Leveraging Behavioral Economics to Equitably Implement Cascade Screening in Individuals With Familial Hypercholesterolemia in Partnership With the Family Heart Foundation
Conditions: Familial Hypercholesterolemia
Sponsor: Northwestern University

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Protocol Title: Leveraging behavioral economics to equitably implement cascade screening in 
individuals with familial hypercholesterolemia in partnership with the Family Heart Foundation 
 
 
NCT05430191 
 
 
Document Date: October 20, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Title: Leveraging behavioral economics to equitably implement cascade screening in 
individuals with familial hypercholesterolemia in partnership with the Family Heart Foundation 
 
Principal Investigators 
• 
Kevin Volpp, MD, PhD volpp70@wharton.upenn.edu 
• 
Rinad Beidas, PhD rinad.beidas@northwestern.edu 
• 
Daniel Rader, MD rader@pennmedicine.upenn.edu 
 
Funding Sponsor: NHLBI (R61/R33 mechanism) 
NIH Grant Number:  R61HL161752 
IRB Number: 851061 
 
Table of Contents 
1 
INTRODUCTION ...................................................................................................................................... 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................................... 3 
2 
STUDY OBJECTIVES ................................................................................................................................. 5 
3 
INVESTIGATIONAL PLAN & DESIGN .......................................................................................................... 5 
3.1 
STUDY MEASURES ................................................................................................................................... 5 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ......................................................................... 6 
4.1 
ELIGIBILITY CRITERIA ................................................................................................................................ 6 
4.2 
SUBJECT RECRUITMENT ............................................................................................................................. 6 
5 
STUDY PROCEDURES ............................................................................................................................... 7 
5.1 
SUBJECT COMPENSATION .......................................................................................................................... 9 
5.2 
SUBJECT WITHDRAWAL ............................................................................................................................. 9 
6 
STATISTICAL PLAN .................................................................................................................................. 9 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................................ 9 
8 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING ....................................................... 10 
8.1 
CONFIDENTIALITY .................................................................................................................................. 10 
8.2 
DATA COLLECTION AND MANAGEMENT ....................................................................................................... 11 
8.3 
RISKS................................................................................................................................................. 12 
8.4 
BENEFITS ............................................................................................................................................ 13 
8.5 
RISK BENEFIT ASSESSMENT ...................................................................................................................... 13 
8.6 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ................................................................................. 13 
9 
STUDY FINANCES .................................................................................................................................. 14 
 
 
 

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1 
Introduction 
Familial hypercholesterolemia (FH) is a genetic disorder of cholesterol metabolism that affects one in 250 
(more than 1.3 million) American men, women, and children of all races and ethnicities. FH causes lifelong 
elevation of low-density lipoprotein cholesterol (LDL-C) (over 190 mg/dL) and increased risk for premature 
atherosclerotic cardiovascular disease (ASCVD), and is associated with a 10- to 20-fold increase in risk of 
major adverse cardiac events (myocardial infarction, coronary revascularization, stroke, or transient 
ischemic attack). Early diagnosis followed by proactive treatment can prevent or delay the onset of ASCVD 
and save lives. National Heart, Lung, and Blood Institute (NHLBI), and American Academy of Pediatrics 
recommend evidence-based guidelines for FH screening, diagnosis, and treatment, but despite this broad 
consensus, up to 90% of FH patients remain undiagnosed. Cascade screening is an evidence-based practice 
of contacting and screening relatives of individuals after their FH diagnosis; it improves timely diagnosis, 
reduces morbidity, and has been shown to be cost-effective in other countries. However, implementation 
in the U.S. is challenging due to regulatory restrictions and lack of a national healthcare system and thus, 
usual care in the U.S. relies on the proband (i.e. the first person in the family who receive an FH diagnosis) 
to contact family members and encourage FH screening. Improving implementation of cascade screening 
may have particular promise for subgroups of patients at risk of, or already experiencing, health inequities. 
Although improved identification and treatment of FH is needed for all groups, there is evidence of 
inequities in diagnosis and effective treatment among several sociodemographic groups, including Black 
or African American and Asian people, and women.  
 
The NHLBI awarded our team an R61/R33 grant to refine and test two promising approaches to implement 
cascade screening in partnership with the Family Heart Foundation (i.e. Family Heart), a nonprofit 
research and advocacy organization. As part of the R61 phase, we will co-design two patient-facing 
implementation strategies using behavioral economics in partnership with Family Heart and key partners 
from diverse backgrounds. We will then pilot our strategies with 20 patients with high cholesterol and/or 
FH to ascertain feasibility, acceptability, and appropriateness. As part of the R33 phase, we will conduct a 
3-arm hybrid Type 3 effectiveness-implementation randomized controlled trial. PLEASE NOTE: this 
protocol only outlines the R61 activities as this is a multiphase award from NHLBI. Before we begin any 
R33 activities, we will submit a modification to the IRB for review and approval.  
 
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. 
 
