This thesis presents Pathway Informed Analysis (PIA), a classification method for predicting disease states (diagnosis) from metabolic profile measurements that incorporates biological knowledge in the form of metabolic pathways. A metabolic pathway describes a set of chemical reactions that perform a specific biological function. A significant amount of biological knowledge produced by efforts to identify and understand these pathways is formalized in readily accessible databases such as the Kyoto Encyclopedia of Genes and Genomes. PIA uses metabolic pathways to identify relationships among the metabolite concentrations that are measured by a metabolic profile. Specifically, PIA assumes that the class-conditional metabolite concentrations (diseased vs. healthy, respectively) follow multivariate normal distributions. It further assumes that conditional independence statements about these distributions derived from the pathways relate the concentrations of the metabolites to each other. The two assumptions allow for a natural representation of the class-conditional distributions using a type of probabilistic graphical model called a Gaussian Markov Random Field. PIA efficiently estimates the parameters defining these distributions from example patients to produce a classifier. It classifies an undiagnosed patient by evaluating both models to determine the most probable class given their metabolic profile. We apply PIA to a data set of cancer patients to diagnose those with a muscle wasting disease called cachexia. Standard machine learning algorithms such as Naive Bayes, Tree-augmented Naive Bayes, Support Vector Machines and C4.5 are used to evaluate the performance of PIA. The overall classification accuracy of PIA is better than these algorithms on this data set but the difference is not statistically significant. We also apply PIA to several other classification tasks. Some involve predicting various manipulations of the metabolic processes performed in experiments with worms. Other tasks are to classify pigs according to properties of their dietary intake. The accuracy of PIA at these tasks is not significantly better than the standard algorithms.

No description available.

Modelling interactions between genes and their regulators is fundamental to understanding how, for example a disease progresses, or the impact of inserting a synthetic circuit into a cell. We use an existing method to infer regulatory networks under multiple conditions: the Joint Graphical Lasso (JGL), a shrinkage based Gaussian graphical model. We apply this method to two data sets: one, a publicly available set of microarray experiments perturbing the gram-positive bacteria Bacillus subtilis under multiple experimental conditions; the second, a set of RNA-seq samples of Mouse (Mus musculus) embryonic fibroblasts (MEFs) infected with different strains of the parasite Toxoplasma gondii. In both cases we infer a subset of the regulatory networks using relatively small sample sizes. For the Bacillus subtilis analysis we focused on the use of these regulatory networks in synthetic biology and found examples of transcriptional units active only under a subset of conditions, this information can be useful when designing circuits to have condition dependent behaviour. We developed methods for large network decomposition that made use of the condition information and showed a greater specificity of identifying single transcriptional units from the larger network using our method. Through annotating these results with known information we were able to identify novel connections and found supporting evidence for a selection of these from publicly available experimental results. Biological data collection is typically expensive and due to the relatively small sample sizes of our MEF data set we developed a novel empirical Bayes method for reducing the false discovery rate when estimating block diagonal covariance matrices. Using these methods we were able to infer regulatory networks for the host infected with either the ME49 or RH strain of the parasite. This enabled the identification of known and novel regulatory mechanisms. The Toxoplasma gondii parasite has shown to subvert host function using similar mechanisms as cancers and through our analysis we were able to identify genes, networks and ontologies associated with cancer, including connections that have not previously been associated with T. gondii infection. Finally a Shiny application was developed as an online resource giving access to the Bacillus subtilis inferred networks with interactive methods for exploring the networks including expansion of sub networks and large network decomposition.

abstract: Sparse learning is a powerful tool to generate models of high-dimensional data with high interpretability, and it has many important applications in areas such as bioinformatics, medical image processing, and computer vision. Recently, the a priori structural information has been shown to be powerful for improving the performance of sparse learning models. A graph is a fundamental way to represent structural information of features. This dissertation focuses on graph-based sparse learning. The first part of this dissertation aims to integrate a graph into sparse learning to improve the performance. Specifically, the problem of feature grouping and selection over a given undirected graph is considered. Three models are proposed along with efficient solvers to achieve simultaneous feature grouping and selection, enhancing estimation accuracy. One major challenge is that it is still computationally challenging to solve large scale graph-based sparse learning problems. An efficient, scalable, and parallel algorithm for one widely used graph-based sparse learning approach, called anisotropic total variation regularization is therefore proposed, by explicitly exploring the structure of a graph. The second part of this dissertation focuses on uncovering the graph structure from the data. Two issues in graphical modeling are considered. One is the joint estimation of multiple graphical models using a fused lasso penalty and the other is the estimation of hierarchical graphical models. The key technical contribution is to establish the necessary and sufficient condition for the graphs to be decomposable. Based on this key property, a simple screening rule is presented, which reduces the size of the optimization problem, dramatically reducing the computational cost. / Dissertation/Thesis / Doctoral Dissertation Computer Science 2014

Health care represents an increasing proportion of global consumption. We discuss ways to model health care utilization on an individual basis. We present a probabilistic, generative model of utilization. Leveraging previously observed utilization levels, we learn a latent structure that can be used to accurately understand risk and make predictions. We evaluate the effectiveness of the model using data from a large population.

