The proposed project leverages our longstanding partnership with the Familial Hypercholesterolemia (FH)
Foundation, a nonprofit research and advocacy organization, to refine and test two promising approaches to
implement cascade screening in individuals with FH. Despite evidence-based guidelines for FH diagnosis and
treatment, over 1 million Americans with this inherited condition remain undiagnosed, and substantial disparities
exist with regard to racial/ethnic minorities (Black and African American people, Asian people) and gender
(women). Cascade screening is an evidence-based practice of contacting and screening first-degree biological
relatives of FH probands and improves timely FH diagnosis and reduces morbidity cost-effectively. Cascade
screening programs have been successful in other countries where health systems play a key role in notification
of relatives, but major implementation challenges limit uptake in the U.S. Pilot projects have identified barriers
including regulatory constraints limiting health system outreach and difficulty contacting family members outside
a given health system. In the U.S., cascade screening must involve the proband given regulatory constraints.
Applying advances in behavioral economics has great potential to improve implementation of cascade screening
via proband-mediated strategies. Led by MPIs with expertise in implementation science (Beidas), behavioral
economics (Volpp), and FH (Rader), we will co-design, pilot, and test two patient-facing implementation
strategies to increase reach of cascade screening with 300 probands within Penn Medicine. Our randomized
controlled trial will test (a) a health system-mediated strategy using automated text messages, (b) a FH
Foundation-mediated strategy using a navigator, and (c) the “usual care” approach to cascade screening. Both
active strategies will be informed by behavioral economics. In the R61 phase, we will co-design health system-
and FH Foundation-mediated implementation strategies using behavioral economics in partnership with the FH
Foundation and key stakeholders from diverse backgrounds (Aim 1) and then pilot our strategies with 20 FH
probands to ascertain feasibility, acceptability, and appropriateness (Aim 2). In the R33 phase, we will conduct
a 3-arm hybrid Type 3 effectiveness-implementation RCT, and compare the effect of health system-mediated,
FH Foundation-mediated, and usual care approaches on reach (proportion of probands who have at least one
family member who completes screening), number of family members screened, number of family members
diagnosed with FH, and proband LDL-C levels (Aim 1). We will use mixed methods to identify implementation
strategy mechanisms focusing on health equity by oversampling populations that experience disparities (Aim 2).
By testing sustainable and scalable implementation approaches, our study results will be poised to guide future
wide-scale implementation of cascade screening for FH and other genetic conditions within and outside large
health systems while also answering important questions related to equitable implementation. Successful
strategies can be taken to scale nationally to save lives, in keeping with NHLBI Strategic Objective 6.