1.1 
Background and Relevant Literature  
FH is a genetic disorder of cholesterol metabolism that affects more than 1.3 million American men, 
women, and children of all races and ethnicities.1 One in 250 Americans have FH. It causes lifelong 
elevation of low-density lipoprotein cholesterol (LDL-C; >190 mg/dL in adults, >160 mg/dL in children) and 
increased risk for premature atherosclerotic cardiovascular disease (ASCVD), and is associated with a 10- 
to 20-fold increase in risk of major adverse cardiac events (myocardial infarction, coronary 
revascularization, stroke, or transient ischemic attack).2,3 Atherosclerosis begins in childhood, and in 
untreated patients, major cardiovascular events are common in middle adulthood.4,5 Early diagnosis 
followed by aggressive treatment can prevent or delay the onset of ASCVD and save lives. The American 
Heart Association, American College of Cardiology, Centers for Disease Control and Prevention (CDC), 
NHLBI, and American Academy of Pediatrics recommend evidence-based guidelines for FH screening, 
diagnosis, and treatment, but despite this broad consensus, up to 90% of FH patients remain 
undiagnosed.6 When a diagnosis is made, it often comes decades late. The Family Heart Foundation’s 
national longitudinal CASCADE FH® Registry initiative, the only one of its kind in the U.S., shows that the 

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average ages of statin initiation and FH diagnosis are 39 and 47, respectively, even though diagnosis and 
treatment can and should begin at ages 2 and 10, respectively.7 
 
Cascade screening—an evidence-based practice of contacting and screening relatives of individuals after 
their FH diagnosis—improves timely diagnosis, reduces morbidity, and has been shown to be cost-
effective in other countries.8,9,10,11,12,13,14 First-degree biological relatives (parents, siblings, children) have 
a 50% chance of having FH, and systematic testing facilitates early diagnosis and connection to care.15 
Each newly identified case becomes a proband for broader cascading.10 Family cascade screening is 
recommended by national and international bodies, and is a CDC Tier 1 genomic application with Grade 
A evidence-based recommendations.2,10,16 The most successful approach to cascade screening was 
implemented in the Netherlands.17 When a proband was identified and genetically confirmed, their 
contact information was shared with the Foundation for Tracing Hereditary Hypercholesterolemia, which 
served as a centralized coordinating body that contacted the proband to identify family members and 
then directly contacted family members for screening. The program identified 70% of FH cases 
nationwide. Its success is attributed, in part, to the direct contact with family members, which involved 
significant outreach outside of a visit-based healthcare model.17 
 
Despite the proven effectiveness of cascade screening in other countries and broad consensus on its 
importance, implementation in the U.S. is challenging.18 Due to regulatory restrictions and lack of a 
national healthcare system, usual care in the U.S. relies on probands to contact family members and 
encourage FH screening.19 In one of the few studies available,20 we randomized 240 individuals with a 
clinical diagnosis of FH to genetic testing for FH (n=160) or usual care with lipid testing alone (n=80). The 
primary study endpoint was the proportion of probands with at least one relative enrolled in the study 
within 1 year after notification of results. Despite active attempts to encourage cascade screening, only 
38 (15.8%) probands overall had at least one family member contact the study team and of these, only 28 
probands (11.7%) had at least one family member enroll. Overall, a total of only 43 family members (0.2 
family members per proband) were enrolled over the 12-month study period. These data demonstrate 
the challenges of cascade screening. The reasons for this include the need for the proband to be 
responsible for contacting and communicating medical information to family members, geographical and 
sometimes emotional dispersion of families, and the lack of incentive for the health system in which the 
proband is treated to ensure screening of family who are not a part of that system.  
 
Improving implementation of cascade screening may have particular promise for subgroups of patients at 
risk of, or already experiencing, health inequities. Although improved identification and treatment of FH 
is needed for all groups, there is evidence of inequities in diagnosis and effective treatment among several 
sociodemographic groups, including Black or African American people and Asian people, and women.21 
For example, Black people (across genders) and women were found to be diagnosed with FH several years 
later than average, and Black and Asian people were 50% less likely to achieve LDL-C<100 mg/dL.21 This is 
especially concerning because racial and ethnic minorities already experience notable inequities in 
incidence and treatment of other cardiovascular risk factors such as hypertension and diabetes, and 
women experience other inequities in cardiac care, such as less timely and accurate diagnosis of heart 
attacks.22,23,24,25,26,27,28,29 Low income is also a major risk factor for poor cardiovascular health.30,31 As a 
result, undetected FH likely represents compounded risk for these groups.46 At the same time, concerns 
among certain communities such as medical mistrust among those who have experienced discrimination32 
may influence acceptability of implementation approaches to cascade screening. For example, prior 
research in other areas of health behavior suggests that messaging from health systems may be less 
effective for Black men.33 Yet 74% of studies in a scoping review of the cascade screening literature did 
not include information on participants’ race or ethnicity, and none of those that did focused on racial 
and ethnic minority populations.34 In order to ensure that cascade screening efforts do not exacerbate 

