Secondary Analysis of Case-Control Studies in Genomic Contexts

This dissertation consists of five independent projects. In each project, a novel statistical method was developed to address a practical problem encountered in genomic contexts. For example, we considered testing for constant nonparametric effects in a general semiparametric regression model in genetic epidemiology; analyzed the relationship between covariates in the secondary analysis of case-control data; performed model selection in joint modeling of paired functional data; and assessed the prediction ability of genes in gene expression data generated by the CodeLink System from GE. In the first project in Chapter II we considered the problem of testing for constant nonparametric effects in a general semiparametric regression model when there is the potential for interaction between the parametrically and nonparametrically modeled variables. We derived a generalized likelihood ratio test for this hypothesis, showed how to implement it, and gave evidence that it can improve statistical power when compared to standard partially linear models. The second project in Chapter III addressed the issue of score testing for the independence of X and Y in the second analysis of case-control data. The semiparametric efficient approaches can be used to construct semiparametric score tests, but they suffer from a lack of robustness to the assumed model for Y given X. We showed how to adjust the semiparametric score test to make its level/Type I error correct even if the assumed model for Y given X is incorrect, and thus the test is robust. The third project in Chapter IV took up the issue of estimation of a regression function when Y given X follows a homoscedastic regression model. We showed how to estimate the regression parameters in a rare disease case even if the assumed model for Y given X is incorrect, and thus the estimates are model-robust. In the fourth project in Chapter V we developed novel AIC and BIC-type methods for estimating the smoothing parameters in a joint model of paired, hierarchical sparse functional data, and showed in our numerical work that they are many times faster than 10-fold crossvalidation while at the same time giving results that are remarkably close to the crossvalidated estimates. In the fifth project in Chapter VI we introduced a practical permutation test that uses cross-validated genetic predictors to determine if the list of genes in question has ?good? prediction ability. It avoids overfitting by using cross-validation to derive the genetic predictor and determines if the count of genes that give ?good? prediction could have been obtained by chance. This test was then used to explore gene expression of colonic tissue and exfoliated colonocytes in the fecal stream to discover similarities between the two.