Knowledge Translation in the Era of Precision Diagnostics: Examining the Use of Clinical Exome and Genome Sequencing for Rare Genetic Disease Diagnosis

Abstract

In just over a decade, exome sequencing and genome sequencing (ES/GS) has transitioned from a research method to an implemented test for patients with suspected rare genetic diseases (RGDs) worldwide, and healthcare systems are challenged to optimize its use within their jurisdictions. This thesis aimed to examine the rapidly evolving scientific evidence base related to ES/GS and how it has been translated into diagnostic care for families with RGDs to inform practice and policy in the future. Guided by the Knowledge-to-Action (KTA) conceptual framework, I designed and conducted three original studies: two aimed to generate evidence related to the KTA concept of Knowledge Creation, and the third studied the Action Cycle. In Article 1, we examined the knowledge base and determined that evidence related to the etiologies of RGDs and analytical processes related to ES/GS testing are progressing at a pace that has diagnostic implications. Next, in Article 2, we examined knowledge refinement and found that one knowledge user, organizations representing genetics professionals, have produced clinical recommendations related to a broad range of topics connected to ES/GS for RGD diagnosis, but the quality of clinical guidance documents is low, overall, and with specific reference to the rigour of the methods developers used. Finally, in Article 3, we studied the Action Cycle and found that implementing publicly-funded ES/GS using a set of clinical eligibility criteria in the Ontario healthcare system resulted in clinically-valid diagnoses for patients that met provincial benchmarks for diagnostic yield. Together, the results of these studies informed eight considerations for optimizing ES/GS testing with implications for healthcare practitioners, patients, guidance developers, payers, and researchers. Importantly, this thesis provides evidence of the necessity for continued evaluation and improved guidance development related to ES/GS to optimize this testing. It offers a foundation for future studies that may investigate knowledge translation into policy and practice in this and other rapidly evolving fields. Ultimately, these findings will enable better diagnostic care for families with RGDs.