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existing inequities, special attention to these concerns is warranted.35 Attending meaningfully to racial 
and ethnic inequities in FH identification and treatment is a key priority.36 
 
The latest advances in implementation science and behavioral economics have great potential to improve 
cascade screening by directly addressing identified barriers. Maximizing the effectiveness of cascade 
screening requires best practices from implementation science; attention to patient/family, clinician, and 
health system perspectives; effective engagement and utilization of strategies that facilitate contact with 
patients and their families outside of health care settings; and inclusion of key principles related to 
decision-making and behavior. The proposed project will integrate these fields to develop and pilot two 
implementation strategies that promote a centralized, direct contact approach: a health system-mediated 
strategy using automated text messages and a Family Heart Foundation-mediated strategy delivered by a 
navigator, outside of the healthcare setting.36 Prior to testing in an RCT during the R33 phase, both active 
conditions will be piloted and refined in the R61 phase using both partner feedback and behavioral 
economics principles that have been shown to increase uptake of desired health behaviors. By testing and 
directly comparing two scalable approaches, our study results will help to answer important questions 
about what strategies work for whom and will be poised to guide future wide-scale implementation of 
cascade screening for FH and other genetic conditions in large health systems as well as nationally outside 
of usual healthcare settings. Our strong partnership with the Family Heart Foundation will help successful 
strategies be taken to scale nationally to save lives. 
 
2 
Study Objectives 
We will design, refine, and pilot the two implementation approaches using behavioral economics and then 
seek further feedback prior to our proposed R33 clinical trial, consistent with these recommendations. 
• 
R61 Aim 1. Co-design both implementation strategies using behavioral economics in partnership 
with the Family Heart Foundation and key partners from diverse backgrounds. 
• 
R61 Aim 2. Pilot strategies with 20 patients with high cholesterol and/or with FH to ascertain 
feasibility, acceptability, appropriateness. 
 
3 
Investigational Plan & Design  
• 
R61 Aim 1. We will engage in interviews with patients with high cholesterol and/or FH, family 
members, and clinicians to identify common barriers and facilitators for individuals to engage in 
cascade screening. These activities will occur in the first 6 months and will serve as inputs into the 
design of the implementation strategies to ensure that strategies address determinants identified 
in the interviews.  
• 
R61 Aim 2. To maximize success, we will pilot test the implementation strategies and our planned 
data collection approaches.  
 
3.1 
Study Measures 
• 
R61 Aim 1. We developed a semi-structured interview guide, which received IRB approval.  
• 
R61 Aim 2. We developed a semi-structured interview guide to use after each mini pilot. We will 
assess feasibility, acceptability, and appropriateness of the implementation strategies via 3 
questionnaires that will be administered verbally during the interview (12 items total): Feasibility 
of Intervention Measure, Acceptability of Intervention Measure, and Intervention 
Appropriateness Measure. These 4-item psychometrically-validated measures capture the extent 
to which people believe an implementation strategy is feasible, acceptable, and appropriate.  We 
will also ask participants open-ended questions that elaborate on their responses to the 
quantitative measures. We will also ask about their perceptions of and experience with cascade 
screening, including barriers and facilitators. We will iterate to improve on each component 
during each mini-pilot based on responses during the qualitative interviews. 
 

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4 
Study Population and Duration of Participation  
• 
R61 Aim 1 (Interviews). We will conduct interviews with three groups (patients with high 
cholesterol and/or FH, family members, and clinicians [MDs, APPs]) to understand 
barriers and facilitators to cascade screening. 10 clinicians are being interviewed currently 
through our sister protocol 849516 (MPIs: Volpp, Beidas, Rader); in an effort to reduce 
interview burden on clinicians, the 849516 study team submitted a modification to add 
questions to their interview guide about barriers and facilitator for individuals to engage 
in cascade screening. As part of this protocol, we will focus on conducting interviews 
with 15 Penn Medicine patients with high cholesterol and/or FH and 10 family members. 
Duration of participation will last the length of one qualitative interview.  Aim 1 interviews 
will be completed by research team members at Penn.  
• 
R61 Aim 1 (Meeting – NOT HUMAN SUBJECT RESEARCH). We will convene a group of 10 
experts to review and discuss these findings, including people that represent the 
following perspectives: patients with high cholesterol and/or FH, family members, 
clinicians, setting leaders, implementation scientists, behavioral economists, and Family 
Heart Foundation leaders. We will prioritize diversity in the selection of people with 
regard to racial/ethnic minority background, gender, and income. We are not 
conceptualizing these 10 experts as research subjects, i.e. we will not be collecting any 
research data from these individuals. We are simply convening this meeting to help us 
discuss and refine the data collected during interviews to produce the behavioral 
roadmap that describes barriers to implementation of cascade screening and facilitates 
the development of the two implementation strategies we will pilot in Aim 2.  
• 
R61 Aim 2 (Pilot Testing Strategies). Participants will include 20 patients with high 
cholesterol and/or FH. At least half will identify as racial and/or ethnic minorities (i.e., 
Black or African American, Asian), female, and/or have low income. Patients will be 
randomized to receive the health system-mediated strategy or the Family Heart 
Foundation-mediated strategy. Duration of participation will last up to 1-2 months for 
each participant. Our goal is to have 20 patients complete the mini-pilots; we anticipate 
more than 20 patients will need to be enrolled in order to reach our target of 20 
completed participants (e.g., due to loss to follow-up and subject dropout). Study team 
members at Penn and Northwestern will collaborate closely to outreach participants and 
conduct these activities. Participants will be identified via Penn’s EHR and/or using the 
CASCADE FH registry (see more info here: https://familyheart.org/cascade-fh-registry-
clinical), which is a registry of patients who have FH and is maintained by the Family Heart 
Foundation. We would only outreach individuals from the registry who are Penn Medicine 
patients. 
 
