Leveraging Behavioral Economics to Equitably Implement Cascade Screening in Individuals With Familial Hypercholesterolemia in Partnership With the FH Foundation (R33 Phase)
Phase: NA
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 (R33 Phase) 
 
 
NCT Number: TBD 
 
 
Document Date: December 22, 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 ................................................................................................................................... 6 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ......................................................................... 6 
4.1 
ELIGIBILITY CRITERIA ................................................................................................................................ 7 
4.2 
SUBJECT RECRUITMENT ............................................................................................................................. 8 
5 
STUDY PROCEDURES ............................................................................................................................... 9 
5.1 
SUBJECT COMPENSATION ........................................................................................................................ 14 
5.2 
SUBJECT WITHDRAWAL ........................................................................................................................... 14 
6 
STATISTICAL PLAN ................................................................................................................................ 14 
7 
SAFETY AND ADVERSE EVENTS .............................................................................................................. 16 
8 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING ....................................................... 16 
8.1 
CONFIDENTIALITY .................................................................................................................................. 16 
8.2 
DATA COLLECTION AND MANAGEMENT ....................................................................................................... 17 
8.3 
RISKS................................................................................................................................................. 18 
8.4 
BENEFITS ............................................................................................................................................ 19 
8.5 
RISK BENEFIT ASSESSMENT ...................................................................................................................... 19 
8.6 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ................................................................................. 19 
9 
STUDY FINANCES .................................................................................................................................. 21 
 
 
 

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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. FHF), 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 Foundation 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.  
 
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 
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 
 

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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 
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 
 

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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. 
Then, we will conduct a three-arm hybrid Type 3 effectiveness-implementation randomized controlled 
trial of different strategies to encourage family cascade screening for familial hypercholesterolemia. 
• 
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. 
• 
R33 Aim 1. Compare the effect of the three arms on: 
○ Reach (primary outcome): proportion of probands who have at least one family member who 
completes a lipid panel and/or a FH genetic test within 6 months of proband randomization.  
○ We also include a co-primary outcome of engagement, defined as the number of probands 
who respond to at least one outreach contact attempt divided by the number of probands 
outreached. 
○ We will also explore secondary endpoints: absolute number of family members screened and 
absolute number of family members with a new FH diagnosis 6 months after proband 
randomization, and proband LDL-C levels (12 months after proband randomization).  
• 
R33 Aim 2: Use mixed methods to identify implementation strategy mechanisms with a focus on 
health equity. 
○ Aim 2a. Conduct interviews to understand proband perspectives on mechanisms using the 
Consolidated Framework for Implementation Research, oversampling for populations at risk 
for disparities. 
○ Aim 2b: Explore disparities quantitatively by evaluating differential strategy effectiveness by 
race/ethnicity and gender; and descriptively explore differential strategy effectiveness by 
income and medical mistrust. 
 
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.  

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• 
R61 Aim 2. To maximize success, we will pilot test the implementation strategies and our planned 
data collection approaches.  
• 
R33 Aim 1. We will enroll 300 Penn Medicine patients with FH and/or high cholesterol 
(“probands”) in a three-arm RCT (100 per arm: Penn [health system] mediated-strategy, Family 
Heart Foundation-mediated strategy, usual care). The arms are described in detail below in Study 
Procedures. 
• 
R33 Aim 2. We will conduct qualitative interviews with a purposive sample of RCT (Aim 1) proband 
participants, as well as Family Heart Foundation staff, to identify potential mechanisms of 
implementation strategy effectiveness. 
 
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. 
• 
R33 Aim 1. Data for the RCT will be gathered via several platforms: the Penn Medicine EHR (e.g., 
proband race/ethnicity, gender), Way To Health and REDCap (e.g., self-report of lipid and/or 
genetic test results via REDCap survey link sent via Way To Health), and phone call (e.g., self-
report of lipid and/or genetic test results by family members in the Penn and Family Heart 
Foundation arms to the study clinician during a telemedicine call). See below description of study 
arms (Study Procedures) for more details. 
• 
R33 Aim 2. We will develop a semi-structured interview guide and informed consent form, and 
will submit them for IRB approval before beginning this activity. The guide will also contain 
quantitative measures (to be administered verbally) regarding medical mistrust and income. 
 
