Likelihood ratio tests for association with multiple disease susceptibility alleles, genotyping errors, or missing parental data

by Morris, Richard Wayne.

MORRIS, RICHARD WAYNE. Likelihood ratio tests for association with multiple disease susceptibility alleles, genotyping errors, or missing parental data. (Under the direction of Norman L. Kaplan.) Multiple disease susceptibility alleles, genotype errors, or missing genotype data can create problems when testing for association between alleles or genotypes at a genetic marker and a dichotomous phenotype. I used likelihood methods to study the impact of each of these factors on detecting association. In the presence of multiple disease susceptibility alleles, I found that power of the likelihood ratio test (LRT) declines less when based on haplotypes made up of tightly linked single nucleotide polymorphisms (SNPs) than when based on individual SNPs. The result suggests that statistical methods based on haplotypes may be useful to identify and locate complex disease genes. Genotype errors can lead to excess type I error in nuclear family (caseparents) studies when errors resulting in Mendelian inconsistent families are corrected but other errors remain in the data. I developed a LRT for single SNPs or haplotypes that incorporates nuisance parameters for genotype errors and showed that type I error rate can be controlled at little cost to power. For nuclear family data in which missing parents and additional siblings create a diversity of family structures, I developed a unified approach to computing LRT power for a test of association. Comparison of LRT power with power of a family-based association test showed that LRT has greater power. 1 Likelihood Ratio Tests for Association with Multiple Disease Susceptibility Alleles, Genotyping Errors, or Missing Parental Data by Richard Wayne Morris A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Biomathematics Raleigh 2003 Approved by Norman L. Kaplan Co-Chair of Advisory Committee Jeffrey L. Thorne Co-Chair of Advisory Committee Bruce S. Weir Dahlia M. Nielsen 2 to Jackie …the adventure continues ii Biography I grew up in San Diego, California, and graduated from San Diego State University with a BS in Zoology. I then attended the University of California, Berkeley, and completed requirements for a PhD in Genetics, except for writing the dissertation. I moved to Raleigh, North Carolina, in 1978 and held various research positions in the Departments of Statistics and Genetics at North Carolina State University. I completed a Master of Statistics at NCSU in 1984 and worked on statistical problems in toxicology in a contract-research environment for 17 years. I entered the PhD program in Biomathematics in 1994 and continued to work full time while pursuing coursework in statistics and mathematics. I joined the Biostatistics Branch at the National Institute of Environmental Health Sciences in 2001 and completed a PhD in Biomathematics in 2003. iii