 
4.1 
Eligibility Criteria 
• 
Patients with high cholesterol and/or FH (R61 Aims 1 and 2 Interviews and R61 Aim 2 Pilot 
Testing Strategies). Adults aged 18 and older with clinically diagnosed FH who are treated within 
Penn Medicine 
• 
Family Members (R61 Aims 1 and 2 interviews). Adults aged 18 and older who have a family 
member who has been identified as a patient with high cholesterol and/or FH who is treated 
within Penn Medicine  
 
4.2 
Subject Recruitment  
Our recruitment strategy does not target any populations defined by HHS regulations 45 CFR 46 subparts 
B, C, or D as vulnerable (i.e. children, pregnant women, fetuses, neonates, or prisoners) as part of this 
research study and thus this protocol does not require additional protection consideration. Our 

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recruitment strategy also does not target participants who are likely to be vulnerable to undue influence 
or coercion. Once all study documents are finalized and approved by the IRB, potential participants will 
receive an initial contact via email or phone by a research staff. We will follow-up no more than six 
additional times to recruit them to participate in this research protocol.    
• 
Patients with high cholesterol and/or FH (R61 Aims 1 and 2 Interviews and R61 Aim 2 Pilot 
Testing Strategies). Patients with high cholesterol and/or FH will be recruited from the University 
of Pennsylvania Health System (UPHS) which consists of six large hospitals including the Hospital 
of the University of Pennsylvania, Penn Presbyterian Medical Center, Pennsylvania Hospital, 
Chester County Hospital, Princeton Health, and Lancaster General Hospital. We will be recruiting 
from primary care and cardiology practices at UPHS throughout Pennsylvania and New Jersey. 
Target population: The UPHS population includes patients of mixed socioeconomic status. It is 
estimated that there are 18,000 patients at UPHS with FH (based on the national FH prevalence 
of one in 250). This will provide an ample population from which to perform the proposed clinical 
trial. Potentially eligible patients will be identified using data from the electronic health record 
(PennChart) and Clarity, PennChart’s reporting database.  
• 
Family Members (R61 Aims 1 and 2 interviews). Patients with high cholesterol and/or with FH 
will be asked to identify family members who would be willing to engage in an interview with our 
study team.  
 
5 
Study Procedures  
• 
R61 Aim 1 (Interviews).  
○ Individuals will be invited to complete an eligibility screen either through REDCap or the Way 
to Health platform along with an electronic consent (which will contain a contact phone 
number in case of questions), in keeping with prior studies. Patients can register electronically 
or directly with the study coordinator.  
○ Interviews will occur either by phone or videoconference to maximize convenience and 
participant preference. We will use purposive sampling to recruit 15 patients with high 
cholesterol and/or FH and 10 family members to ensure diversity in responses; however, we 
will continue interviewing until we reach thematic saturation. We will oversample for the 
following patient populations given established inequities: Black or African American 
individuals, Asian individuals, women of all races, and people with low income. We will also 
ensure diversity in age, given that privacy and health concerns may vary based on an 
individual’s stage of life or generation. Interviews will be digitally recorded with the 
participants’ permission.  
○ Interviews will be 30-60 minutes in length and will focus on how individuals understand 
cascade screening, barriers to engagement including reasons why individuals do and do not 
share health information with family members, and preferred approaches to engaging family 
members, with a focus on acceptability, appropriateness, and feasibility of our planned 
implementation strategies. We will attend to structural factors such as medical mistrust and 
experiences of racism in health care, and ask about preferences and logistics to incorporate 
preference into our R33 trial design. Our approach is consistent with the gold-standard 
approach that we have used in other studies. Acknowledging that individuals are not always 
able to report accurately on factors influencing their behavior, we will also deploy an 
approach used in previous work to infer behavioral barriers driving suboptimal 
implementation behavior.  
○ Participants will be compensated $25 via e-Clincard for engaging in this one time interview. 
○ Aim 1 interviews will be conducted by members of the Penn research team.  
• 
R61 Aim 1 (Behavioral Roadmap and Development of implementation strategies (NOT HUMAN 
SUBJECT RESEARCH). 

