs and gene promoter regions, we can construct initial connection matrix and solve the network inference using a constraint least-squares approach named motif-guided network component analysis (mNCA). However, connection matrix usually contains a considerable amount of false positives and false negatives that make inference results questionable. To circumvent this problem, we propose a knowledge based stability analysis (kSA) approach to test the conditional relevance of individual TFs, by checking the discrepancy of multiple estimations of transcription factor activity with respect to different perturbations on the connections. The rationale behind stability analysis is that the consistency of observed gene expression and true network connection shall remain stable after small perturbations are applied to initial connection matrix. With condition-specific TFs prioritized by kSA, we further propose to use multivariate regression to highlight condition-specific target genes. Through simulation studies comparing with several competing methods, we show that the proposed schemes are more sensitive to detect relevant TFs and target genes for network inference purpose. Experimentally, we have applied stability analysis to yeast cell cycle experiment and further to a series of anti-estrogen breast cancer studies. In both experiments not only biologically relevant regulators are highlighted, the condition-specific transcriptional regulatory networks are also constructed, which could provide further insights into the corresponding cellular mechanisms.
(b) if only single TF's protein-DNA information is available:
this happens when protein-DNA binding relationship of individual TF is measured through experiments. Since original mNCA requires a complete connection matrix to perform estimation, an incomplete knowledge of single TF is not applicable for such approach. Moreover, binding information derived from experiments could still be inconsistent with gene expression levels. To overcome these limitations, we propose a linear extraction scheme called regulatory component analysis (RCA), which can infer underlying regulation relationships, even with partial biological knowledge. Numerical simulations show significant improvement of RCA over other traditional methods to identify target genes, not only in low signal-to-noise-ratio situations and but also when the given biological knowledge is incomplete and inconsistent to data. Furthermore, biological experiments on Escherichia coli regulatory network inferences are performed to fairly compare traditional methods, where the effectiveness and superior performance of RCA are confirmed.
The second part of the dissertation moves from protein-DNA interaction network up to protein-protein interaction network, to identify dys-regulated protein sub-networks by integrating gene expression data and protein-protein interaction information. Specifically, we propose a statistically principled method, namely Metropolis random walk on graph (MRWOG), to highlight condition-specific PPI sub-networks in a probabilistic way. The method is based on the Markov chain Monte Carlo (MCMC) theory to generate a series of samples that will eventually converge to some desired equilibrium distribution, and each sample indicates the selection of one particular sub-network during the process of Metropolis random walk. The central idea of MRWOG is built upon that the essentiality of one gene to be included in a sub-network depends on not only its expression but also its topological importance. Contrasted to most existing methods constructing sub-networks in a deterministic way and therefore lacking relevance score for each protein, MRWOG is capable of assessing the importance of each individual protein node in a global way, not only reflecting its individual association with clinical outcome but also indicating its topological role (hub, bridge) to connect other important proteins. Moreover, each protein node is associated with a sampling frequency score, which enables the statistical justification of each individual node and flexible scaling of sub-network results. Based on MRWOG approach, we further propose two strategies: one is bootstrapping used for assessing statistical confidence of detected sub-networks; the other is graphic division to separate a large sub-network to several smaller sub-networks for facilitating interpretations. MRWOG is easy to use with only two parameters need to be adjusted, one is beta value for performing random walk and another is Quantile level for calculating truncated posteriori mean. Through extensive simulations, we show that the proposed scheme is not sensitive to these two parameters in a relatively wide range. We also compare MRWOG with deterministic approaches for identifying sub-network and prioritizing topologically important proteins, in both cases MRWG outperforms existing methods in terms of both precision and recall. By utilizing MRWOG generated node/edge sampling frequency, which is actually posteriori mean of corresponding protein node/interaction edge, we illustrate that condition-specific nodes/interactions can be better prioritized than the schemes based on scores of individual node/interaction. Experimentally, we have applied MRWOG to study yeast knockout experiment for galactose utilization pathways to reveal important components of corresponding biological functions; we also applied MRWSOG to study breast cancer patient prognostics problems, where the sub-network analysis could lead to an understanding of the molecular mechanisms of antiestrogen resistance in breast cancer.
Finally, we conclude this dissertation with a summary of the original contributions, and the future work for deepening the theoretical justification of the proposed methods and broadening their potential biological applications such as cancer studies. / Ph. D.
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Bayesian Approach Dealing with Mixture Model ProblemsZhang, Huaiye 05 June 2012 (has links)
In this dissertation, we focus on two research topics related to mixture models. The first topic is Adaptive Rejection Metropolis Simulated Annealing for Detecting Global Maximum Regions, and the second topic is Bayesian Model Selection for Nonlinear Mixed Effects Model.
In the first topic, we consider a finite mixture model, which is used to fit the data from heterogeneous populations for many applications. An Expectation Maximization (EM) algorithm and Markov Chain Monte Carlo (MCMC) are two popular methods to estimate parameters in a finite mixture model. However, both of the methods may converge to local maximum regions rather than the global maximum when multiple local maxima exist. In this dissertation, we propose a new approach, Adaptive Rejection Metropolis Simulated Annealing (ARMS annealing), to improve the EM algorithm and MCMC methods. Combining simulated annealing (SA) and adaptive rejection metropolis sampling (ARMS), ARMS annealing generate a set of proper starting points which help to reach all possible modes. ARMS uses a piecewise linear envelope function for a proposal distribution. Under the SA framework, we start with a set of proposal distributions, which are constructed by ARMS, and this method finds a set of proper starting points, which help to detect separate modes. We refer to this approach as ARMS annealing. By combining together ARMS annealing with the EM algorithm and with the Bayesian approach, respectively, we have proposed two approaches: an EM ARMS annealing algorithm and a Bayesian ARMS annealing approach. EM ARMS annealing implement the EM algorithm by using a set of starting points proposed by ARMS annealing. ARMS annealing also helps MCMC approaches determine starting points. Both approaches capture the global maximum region and estimate the parameters accurately. An illustrative example uses a survey data on the number of charitable donations.
The second topic is related to the nonlinear mixed effects model (NLME). Typically a parametric NLME model requires strong assumptions which make the model less flexible and often are not satisfied in real applications. To allow the NLME model to have more flexible assumptions, we present three semiparametric Bayesian NLME models, constructed with Dirichlet process (DP) priors. Dirichlet process models often refer to an infinite mixture model. We propose a unified approach, the penalized posterior Bayes factor, for the purpose of model comparison. Using simulation studies, we compare the performance of two of the three semiparametric hierarchical Bayesian approaches with that of the parametric Bayesian approach. Simulation results suggest that our penalized posterior Bayes factor is a robust method for comparing hierarchical parametric and semiparametric models. An application to gastric emptying studies is used to demonstrate the advantage of our estimation and evaluation approaches. / Ph. D.
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