Structural equation modelling (SEM) is carried out with the aim of testing hypotheses on the model of the researcher in a quantitative way, using the sampled data. Although SEM has developed in many aspects over the past few decades, there are still numerous advances which can make SEM an even more powerful technique. We propose representing the nal theoretical SEM by a Bayesian Network (BN), which we would like to call a Probabilistic Structural Equation Model (PSEM). With the PSEM, we can take things a step further and conduct inference by explicitly entering evidence into the network and performing di erent types of inferences. Because the direction of the inference is not an issue, various scenarios can be simulated using the BN. The augmentation of SEM with BN provides signi cant contributions to the eld. Firstly, structural learning can mine data for additional causal information which is not necessarily clear when hypothesising causality from theory. Secondly, the inference ability of the BN provides not only insight as mentioned before, but acts as an interactive tool as the `what-if' analysis is dynamic. / Mini Dissertation (MCom)--University of Pretoria, 2018. / Statistics / MCom / Unrestricted

An influence diagram is a widely-used graphical model for representing and solving problems of sequential decision making under imperfect information. A closely-related model for the same class of problems is a partially observable Markov decision process (POMDP). This dissertation leverages the relationship between these two models to develop improved algorithms for solving influence diagrams. The primary contribution is to generalize two classic dynamic programming algorithms for solving influence diagrams, Arc Reversal and Variable Elimination, by integrating them with a dynamic programming technique originally developed for solving POMDPs. This generalization relaxes constraints on the ordering of the steps of these algorithms in a way that dramatically improves scalability, especially in solving complex, multi-stage decision problems. A secondary contribution is the adoption of a more compact and intuitive representation of the solution of an influence diagram, called a strategy. Instead of representing a strategy as a table or as a tree, a strategy is represented as an acyclic graph, which can be exponentially more compact, making the strategy easier to interpret and understand.

The advent of multi-photon microscopes and highly sensitive protein sensors enables the recording of astrocyte activities on a large population of cells over a long-time period in vivo. Existing tools cannot fully characterize these activities, both within single cells and at the population-level, because of the insufficiency of current region-of-interest-based approaches to describe the activity that is often spatially unfixed, size-varying, and propagative. Here, we present Astrocyte Quantitative Analysis (AQuA), an analytical framework that releases astrocyte biologists from the ROI-based paradigm. The framework takes an event-based perspective to model and accurately quantify the complex activity in astrocyte imaging datasets, with an event defined jointly by its spatial occupancy and temporal dynamics. To model the signal propagation in astrocyte, we developed graphical time warping (GTW) to align curves with graph-structured constraints and integrated it into AQuA. To make AQuA easy to use, we designed a comprehensive software package. The software implements the detection pipeline in an intuitive step by step GUI with visual feedback. The software also supports proof-reading and the incorporation of morphology information. With synthetic data, we showed AQuA performed much better in accuracy compared with existing methods developed for astrocytic data and neuronal data. We applied AQuA to a range of ex vivo and in vivo imaging datasets. Since AQuA is data-driven and based on machine learning principles, it can be applied across model organisms, fluorescent indicators, experimental modes, and imaging resolutions and speeds, enabling researchers to elucidate fundamental astrocyte physiology. / Doctor of Philosophy / Astrocyte is an important type of glial cell in the brain. Unlike neurons, astrocyte cannot be electrically excited. However, the concentrations of many different molecules inside and near astrocytes change over space and time and show complex patterns. Recording, analyzing, and deciphering these activity patterns enables the understanding of various roles astrocyte may play in the nervous system. Many of these important roles, such as sensory-motor integration and brain state modulation, were traditionally considered the territory of neurons, but recently found to be related to astrocytes. These activities can be monitored in the intracellular and extracellular spaces in either brain slices and living animals, thanks to the advancement of microscopes and genetically encoded fluorescent sensors. However, sophisticated analytical tools lag far behind the impressive capability of generating the data. The major reason is that existing tools are all based on the region-of-interest-based (ROI) approach. This approach assumes the field of view can be segmented to many regions, and all pixels in the region should be active together. In neuronal activity analysis, all pixels in an ROI (region of interest) correspond to a neuron and are assumed to share a common activity pattern (curve). This is not true for astrocyte activity data because astrocyte activities are spatially unfixed, size-varying, and propagative. In this dissertation, we developed a framework called AQuA to detect the activities directly. We designed an accurate and flexible detection pipeline that works with different types of astrocyte activity data sets. We designed a machine learning model to characterize the signal propagation for the pipeline. We also implemented a compressive and user-friendly software package. The advantage of AQuA is confirmed in both simulation studies and three different types of real data sets.

No description available.

In the past years, several network reconstruction methods modeled as Gaussian Graphical Model in high dimensional settings where proposed. In this work we will analyze three different methods, the Graphical Lasso (GLasso), Graphical Ridge (GGMridge) and a novel method called LPC, or Local Partial Correlation. The evaluation will be performed in high dimensional data generated from different simulated random graph structures (Erdos-Renyi, Barabasi-Albert, Watts-Strogatz ), using Receiver Operating Characteristic or ROC curve. We will also apply the methods in the reconstruction of genetic co-expression network for the differentially expressed genes in cervical cancer tumors. / Vários métodos tem sido propostos para a reconstrução de redes em alta dimensão, que e tratada como um Modelo Gráfico Gaussiano. Neste trabalho vamos analisar três métodos diferentes, o método Graphical Lasso (GLasso), Graphical Ridge (GGMridge) e um novo método chamado LPC, ou Correlação Parcial Local. A avaliação será realizada em dados de alta dimensão, gerados a partir de grafos aleatórios (Erdos-Renyi, Barabasi-Albert, Watts-Strogatz ), usando Receptor de Operação Característica, ou curva ROC. Aplicaremos também os metidos apresentados, na reconstrução da rede de co-expressão gênica para tumores de câncer cervical.