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○ Using the interview results and behavioral insights to understand clinician and patient 
decision-making, consistent with previous work, we will produce a behavioral roadmap that 
describes barriers to implementation of cascade screening. We will lay out the steps in the 
process where there appear to be hurdles and the behavioral biases that might be 
contributing to low rates of cascade screening. This roadmap will additionally account for 
organizational and system-level factors known to potentially hinder implementation of 
evidence-based practices. We anticipate developing two centralized direct contact 
implementation strategies leveraging interview insights and behavioral economics, one 
deployed within the health system context using an automated solution, the other deployed 
through Family Heart outside of healthcare settings using a navigator. We will use our findings 
from Aim 1 and begin the process of matching the observed barriers to implementation 
strategies informed by the implementation mapping approach (i.e. a systematic procedure 
we have successfully used in previous studies), to incorporate key literature, inputs from Aim 
1, and partner input. We will convene a half-day retreat with partners to present and refine 
our implementation strategies in anticipation of the R33 phase. Note, we do not 
conceptualize these activities as human subject research; rather these are activities that are 
required to produce the implementation strategies we will be testing in the Aim 2 pilots and 
ultimately in the R33 phase.   
• 
R61 Aim 2 (Pilot Testing Strategies).  
○ To “learn quickly and fail fast,” we will use rapid cycle approaches method, which is intended 
to accelerate development, initial testing, and refinement of an innovation (e.g., a new 
implementation strategy) to avoid investing potentially unnecessary time and resources at 
scale before determining whether that approach is effective. For example, in testing whether 
a wireless device could improve glycemic control, we first tested ways to increase initial 
engagement with the device. Rapid cycle approaches leverage observation and mini-pilots to 
learn how to design innovations to fit into real-world circumstances in an efficient, cost-
effective, and reliable way. The typical development and refinement process involves several 
cycles of concept definition, implementation of a minimally viable product, evaluation, and 
concept refinement. Given the cost of developing fully functioning implementation strategies, 
this is an ideal way to prototype strategies. 
○ We will refine the development of the content and delivery components of our two 
implementation strategies following mini-pilots. These mini-pilots will be conducted with 
approximately 4 patients per condition per week (n = approximately 8 per week). Following 
the establishment of the procedure, we anticipate that this process will unfold for up to six 
months and include up to 10 mini-pilots, where we will make systematic alterations to the 
implementation strategies following each pilot, based on feedback. One change will be made 
per mini-pilot. For example, during the first mini-pilot, a clinical research coordinator, acting 
as a “fake back end” for the Way to Health platform that delivers automated text messages, 
will deploy text messages with two patients and their family members and rapidly obtain their 
feedback on the timing, content, and tone of the messages. The other patients will engage 
with the Family Heart navigator and provide feedback on the timing, content, and tone of the 
discussions. During the next mini-pilot, we would enroll approximately 4 new patients with 
high cholesterol and/or FH per condition and make modifications based on the previous mini-
pilot. The goal of this will be to refine our 2 active implementation strategies. Both active 
implementation strategies will include centralized outreach to patients with high cholesterol 
and/or FH and direct contact with family members if preferred. Key differences include 
delivery modality (automated SMS messages vs. navigator) and centralization scheme (health 
system vs. a national organization). 
○ Regardless of implementation strategy, family members will be offered FH screening at no 
cost via a blood lipid panel or genetic test. Although this implementation strategy is 

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automated, study participants will also have the opportunity to directly contact research staff 
with questions.  
○ Aim 2 pilot testing strategies will be conducted by the Penn and Northwestern study teams 
working in close collaboration. 
• 
R61 Aim 2 (Interviews).  
○ We will invite patients and family members who participated in the mini-pilots to complete a 
one-time post-pilot interview. Interviews will occur either by phone or videoconference to 
maximize convenience and participant preference. Interviews will be digitally recorded with 
the participants’ permission. During interviews, participants will be asked questions from the 
Aim 2 interview guide as described above. We will obtain verbal informed consent before 
beginning the interviews. Interviews will be conducted by the Penn and/or Northwestern 
study teams. Interviews will last approximately 15-30 minutes. 
• 
 
 
5.1 
Subject Compensation 
• 
R61 Aim 1 (Interviews). Participants will be compensated $25 via e-Clincard for engaging in this 
one time interview.  
• 
R61 Aim 2 (Interviews). Participants will be compensated $25 via e-Clincard each time they 
complete an interview. Family members who complete a lipid panel or genetic test will also be 
compensated $25 via e-Clincard.  
 
5.2 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care.  They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to study 
instructions or unanticipated problems. The Investigator or the funding agency may also withdraw 
subjects who violate the study plan, to protect the subject for reasons related to safety, or for 
administrative reasons.  It will be documented if any subject is withdrawn and reason why. If participants 
request their data be destroyed, the study team will honor all requests. Otherwise, previously collected 
data will be used. The consent form will clearly state this information.  
 
