Christina Nieuwoudt

Title: Simulation and Statistical Methods for Family-Based Sequencing Studies
Date: September 13, 2021
Time: 9:30 am (PDT)
Location: Remote delivery

Abstract

Motivated by the BC Cancer Center’s Lymphoid Cancer Families Study, this dissertation focuses on simulation and statistical methods for family-based sequencing studies. This work is organized in three parts. First, we present methodology to simulate pedigrees ascertained for multiple disease-affected relatives. By incorporating the ascertainment process in the simulation we can better understand the within-family patterns of relationship amongst disease-affected individuals and ages-of-disease onset. Through simulation, we show that affected members of a family segregating a causal rare variant tend to be more numerous and cluster in relationships more closely than those for sporadic disease. We also show that the family ascertainment process can lead to apparent anticipation in the age of onset. Additionally, we use simulation to gain insight into the limit on the proportion of ascertained families segregating a causal rare variant. Next, we propose methodology to simulate sequences conditional on the carrier status of a causal variant. The proposed methodology also allows for allelic or genetic heterogeneity across families with additional functionality to simulate causal rare variants in a pathway. Finally, we present several methodological approaches to prioritize rare variants observed in disease-affected relatives of a family-based study. We build on existing methods and offer several approaches to prioritize rare variants shared among disease subgroups.

Keywords: family-based studies; pedigree simulation; ascertainment bias; anticipation; sequence data simulation; rare-variant analyses