A study of computational methods to analyze gene expression data

The recent advent of new technologies has led to huge amounts of genomic data. With these data come new opportunities to understand biological cellular processes underlying hidden regulation mechanisms and to identify disease related biomarkers for informative diagnostics. However, extracting biological insights from the immense amounts of genomic data is a challenging task. Therefore, effective and efficient computational techniques are needed to analyze and interpret genomic data. In this thesis, novel computational methods are proposed to address such challenges: a Bayesian mixture model, an extended Bayesian mixture model, and an Eigen-brain approach. The Bayesian mixture framework involves integration of the Bayesian network and the Gaussian mixture model. Based on the proposed framework and its conjunction with K-means clustering and principal component analysis (PCA), biological insights are derived such as context specific/dependent relationships and nested structures within microarray where biological replicates are encapsulated. The Bayesian mixture framework is then extended to explore posterior distributions of network space by incorporating a Markov chain Monte Carlo (MCMC) model. The extended Bayesian mixture model summarizes the sampled network structures by extracting biologically meaningful features. Finally, an Eigen-brain approach is proposed to analyze in situ hybridization data for the identification of the cell-type specific genes, which can be useful for informative blood diagnostics. Computational results with region-based clustering reveals the critical evidence for the consistency with brain anatomical structure.

Exact Solution of Bayes and Minimax Change-Detection Problems

The challenge of detecting a change in the distribution of data is a sequential decision problem that is relevant to many engineering solutions, including quality control and machine and process monitoring. This dissertation develops techniques for exact solution of change-detection problems with discrete time and discrete observations. Change-detection problems are classified as Bayes or minimax based on the availability of information on the change-time distribution. A Bayes optimal solution uses prior information about the distribution of the change time to minimize the expected cost, whereas a minimax optimal solution minimizes the cost under the worst-case change-time distribution. Both types of problems are addressed. The most important result of the dissertation is the development of a polynomial-time algorithm for the solution of important classes of Markov Bayes change-detection problems. Existing techniques for epsilon-exact solution of partially observable Markov decision processes have complexity exponential in the number of observation symbols. A new algorithm, called constellation induction, exploits the concavity and Lipschitz continuity of the value function, and has complexity polynomial in the number of observation symbols. It is shown that change-detection problems with a geometric change-time distribution and identically- and independently-distributed observations before and after the change are solvable in polynomial time. Also, change-detection problems on hidden Markov models with a fixed number of recurrent states are solvable in polynomial time. A detailed implementation and analysis of the constellation-induction algorithm are provided. Exact solution methods are also established for several types of minimax change-detection problems. Finite-horizon problems with arbitrary observation distributions are modeled as extensive-form games and solved using linear programs. Infinite-horizon problems with linear penalty for detection delay and identically- and independently-distributed observations can be solved in polynomial time via epsilon-optimal parameterization of a cumulative-sum procedure. Finally, the properties of policies for change-detection problems are described and analyzed. Simple classes of formal languages are shown to be sufficient for epsilon-exact solution of change-detection problems, and methods for finding minimally sized policy representations are described.

Quantification of the human postural control system to perturbations

Human standing posture is inherently unstable. The postural control system (PCS), which maintains standing posture, is composed of the sensory, musculoskeletal, and central nervous systems. Together these systems integrate sensory afferents and generate appropriate motor efferents to adjust posture. The PCS maintains the body center of mass (COM) with respect to the base of support while constantly resisting destabilizing forces from internal and external perturbations. To assess the human PCS, postural sway during quiet standing or in response to external perturbation have frequently been examined descriptively. Minimal work has been done to understand and quantify the robustness of the PCS to perturbations. Further, there have been some previous attempts to assess the dynamical systems aspects of the PCS or time evolutionary properties of postural sway. However those techniques can only provide summary information about the PCS characteristics; they cannot provide specific information about or recreate the actual sway behavior. This dissertation consists of two parts: part I, the development of two novel methods to assess the human PCS and, part II, the application of these methods. In study 1, a systematic method for analyzing the human PCS during perturbed stance was developed. A mild impulsive perturbation that subjects can easily experience in their daily lives was used. A measure of robustness of the PCS, 1/MaxSens that was based on the inverse of the sensitivity of the system, was introduced. 1/MaxSens successfully quantified the reduced robustness to external perturbations due to age-related degradation of the PCS. In study 2, a stochastic model was used to better understand the human PCS in terms of dynamical systems aspect. This methodology also has the advantage over previous methods in that the sway behavior is captured in a model that can be used to recreate the random oscillatory properties of the PCS. The invariant density which describes the long-term stationary behavior of the center of pressure (COP) was computed from a Markov chain model that was applied to postural sway data during quiet stance. In order to validate the Invariant Density Analysis (IDA), we applied the technique to COP data from different age groups. We found that older adults swayed farther from the centroid and in more stochastic and random manner than young adults. In part II, the tools developed in part I were applied to both occupational and clinical situations. In study 3, 1/MaxSens and IDA were applied to a population of firefighters to investigate the effects of air bottle configuration (weight and size) and vision on the postural stability of firefighters. We found that both air bottle weight and loss of vision, but not size of air bottle, significantly decreased balance performance and increased fall risk. In study 4, IDA was applied to data collected on 444 community-dwelling elderly adults from the MOBILIZE Boston Study. Four out of five IDA parameters were able to successfully differentiate recurrent fallers from non-fallers, while only five out of 30 more common descriptive and stochastic COP measures could distinguish the two groups. Fall history and the IDA parameter of entropy were found to be significant risk factors for falls. This research proposed a new measure for the PCS robustness (1/MaxSens) and a new technique for quantifying the dynamical systems aspect of the PCS (IDA). These new PCS analysis techniques provide easy and effective ways to assess the PCS in occupational and clinical environments.