6 
Statistical Plan 
• 
R61 Aim 1 & Aim 2 (Interview Analysis). Interview recordings will be professionally transcribed 
and loaded into QSR NVivo software for data management and analysis. Analysis will be guided 
by an integrated approach that includes identification of a priori attributes (i.e., constructs from 
the CFIR, Health Equity Framework, and behavioral economics) and modified grounded theory, 
which provides a rigorous, systematic approach to identifying emergent codes and themes. This 
integrated approach uses an inductive process of iterative coding. After initial exploration of data, 
a comprehensive coding scheme will be developed and applied to all data to produce a fine-
grained descriptive analysis. Overseen by qualitative experts on the study team, a sample of 
transcripts will be separately coded and their application of the coding scheme compared to 
assess the scheme’s reliability. Any disagreements in coding will be resolved through team 
discussion.  
 
7 
Safety and Adverse Events 
Data Safety and Monitoring. Diligent data and safety monitoring will be conducted by the PI and research 
team throughout the conduct of this study. This monitoring plan includes tracking participant safety and 
demographics, monitoring the safety of data, and monitoring and appropriately reporting adverse event 
activity. The PI and appropriate co-investigators will review data collected to ensure that no study findings 
warrant immediate intervention. We believe this research poses no greater than minimal risk and have 
proposed a monitoring plan that reflects this risk level.  

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The PI will be responsible for oversight of potential adverse events. An adverse event (AE) is any untoward 
medical occurrence in a subject during participation in the clinical study. We anticipate two potential types 
of AEs that could be directly related to study participation. These include distress experienced with regard 
to research participation and breach of confidentiality and privacy. With regard to the former, we have 
protocols in place that include conferring with one of the PIs (who is a licensed clinical psychologist) or a 
staff psychologist. With regard to the latter, we have appropriate safeguards to reduce risk of breach of 
confidentiality and privacy. Any risks related to additional potential AEs are not expected because this 
protocol poses minimal risk to subjects.  
 
All members of the research team who will be involved in the design and conduct of the study must receive 
education in human research subjects protection through the CITI program. The PI will be responsible for 
ensuring project faculty and staff have the equipment and training required to protect privacy and 
confidentiality and will monitor and document that these individuals are properly certified. If new 
personnel and staff become involved in the research, they will be required to engage in the same CITI 
program.  
 
DSMB. We have identified a four-member DSMB from faculty outside of Penn. The DSMB composition 
includes individuals with expertise in: implementation science, behavioral economics, FH, and 
biostatistics. The DSMB will be an independent group of experts charged with reviewing study data for 
data quality and integrity, adherence to the protocol, participant safety, and study conduct and progress. 
They 
will 
also 
make 
determinations 
regarding 
study 
continuations, 
modifications, 
and 
suspensions/terminations. DSMB members will be independent from any professional or financial conflict 
of interest with the research project and/or study investigators. The DSMB will meet annually via 
phone/video conference calls for the duration of the project. The DSMB will elect a Chair to moderate the 
meetings. At the initial meeting, the DSMB will review and approve all study protocols before study 
initiation to ensure participant safety. Protocols will include formal procedures for reporting and tracking 
all adverse reactions to the NIH and IRBs; tracking progress in the study; and identifying any need for 
premature termination of the protocol. At subsequent meetings, the DSMB will be provided with 
summary study progress reports and adverse events. The DSMB will provide a summary report following 
each meeting. We will not require the DSMB to conduct interim analyses of data prior to the end of the 
study. 
 
8 
Study Administration, Data Handling and Record Keeping 
 
8.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  All PHI 
that will be collected as part of this study include:  
• 
Name 
• 
Address  
• 
Date of Birth 

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• 
Phone number 
• 
Email address 
• 
Medical record number 
 
8.2 
Data Collection and Management  
As outlined in the Master Collaboration Agreement (MCA) between Northwestern, Penn, and Family 
Heart, all data saved and stored at Northwestern and Family Heart will be stored in accordance with the 
federal privacy and security regulations set forth at 45 CFR Parts 160 and Part 164 (i.e., HIPAA). Data will 
only be shared between parties as outlined in the MCA, via secure file transfer methods. All members of 
the study teams at Northwestern and Family Heart have completed human subjects training. 
 
At the University of Pennsylvania, we will use secure, encrypted servers to host the data and conduct the 
analysis to minimize the risk of breach of data and confidentiality. The Penn Medicine Academic 
Computing Services (PMACS) will be the hub for the hardware and database infrastructure that will 
support the project. The PMACS provides a secure computing environment for a large volume of highly 
sensitive data, including clinical, genetic, socioeconomic, and financial information. PMACS requires all 
users of data or applications on PMACS servers to complete a PMACS-hosted cybersecurity awareness 
course annually, which stresses federal data security policies under data use agreements with the 
university. The curriculum includes Health Insurance Portability and Accountability Act (HIPAA) training 
and covers secure data transfer, passwords, computer security habits and knowledge of what constitutes 
misuse or inappropriate use of the server. We will implement multiple, redundant protective measures 
to guarantee the privacy and security of the participant data. All investigators and research staff with 
direct access to the identifiable data will be required to undergo annual responsible conduct of research, 
cybersecurity, and HIPAA certification in accordance with University of Pennsylvania regulations. Data will 
be stored, managed, and analyzed on a secure, encrypted server behind the University of Pennsylvania 
Health System (UPHS) firewall. All study personnel that will use this data are listed on the Penn IRB 
application and have completed training in HIPAA standards and the Collaborative IRB Training Initiative 
(CITI) human subjects research. Data access will be password protected. Whenever possible, data will be 
de-identified for analysis. 
 
