Treffer: Optimization methods for effective whole-exome sequencing association study

Ph.D. ; Genome-wide association studies (GWAS) have been successful to identify a great number of genetic loci associated with complex diseases. The availability of large-scale sequencing studies and meta-analysis in the past few years bring forth even more findings. Despite the success, challenges still exist in both discovery and application of genetic markers for clinical practice. Beyond the scope of common variants in GWAS, recent studies, both theoretically and empirically, have proven the significant role of rare variants (Minor Allele Frequency (MAF) <1%) in disease etiology. Development of high-throughput technologies also enables the detection of highly informative rare variants through whole-exome sequencing (WES) and whole-genome sequencing (WGS) studies. It is plausible that the discovery of the new associations driven by rare variants would advance our knowledge of human complex diseases and, eventually move forward towards the goal of developing better treatments and personalized medicine. ; Current rare variant association tests improve the statistical power by combing information across multiple rare variants within a genomic functional unit (e.g. gene, exon). However, the power of major rare variant methods to discover associations is sensitive to variables such as choice of analysis unit and number of variants. A direct application of rare variant analysis based on a gene often leads to power loss as the existence of noises with neutral variants. To address this issue, we propose two optimization methods in Chapter 2-5, a Zoom-Focus Algorithm (ZFA) and a fuzzy Zoom-Focus Algorithm (fuzzy ZFA) as an extension, to optimize the testing region of rare variant methods such that minimum unnecessary noises are included and the statistical power could be therefore enhanced. Specifically, Chapter 2 and 3 describe the methodologies and simulation studies of ZFA and fuzzy ZFA, respectively. The simulation results demonstrate that the optimization methods could improve the power of rare variant methods ...