Understanding and Managing Genomic Uncertainty

Abstract

The overall aim of this dissertation was to study how patients understand and manage uncertainty in genomic medicine arising from Variants of Uncertain Significance, a type of genetic test result. Results from Chapter 2 suggest that, overall, the epistemological source of VUS uncertainty was well recognized by patients and these patients were also accepting of the prevalence of medical uncertainty in general. This acceptance gave them hope that VUS-related uncertainty is manageable would be resolved in future. Patients also identified several issues of VUS-related uncertainty such as implication for family members, and being informed about reclassification. We identified themes representing nearly all issue-related subdomains of Han’s taxonomy of uncertainty which demonstrates the wide range of diagnostic, prognostic, therapeutic and psychosocial difficulties that patients with VUS experience. More importantly however, patients also identified methods for managing VUS-related uncertainty. We organize the various provider and patient level management strategies into a provisional framework of uncertainty management strategies that identify patient and provider level approaches for VUS management. Chapter 3 offers a detailed examination of patients’ VUS-related information seeking behavior and its relation to VUS management behavior. We find that more than half of the survey respondents reported seeking VUS-related information and information from health care providers and cancer research organizations were preferred. In accordance with VUS-related management guidelines, most patients did not undergo surgery (61.8%) or screening (62.5%) based on VUS results, and the majority of patients (69.5%) did not check back for a VUS reclassification; 46.7% asked family members to get a genetic test because of their VUS result. Lack of association between information seeking and VUS management may be explained by the unavailability of actionable VUS information. Results from Chapter 4 showed that men and women are equally knowledgeable about genomic sequencing, and report equal frequency of current familial communication of Colorectal Cancer and Polyposis (CRCP) risk and express future intention to share CRCP related genomic test results with family members. Factual genomic knowledge explained only a small proportion of variation in familial communication of CRCP risk. Application of these findings to VUS family studies requires additional considerations. For example, VUS are a particularly challenging group of variants to communicate to family members and two major barriers to communicating VUS test results are – perception that VUS has no genetic or medical implication for family members, and that probands themselves are ambiguous about the result and thus do not feel confident about sharing. Results from this dissertation add to our understanding of how is VUS-related uncertainty is perceived and managed by patients, how information seeking is used as an uncertainty management strategy and its relationship with VUS management behavior. One specific VUS management strategy is to participate in family studies of variant reclassification that require familial communication - we explore genomic knowledge and gender as determinants of familial communication of genetic risk.