Audio recordings from the interviews will be digitally recorded and stored in REDCap. Audio recordings 
will be sent to TranscribeMe, a professional transcription service. TranscribeMe services include multiple 
safeguards designed to protect the privacy and security of personal health information, along with utilizing 
workers specifically cleared to work with this type of sensitive information. TranscribeMe maintains crowd 
worker teams that are vetted, trained, and authorized to work on content containing PHI/PII.  Data 
submitted to TranscribeMe is stored on servers located inside secure, dedicated Microsoft Azure data 
centers, with state-of-the-art physical and online intrusion prevention measures in place. Data is 
submitted and maintained through a secure file transfer protocol (SFTP) platform that has been set up 
specifically for HIPAA compliance. The service limits the amount of internal staff that has access to 
customer data within this SFTP only to essential personnel. Transcripts will be loaded into NVIVO 
qualitative data analysis software for management and analysis. Qualitative analysis is described in the 
Statistical Analysis section below. 
 
A number of procedures will be utilized to ensure confidentiality of participant data. First, all qualitative 
interview participants will be assigned a random ID number. This ID number will be used on all data 
collected from participants. The names that correlate to those ID numbers will be kept separate, i.e. 
identifiable data will be stored in one file and de-identified research data will be kept in a separate file.  
The key linking ID numbers to participant names will only be kept in REDCap. Only the research team 
outlined in this application will have access to the participant’s identifiable data. Electronic records (e.g., 
digital audio files) will be stored in REDCap as well as on a PMACS HIPAA-compliant server. All requests to 

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use the data will be reviewed by the PI. Any data files provided to other individuals will be de-identified 
and contain only the random ID numbers. Participants will be notified of the above procedures during 
informed consent. 
 
8.3 
Risks 
Participants may experience discomfort when asked to answer questions or complete questionnaires with 
the Penn and/or Northwestern team, Family Heart navigator, or via the REDCap or Way to Health 
platform. These activities may make them feel temporarily uncomfortable or experience an emotional 
response (e.g., anxiety, frustration). Participants may also experience possible embarrassment, distress, 
or inconvenience related to questions regarding personal information. The risk level is low and these risks 
will be minimized by letting participants know that they can choose not to answer a question or 
discontinue their participation at any time; one of the PIs is a licensed clinical psychologist (Beidas) and 
can provide support around distress and appropriate referrals.  
 
Participants will also be informed that their responses will be kept private and not be shared with anyone 
outside of the research team, within the limits to confidentiality in research studies. There is also the 
potential risk of breach of confidentiality. While there is always the possibility of a breach of confidentiality 
when conducting research and while the likelihood of such is very low, we take a number of precautions  
to minimize the possibility of breach of confidentiality, including that: 1) all research team staff will be 
well trained in confidentiality and data security procedures; 2) data will be rendered anonymous to the 
degree possible to minimize likelihood of any individual being identified; 3) all data will be kept locked at 
all times in a secure office building; and 4) all electronic records and audio recordings will be password 
protected. Another possible type of breach of confidentiality is if an organization learns about some of 
the impressions a staff person has about their health system. To minimize this risk, we will de-identify all 
interview transcripts and questionnaires and maintain them in a confidential manner. We will ensure 
there are protections in place so that data are only accessible by the appropriate members of the research 
team.  
 
All risks and the ways in which the research team will minimize them will be explained during the 
consenting of all potential participants. Participants will not be required to complete research measures 
or interviews and lack of participation will not impact the care they receive at Penn Medicine.   
 
The team at Penn Medicine and/or Northwestern will consent participants and, if randomized to the 
Family Heart strategy, the participant's information will be shared with Family Heart so that their 
navigator can reach out directly to the patients with high cholesterol and/or FH to discuss cascade 
screening.  We will work closely with the Penn IRB to mitigate any risks related to this agreement, and we 
will outline this information clearly in the consent. The Family Heart Foundation and Northwestern teams 
will take precautions similar to the above to mitigate the possibility of breach of confidentiality. All 
activities will fall under agreements established between the Family Heart Foundation, Northwestern 
University, and the University of Pennsylvania Office of Research Services.  
 
