Simple Algorithms to Calculate Asymptotic Null Distributions of Robust Tests in Case-Control Genetic Association Studies in R

The case-control study is an important design for testing association between genetic markers and a disease. The Cochran-Armitage trend test (CATT) is one of the most commonly used statistics for the analysis of case-control genetic association studies. The asymptotically optimal CATT can be used when the underlying genetic model (mode of inheritance) is known. However, for most complex diseases, the underlying genetic models are unknown. Thus, tests robust to genetic model misspecification are preferable to the model-dependant CATT. Two robust tests, MAX3 and the genetic model selection (GMS), were recently proposed. Their asymptotic null distributions are often obtained by Monte-Carlo simulations, because they either have not been fully studied or involve multiple integrations. In this article, we study how components of each robust statistic are correlated, and find a linear dependence among the components. Using this new finding, we propose simple algorithms to calculate asymptotic null distributions for MAX3 and GMS, which greatly reduce the computing intensity. Furthermore, we have developed the R package Rassoc implementing the proposed algorithms to calculate the empirical and asymptotic p values for MAX3 and GMS as well as other commonly used tests in case-control association studies. For illustration, Rassoc is applied to the analysis of case-control data of 17 most significant SNPs reported in four genome-wide association studies.

Simple Algorithms to Calculate Asymptotic Null Distributions of Robust Tests in Case-Control Genetic Association Studies in R

The case-control study is an important design for testing association between genetic markers and a disease. The Cochran-Armitage trend test (CATT) is one of the most commonly used statistics for the analysis of case-control genetic association studies. The asymptotically optimal CATT can be used when the underlying genetic model (mode of inheritance) is known. However, for most complex diseases, the underlying genetic models are unknown. Thus, tests robust to genetic model misspecification are preferable to the model-dependant CATT. Two robust tests, MAX3 and the genetic model selection (GMS), were recently proposed. Their asymptotic null distributions are often obtained by Monte-Carlo simulations, because they either have not been fully studied or involve multiple integrations. In this article, we study how components of each robust statistic are correlated, and find a linear dependence among the components. Using this new finding, we propose simple algorithms to calculate asymptotic null distributions for MAX3 and GMS, which greatly reduce the computing intensity. Furthermore, we have developed the R package <b>Rassoc</b> implementing the proposed algorithms to calculate the empirical and asymptotic <i>p</i> values for MAX3 and GMS as well as other commonly used tests in case-control association studies. For illustration, <b>Rassoc</b> is applied to the analysis of case-control data of 17 most significant SNPs reported in four genome-wide association studies

The application of ordinal regression models in quality of life scales used in gerontology

Aim of the Thesis: The area of health-related quality of life has received increasing attention particularly in gerontology. As this area grows in importance, issues such as the design and analysis of instruments that measure this multi-dimensional outcome need to be addressed. Ordinal regression models are statistical methods that can be used to analyse ordered health-related quality of life measures. However, their use is limited in the literature. The aims of this thesis are (i) to compute all ordinal regression models and compare these models with other statistical methods (such as linear regression and binary logistic regression models) and (ii) assess the use of the stereotype ordinal regression model. Procedure: The data used to implement the regression models was from the Medical Research Council Cognitive and Function Ageing Study (MRC CFAS). In particular, two measures were chosen: the Townsend Disability Scale and the Health Status question. Results: Linear regression models were found to summarise the ordinal data inadequately given both ordinal measures. Binary logistic regression models were only adequate for analysing ordinal quality of life scales, if one could assume that the odds ratios were the same over all the binary groupings of the ordinal scale. However, one may still encounter other problems related to multiple testing or different effects in different models. Ordinal regression models provide a more sensitive and comprehensive analysis. These methods are easily adapted to different types of ordinal quality of life data. The 'best-fit' ordinal regression model for the health status ordinal categories was the partially constrained adjacent category model. The 'best-fit' model for the Townsend Disability Scale was the fully constrained continuation ratio model. Conclusions: This study has provided a method (based on first principles) of implementing all ordinal regression models. The comprehensive results from this thesis, suggest that ordinal regression models are indeed superior compared to other methods for analysing ordinal quality of life data. Evidence suggested that the stereotype model was of little use. Key words: Gerontology, health-related quality of life, ordinal regression models

Statistical Analysis in Art Conservation Research

Evaluates all components of data analysis and shows that statistical methods in conservation are vastly underutilized. Also offers specific examples of possible improvements

Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse

<p>Abstract</p> <p>Background</p> <p>Caloric restriction (CR) counters deleterious effects of aging and, for most mouse genotypes, increases mean and maximum lifespan. Previous analyses of microarray data have identified gene expression responses to CR that are shared among multiple mouse tissues, including the activation of anti-oxidant, tumor suppressor and anti-inflammatory pathways. These analyses have provided useful research directions, but have been restricted to a limited number of tissues, and have focused on individual genes, rather than whole-genome transcriptional networks. Furthermore, CR is thought to oppose age-associated gene expression patterns, but detailed statistical investigations of this hypothesis have not been carried out.</p> <p>Results</p> <p>Systemic effects of CR and aging were identified by examining transcriptional responses to CR in 17 mouse tissue types, as well as responses to aging in 22 tissues. CR broadly induced the expression of genes known to inhibit oxidative stress (e.g., <it>Mt1</it>, <it>Mt2</it>), inflammation (e.g., <it>Nfkbia</it>, <it>Timp3</it>) and tumorigenesis (e.g., <it>Txnip</it>, <it>Zbtb16</it>). Additionally, a network-based investigation revealed that CR regulates a large co-expression module containing genes associated with the metabolism and splicing of mRNA (e.g., <it>Cpsf6</it>, <it>Sfpq</it>, <it>Sfrs18</it>). The effects of aging were, to a considerable degree, similar among groups of co-expressed genes. Age-related gene expression patterns characteristic of most mouse tissues were identified, including up regulation of granulin (<it>Grn</it>) and secreted phosphoprotein 1 (<it>Spp1</it>). The transcriptional association between CR and aging varied at different levels of analysis. With respect to gene subsets associated with certain biological processes (e.g., immunity and inflammation), CR opposed age-associated expression patterns. However, among all genes, global transcriptional effects of CR were only weakly related to those of aging.</p> <p>Conclusion</p> <p>The study of aging, and of interventions thought to combat aging, has much to gain from data-driven and unbiased genomic investigations. Expression patterns identified in this analysis characterize a generalized response of mammalian cells to CR and/or aging. These patterns may be of importance in determining effects of CR on overall lifespan, or as factors that underlie age-related disease. The association between CR and aging warrants further study, but most evidence indicates that CR does not induce a genome-wide "reversal" of age-associated gene expression patterns.</p

Preliminary investigation of bald eagle distribution, productivity and nest site requirements in Northern Ontario

Bald eagles {Haliaeetus leucocephalus alascanus) have been declared an endangered species in Ontario. For protection of bald eagles from behavioural and habitat disturbance, their nests are defined as Areas of Concerns by the Ontario Government. To direct the management of these areas, the Ontario Ministry of Natural Resources reviewed the available literature and produced the Ontario Management Guidelines. However, the information available on Northern Ontario's bald eagles is limited, referring to the Lake of tire Woods Area only. To study bald eagles and evaluate Ontario's guidelines I gathered and analyzed data from across Northern Ontario on bald eagle habitat (1990, 1991, 1992), the effect of timber management on their reproduction (1990) and bald eagle distribution (1990). Data were analyzed univariately and I developed logistic regression models for topographical, limnological and vegetation characteristics. Variables important for defining the probability of a nest occurring include lake dimensions, stand density and tire availability of super-dominant, accessible perch trees. Of the models developed, two had practical implications: a limnological model which could be used to define potential foraging lakes and thus prevent unnecessary surveys and a vegetation model which could be used to evaluate habitat quality. Natality rates of bald eagles did not differ significantly among areas harvested according to guidelines, harvested without reference to the guidelines and undisturbed. The habitat features of forests, surrounding Northern Ontario bald eagle nest sites are similar to elsewhere except for a greater significance of perch trees. This justifies the Ontario Ministry of Natural Resource's use of available data, but the guidelines may underestimate the number of large perch and nest trees in optimal bald eagle habitat

The links between organisational strategy and project management: the process and the Key Decision Factors (KDF) of strategic projects implementation route selection

[Taken from document 5] This thesis has the main objectives of identifying the route selection process, used for choosing a method of strategic projects’ implementation, used in practice and assessing the relevant Key Decision Factors (KDF) in that decision making process. The study is based on conclusions from previous research documents and the latest findings from literature review. Past literature relied on neoclassical normative project management theory to provide a set of guiding principles, and focused on proximity to specific implementation directions. In modern literature, however, to the topic has been viewed through the prism of a different paradigm. Moreover, the qualitative research chosen in this study adopted a realist approach, attempting to understand the implementation routes phenomenon. This methodology comprised semi-structured interviews of participants, observation of three Greek organisations in the service sector, and collection of documents. Subsequently, data analysis called for results from qualitative research related to, and triangulated with, findings of literature review. As a result, a list of Key Decision Factors and the route selection framework was developed