Bayesian methodology for genetics of complex diseases

Genetic research of complex diseases is a challenging, but exciting, area of research. The early development of the research was limited, however, until the completion of the Human Genome and HapMap projects, along with the reduction in the cost of genotyping, which paves the way for understanding the genetic composition of complex diseases. In this thesis, we focus on the statistical methods for two aspects of genetic research: phenotype definition for diseases with complex etiology and methods for identifying potentially associated Single Nucleotide Polymorphisms (SNPs) and SNP-SNP interactions. With regard to phenotype definition for diseases with complex etiology, we firstly investigated the effects of different statistical phenotyping approaches on the subsequent analysis. In light of the findings, and the difficulties in validating the estimated phenotype, we proposed two different methods for reconciling phenotypes of different models using Bayesian model averaging as a coherent mechanism for accounting for model uncertainty. In the second part of the thesis, the focus is turned to the methods for identifying associated SNPs and SNP interactions. We review the use of Bayesian logistic regression with variable selection for SNP identification and extended the model for detecting the interaction effects for population based case-control studies. In this part of study, we also develop a machine learning algorithm to cope with the large scale data analysis, namely modified Logic Regression with Genetic Program (MLR-GEP), which is then compared with the Bayesian model, Random Forests and other variants of logic regression.

A Monte-Carlo tree search in argumentation

Monte-Carlo Tree Search (MCTS) is a heuristic to search in large trees. We apply it to argumentative puzzles where MCTS pursues the best argumentation with respect to a set of arguments to be argued. To make our ideas as widely applicable as possible, we integrate MCTS to an abstract setting for argumentation where the content of arguments is left unspecified. Experimental results show the pertinence of this integration for learning argumentations by comparing it with a basic reinforcement learning.

A Python package for Bayesian estimation using Markov Chain Monte Carlo

Markov chain Monte Carlo (MCMC) estimation provides a solution to the complex integration problems that are faced in the Bayesian analysis of statistical problems. The implementation of MCMC algorithms is, however, code intensive and time consuming. We have developed a Python package, which is called PyMCMC, that aids in the construction of MCMC samplers and helps to substantially reduce the likelihood of coding error, as well as aid in the minimisation of repetitive code. PyMCMC contains classes for Gibbs, Metropolis Hastings, independent Metropolis Hastings, random walk Metropolis Hastings, orientational bias Monte Carlo and slice samplers as well as specific modules for common models such as a module for Bayesian regression analysis. PyMCMC is straightforward to optimise, taking advantage of the Python libraries Numpy and Scipy, as well as being readily extensible with C or Fortran.

A pseudo-marginal sequential Monte Carlo algorithm for random effects models in Bayesian sequential design

A computationally efficient sequential Monte Carlo algorithm is proposed for the sequential design of experiments for the collection of block data described by mixed effects models. The difficulty in applying a sequential Monte Carlo algorithm in such settings is the need to evaluate the observed data likelihood, which is typically intractable for all but linear Gaussian models. To overcome this difficulty, we propose to unbiasedly estimate the likelihood, and perform inference and make decisions based on an exact-approximate algorithm. Two estimates are proposed: using Quasi Monte Carlo methods and using the Laplace approximation with importance sampling. Both of these approaches can be computationally expensive, so we propose exploiting parallel computational architectures to ensure designs can be derived in a timely manner. We also extend our approach to allow for model uncertainty. This research is motivated by important pharmacological studies related to the treatment of critically ill patients.

Monte Carlo analysis of a puzzle game

When a puzzle game is created, its design parameters must be chosen to allow solvable and interesting challenges to be created for the player. We investigate the use of random sampling as a computationally inexpensive means of automated game analysis, to evaluate the BoxOff family of puzzle games. This analysis reveals useful insights into the game, such as the surprising fact that almost 100% of randomly generated challenges have a solution, but less than 10% will be solved using strictly random play, validating the inventor’s design choices. We show the 1D game to be trivial and the 3D game to be viable.

Effects of collimator backscatter in an Elekta linac by Monte Carlo simulation

The effects of radiation backscattered from the secondary collimators into the monitor chamber in an Elekta linac (producing 6 and 10 MV photon beams) are investigated using BEAMnrc Monte Carlo simulations. The degree and effects of this backscattered radiation are assessed by evaluating the changes to the calculated dose in the monitor chamber, and by determining a correction factor for those changes. Additionally, the fluency and energy characteristics of particles entering the monitor chamber from the downstream direction are evaluated by examining BEAMnrc phase-space data. It is shown that the proportion of particles backscattered into the monitor chamber is small (<0.35 %), for all field sizes studied. However, when the backscatter plate is removed from the model linac, these backscattered particles generate a noticeable increase in dose to the monitor chamber (up to approximate to 2.4 % for the 6 MV beam and up to 4.4 % for the 10 MV beam). With its backscatter plate in place, the Elekta linac (operating at 6 and 10 MV) is subject to negligible variation of monitor chamber dose with field size. At these energies, output variations in photon beams produced by the clinical Elekta linear accelerator can be attributed to head scatter alone. Corrections for field-size-dependence of monitor chamber dose are not necessary when running Monte Carlo simulations of the Elekta linac operating at 6 and 10 MV.

Population Monte Carlo Algorithm in High Dimensions

The population Monte Carlo algorithm is an iterative importance sampling scheme for solving static problems. We examine the population Monte Carlo algorithm in a simplified setting, a single step of the general algorithm, and study a fundamental problem that occurs in applying importance sampling to high-dimensional problem. The precision of the computed estimate from the simplified setting is measured by the asymptotic variance of estimate under conditions on the importance function. We demonstrate the exponential growth of the asymptotic variance with the dimension and show that the optimal covariance matrix for the importance function can be estimated in special cases.

A cost-based optimization of a fiberboard pressing plant using Monte-Carlo simulation (a reliability program)

In this research the reliability and availability of fiberboard pressing plant is assessed and a cost-based optimization of the system using the Monte- Carlo simulation method is performed. The woodchip and pulp or engineered wood industry in Australia and around the world is a lucrative industry. One such industry is hardboard. The pressing system is the main system, as it converts the wet pulp to fiberboard. The assessment identified the pressing system has the highest downtime throughout the plant plus it represents the bottleneck in the process. A survey in the late nineties revealed there are over one thousand plants around the world, with the pressing system being a common system among these plants. No work has been done to assess or estimate the reliability of such a pressing system; therefore this assessment can be used for assessing any plant of this type.