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).