Regardless of implementation strategy, family members may be offered FH screening at no cost via a 
blood lipid panel or genetic test. If a family member receives a blood lipid panel, the risks of venipuncture 
for blood drawing (for lipid panel) include pain, bleeding, bruising, infection, and inflammation at the site. 
The risk level is minimal and unlikely to impact subjects as blood draws are very common and will be 
performed by trained phlebotomists. If the family member receives a genetic test, the physical risk of 
saliva genetic test is minimal. However, genetic tests that generate information about subjects' personal 
health risks can provoke anxiety and confusion, damage familial relationships, and compromise the 
subjects' insurability and employment opportunities. The risks of genetic tests will be discussed at length 
with participants and participants are not required to get genetic tests in order to participate in this study.  

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8.4 
Benefits 
There are no direct benefits of the proposed research to the participants. Participants may indirectly 
benefit from participation. Patients with high cholesterol and/or FH and family members may learn about 
FH, risks related to this disorder, and ways to minimize health risks. Discussing their experiences with the 
implementation strategies may contribute to participants reflecting on how to reduce their risk of cardiac 
events as it relates to FH. 
 
8.5 
Risk Benefit Assessment 
Cascade screening is an evidence-based practice of contacting and screening relatives of individuals after 
their FH diagnosis and improves timely diagnosis, reduces morbidity, and has been shown to be cost-
effective in other countries. Improving implementation of cascade screening may have particular promise 
for subgroups of patients at risk of health inequities. Behavioral economic approaches, which include the 
use of ‘choice architecture’ to harness the power of the environment to support behavior change, have 
been effectively leveraged to change behavior in multiple areas of medicine. Study results will help us 
determine promising strategies to increase equitable implementation of cascade screening with the 
ultimate goal of improving detection and outcomes for individuals with FH. Participants may indirectly 
benefit from participation by knowing that their participation is contributing to the improvement of 
detection and outcomes for individuals with FH. The ratio of risks to benefit is reasonable given the 
importance of the information to be gained by this research. 
 
8.6 
Informed Consent Process / HIPAA Authorization  
Waiver of Written Documentation of Consent. We are requesting a waiver of written documentation of 
consent for participants who agree to participate in the Aim 1 and 2 interviews. Because all interviews will 
be conducted remotely and all surveys will be completed via REDCap, it is not feasible to collect a signed 
copy of the combined consent and HIPAA document. These research activities present no more than 
minimal risk of harm to subjects and involves no procedures for which written consent is normally 
required outside of the research context. 
 
Individuals will be informed that the study is 100% voluntary and not mandatory. It will be clearly stated 
that patients do not have to participate in this research in order to get care at Penn Medicine. The research 
team will ensure that the potential participant has all the additional necessary information (e.g., the 
research objectives, procedures, duration, risks, benefits, etc.) to make an informed decision about 
whether or not they want to participate in the study. 
 
• 
For Aim 1 and Aim 2 qualitative interviews, consent and HIPAA authorization will be obtained either 
by phone or via videoconference. The study team member (from Penn and/or Northwestern) will ask 
the participant to be in a private location during the call. We will schedule the interview at a time 
most convenient to the participant. The interviews will be audio-recorded. We will review the 
required elements of informed consent and HIPAA authorization and answer any questions the 
potential participant might have before any research questions are asked and audio-recorded. 
Potential participants will be encouraged to ask questions about the project. Participants will be 
emailed a copy of the IRB approved consent document for their records. If they agree to participate, 
the interview team will document the consent process in REDCap.  
 
• 
For Aim 2 family member outreach, we will use passive consent language in the form of an “opt out” 
letter that explains FH, primes them that someone will reach out to them about cascade screening, 
and provides instructions on how to opt out of being contacted.  
 
Waiver of Consent.  

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For patients enrolling in Aim 2 mini-pilots, we are requesting a waiver of consent and HIPAA 
authorization. The research activities are minimal risk and involve minimal collection of PHI. Because we 
are studying the effect of communicating about cascade screening and we are ultimately planning to 
conduct a pragmatic trial, we do not want to send a primer letter for probands to opt out because we do 
not want to add another layer of communication that could impact the effect we are seeing from these 
strategies. We believe additional communication in the form of a consent would affect the organic 
response of probands and alter the research results. A primary goal of ours is also to improve equitable 
delivery of cascade screening, and so understanding the real-life challenges healthcare providers would 
face when trying to contact probands about cascade screening is at the heart of this research. You will 
also note in the implementation strategy language we uploaded that some elements of consent are 
naturally contained in the outreach language – we are striving to integrate as much communication into 
the implementation strategies as possible to mimic what we believe would happen outside of a research 
study. In summary and in accordance with 45 CFR § 46.116, this research:  
 
1) involves no more than minimal risk to subjects;  
2) could not be carried out practicably without the waiver or alteration;  
3) the waiver or alteration will not adversely affect the rights and welfare of the subjects; and,  
4) the subjects will be provided with additional information about their participation.   
 
9 
Study Finances 
This study is financed through an R61/R33 grant from the US National Heart, Lung, and Blood Institute. 
No investigators have any conflicts of interest.  
 
 
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