Comparing Direct and Indirect Methods for Cascade Screening in Familial Hypercholesterolemia (FH) and Long QT Syndrome (LQTS)

PROJECT SUMMARY An important aspect of successful genomic medicine implementation is developing effective approaches for screening at-risk family members after probands are identified, also known as cascade screening. Most cascade screening studies conducted to date have been conducted outside the US, and very few studies have used a rigorous approach involving a comparator group or randomized controlled design. As such, a critical gap exists in our knowledge of the most effective delivery strategies of cascade screening and their ethical acceptability. The goal of the research we propose is to compare direct (i.e., contacting relatives of probands directly by study team) vs indirect (i.e., traditional, proband-initiated contact) implementation of cascade screening using familial hypercholesterolemia (FH) and Long QT Syndrome (LQTS) as model cases. We will focus on screening two pathogenic variants, KCNQ1 Met224Thr, which causes LQTS, and APOB Arg3527Gln, a variant known to cause FH. Both variants have a high carrier frequency (2% and 12%, respectively) in the Amish due to founder effects. Cascade screening for FH is recommended as a tier 1 condition by the Centers for Disease Control and Prevention. This very large number of subjects carrying the same actionable variants for LQTS and FH, coupled with our history of engagement in the Amish community, provides an outstanding opportunity to address the knowledge gap. Specifically, we will conduct a randomized controlled trial of participants with pathogenic variants causing LQTS and FH to compare direct vs indirect methods for cascade screening coupled with implementation evaluation outcomes to assess the ethical and social impacts of the intervention. We hypothesize that, compared to traditional proband-initiated contact, direct contact will lead to greater efficiency of cascade screening, greater patient knowledge, and promote autonomous decision-making by relatives, while still maintaining acceptable levels of privacy and autonomy. In Aim 1 we will assess efficacy of the cascade screening strategies by comparing uptake in the direct versus indirect arms. In Aim 2 we will assess the mode of contact on self-reported alignment with ethical principles, anxiety, perceived pressure to undergo testing, and knowledge of disease. Aim 3 will characterize implementation evaluation outcomes such as reach, fidelity, and cost of the two contact approaches based on the RE-AIM Framework (reach, effectiveness, adoption, implementation, maintenance) and CFIR (Consolidated Framework for Implementation Research).