Statistical Methods For Detecting Genetic Risk Factors of a Disease with Applications to Genome-Wide Association Studies

This thesis aims to develop various statistical methods for analysing the data derived from genome wide association studies (GWAS). The GWAS often involves genotyping individual human genetic variation, using high-throughput genome-wide single nucleotide polymorphism (SNP) arrays, in thousands of individuals and testing for association between those variants and a given disease under the assumption of common disease/common variant. Although GWAS have identified many potential genetic factors in the genome that affect the risks to complex diseases, there is still much of the genetic heritability that remains unexplained. The power of detecting new genetic risk variants can be improved by considering multiple genetic variants simultaneously with novel statistical methods. Improving the analysis of the GWAS data has received much attention from statisticians and other scientific researchers over the past decade. There are several challenges arising in analysing the GWAS data. First, determining the risk SNPs might be difficult due to non-random correlation between SNPs that can inflate type I and II errors in statistical inference. When a group of SNPs are considered together in the context of haplotypes/genotypes, the distribution of the haplotypes/genotypes is sparse, which makes it difficult to detect risk haplotypes/genotypes in terms of disease penetrance. In this work, we proposed four new methods to identify risk haplotypes/genotypes based on their frequency differences between cases and controls. To evaluate the performances of our methods, we simulated datasets under wide range of scenarios according to both retrospective and prospective designs. In the first method, we first reconstruct haplotypes by using unphased genotypes, followed by clustering and thresholding the inferred haplotypes into risk and non-risk groups with a two-component binomial-mixture model. In the method, the parameters were estimated by using the modified Expectation-Maximization algorithm, where the maximisation step was replaced the posterior sampling of the component parameters. We also elucidated the relationships between risk and non-risk haplotypes under different modes of inheritance and genotypic relative risk. In the second method, we fitted a three-component mixture model to genotype data directly, followed by an odds-ratio thresholding. In the third method, we combined the existing haplotype reconstruction software PHASE and permutation method to infer risk haplotypes. In the fourth method, we proposed a new way to score the genotypes by clustering and combined it with a logistic regression approach to infer risk haplotypes. The simulation studies showed that the first three methods outperformed the multiple testing method of (Zhu, 2010) in terms of average specificity and sensitivity (AVSS) in all scenarios considered. The logistic regression methods also outperformed the standard logistic regression method. We applied our methods to two GWAS datasets on coronary artery disease (CAD) and hypertension (HT), detecting several new risk haplotypes and recovering a number of the existing disease-associated genetic variants in the literature

Search for Risk Haplotype Segments with GWAS Data by Use of Finite Mixture Models

The region-based association analysis has been proposed to capture the collective behavior of sets of variants by testing the association of each set instead of individual variants with the disease. Such an analysis typically involves a list of unphased multiple-locus genotypes with potentially sparse frequencies in cases and controls. To tackle the problem of the sparse distribution, a two-stage approach was proposed in literature: In the first stage, haplotypes are computationally inferred from genotypes, followed by a haplotype co-classification. In the second stage, the association analysis is performed on the inferred haplotype groups. If a haplotype is unevenly distributed between the case and control samples, this haplotype is labeled as a risk haplotype. Unfortunately, the in-silico reconstruction of haplotypes might produce a proportion of false haplotypes which hamper the detection of rare but true haplotypes. Here, to address the issue, we propose an alternative approach: In Stage 1, we cluster genotypes instead of inferred haplotypes and estimate the risk genotypes based on a finite mixture model. In Stage 2, we infer risk haplotypes from risk genotypes inferred from the previous stage. To estimate the finite mixture model, we propose an EM algorithm with a novel data partition-based initialization. The performance of the proposed procedure is assessed by simulation studies and a real data analysis. Compared to the existing multiple Z-test procedure, we find that the power of genome-wide association studies can be increased by using the proposed procedure

Business Value Is not only Dollars - Results from Case Study Research on Agile Software Projects

Business value is a key concept in agile software development. This paper presents results of a case study on how business value and its creation is perceived in the context of agile projects. Our overall conclusion is that the project participants almost never use an explicit and structured approach to guide the value creation throughout the project. Still, the application of agile methods in the studied cases leads to satisfied clients. An interesting result of the study represents the fact that the agile process of many projects differs significantly from what is described in the agile practitioners’ books as best practices. The key implication for research and practice is that we have an incentive to pursue the study of value creation in agile projects and to complement it by providing guidelines for better client’s involvement, as well as by developing structured methods that will enhance the value-creation in a project

Integrating memory context into personal information re-finding

Personal information archives are emerging as a new challenge for information retrieval (IR) techniques. The user’s memory plays a greater role in retrieval from person archives than from other more traditional types of information collection (e.g. the Web), due to the large overlap of its content and individual human memory of the captured material. This paper presents a new analysis on IR of personal archives from a cognitive perspective. Some existing work on personal information management (PIM) has begun to employ human memory features into their IR systems. In our work we seek to go further, we assume that for IR in PIM system terms can be weighted not only by traditional IR methods, but also taking the user’s recall reliability into account. We aim to develop algorithms that combine factors from both the system side and the user side to achieve more effective searching. In this paper, we discuss possible applications of human memory theories for this algorithm, and present results from a pilot study and a proposed model of data structure for the HDMs achieves

Industry-scale application and evaluation of deep learning for drug target prediction

Artificial intelligence (AI) is undergoing a revolution thanks to the breakthroughs of machine learning algorithms in computer vision, speech recognition, natural language processing and generative modelling. Recent works on publicly available pharmaceutical data showed that AI methods are highly promising for Drug Target prediction. However, the quality of public data might be different than that of industry data due to different labs reporting measurements, different measurement techniques, fewer samples and less diverse and specialized assays. As part of a European funded project (ExCAPE), that brought together expertise from pharmaceutical industry, machine learning, and high-performance computing, we investigated how well machine learning models obtained from public data can be transferred to internal pharmaceutical industry data. Our results show that machine learning models trained on public data can indeed maintain their predictive power to a large degree when applied to industry data. Moreover, we observed that deep learning derived machine learning models outperformed comparable models, which were trained by other machine learning algorithms, when applied to internal pharmaceutical company datasets. To our knowledge, this is the first large-scale study evaluating the potential of machine learning and especially deep learning directly at the level of industry-scale settings and moreover investigating the transferability of publicly learned target prediction models towards industrial bioactivity prediction pipelines.Web of Science121art. no. 2

2017 Texas Bays and Estuaries Meeting

Program for the 2017 Texas Bays and Estuaries Meeting held in Port Aransas, Texas, April 12-13, 2017.Coastal Bend Bays & Estuaries Program, Coastal Bend Bays Foundation, The University of Texas Marine Science Institute, Sea Grant Texas at Texas A&M University, Harte Research Institute for Gulf of Mexico Studies, and Mission Aransas National Estuarine Research Reserve.Marine Scienc