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 

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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. 
• 
R33 Aim 1 (RCT). We will enroll 300 Penn Medicine patients with high cholesterol and/or FH 
(“probands”) in the RCT. Probands will be randomized to one of the  three study arms (n=100 per 
arm) and will receive outreach according to the study arm they are randomized to (described 
below in Study Procedures). In the health system- and Family Heart Foundation-mediated arms, 
probands will be invited to reach out directly, or give permission for the health system or FHF 
staff (respectively) to reach out, to their eligible family members (first-degree biological 
relatives). With either approach, family members will be provided education about cascade 
screening and given information about how to obtain lipid and/or genetic testing for FH. In the 
usual care arm, probands will not receive any contact at baseline. We will collect lipid and/or 
genetic testing data from family members in the Penn and FHF arms for up to 6 months from 
proband randomization. We will also send a REDCap survey to probands in all study arms at 
approximately 6 months post-proband randomization to collect: family member testing and 
diagnosis data (from the usual care arm), or additional family member testing and diagnosis data 
not yet collected via the Penn Medicine and Family Heart Foundation implementation strategies. 
Family members in the usual care arm will not be contacted by the research team and will not 
be enrolled in this study. Probands in all arms will be outreached approximately 10 months after 
initial randomization to invite them to complete a lipid panel within 12 months of their initial 
randomization date. Proband participation will be completed after: this 12-month lipid testing 
is completed, participants do not respond to our lipid testing invitations, or participants decline 
to participate in the 12-month lipid testing. 
• 
R33 Aim 2 (Interviews). A purposive sample of 60 RCT (Aim 1) proband participants, as well as 
8 Family Heart Foundation staff/leadership, will be invited to participate in one-time qualitative 
interviews at that seek to understand potential mechanisms of implementation strategy 
effectiveness. Probands will be invited to participate at approximately 6 months post-
randomization; Family Heart Foundation staff/leadership will be interviewed in Year 4-5 of the 
grant period (March 2025-February 2027). 
 
 
4.1 
Eligibility Criteria 
• 
Patients with high cholesterol and/or FH (i.e., “probands;” 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  

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• 
Probands (R33 Aim 1 and Aim 2 interviews). Adults aged 18 and older with clinically diagnosed 
FH and/or high cholesterol who are treated within Penn Medicine who: (1) are the first person in 
their immediate family to be diagnosed with FH, and have not previously participated in cascade 
screening attempts with first-degree biological relatives (i.e., parent, sibling, child); (2) have 
contact information for at least one living, first-degree biological relative in the U.S.; and (3) have 
a cell phone with texting capabilities. 
• 
Family Members (R33 Aim 1, Penn Medicine and Family Heart Foundation arms only). 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 (i.e., adult relatives of probands). 
(Family members in the usual care arm will not be contacted by the research team and will not 
be enrolled in this study.) 
• 
Family Heart Foundation staff and leadership (R33 Aim 2 interviews). All Family Heart 
Foundation staff and leadership will be eligible to participate in an interview. 
 
4.2 
Subject Recruitment  
 
R61 Phase. 
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 
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.  
 
R33 Phase. 
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 
recruitment strategy also does not target participants who are likely to be vulnerable to undue influence 
or coercion. 
 
R33 Aim 1.  
• 
Patients with high cholesterol and/or FH (“probands”). Patients with high cholesterol and/or FH 
(probands) 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 

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Presbyterian Medical Center, Pennsylvania Hospital, Chester County Hospital, Princeton Health, 
and Lancaster General Hospital. We will identify probands using two approaches: (a) a search of 
the Penn Medicine EHR for the FH ICD-10 code (E78.01); and (b) application of the FIND FH® tool 
(outlined in sister protocol #849516; MPIs: Volpp, Beidas, Rader) to the Penn Medicine EHR to 
find patients with “highest probability” scores; only patients who have already been notified of 
their diagnosis via sister protocol #849516 will be recruited for the present study.  
○ For the Penn Medicine and Family Heart Foundation arms, potential proband participants will 
receive initial contact via text message, email, patient portal message, and/or phone by 
research staff at Penn and/or Northwestern. We will follow-up no more than five additional 
times (six attempts total) to invite them to participate in this study. We will use these same 
methods to reach out to probands to invite them to complete the 6-month Follow-Up survey, 
described below in Study Procedures. 
○ For the usual care arm, we will not reach out to probands at baseline. We will contact usual 
care probands via email, text, phone, and/or patient portal message to invite them to 
participate in a REDCap survey that asks about our Aim 1 outcomes (6-month Follow-Up 
Survey) at approximately 6 months post-randomization. We will reach out no more than 6 
times to invite them to participate. 
○ At approximately 10 months post-randomization (for all arms), we will reach out to probands 
via phone, email, text message, and/or patient portal to invite them to complete a new lipid 
panel and ask them to self-report a lipid panel (obtained as part of their routine medical care) 
from before their date of randomization. We will reach out no more than 6 times to invite 
probands to participate in this activity. 
• 
Family Members. Probands who do not opt-out of the study will be asked to identify first-degree 
biological relatives (“family members”) whom either a) the proband is willing to reach out to 
directly, or b) the proband is willing to have Penn/Northwestern research staff (on behalf of Penn 
Medicine) / FHF staff reach out to. For option (a), probands will be given educational information 
and information about obtaining a lipid and/or genetic test for FH, which they can share with 
family members. For option (b), family members will be contacted directly by the 
Penn/Northwestern research or FHF staff via the contact information shared by the proband. 
Probands will be given the option to give their family members a “heads up” before Penn 
Medicine / FHF reaches out. We will reach out to the family member no more than 6 times to 
invite them to participate. A link to an opt-out letter will also be sent to the family members during 
this initial recruitment; only those who do not opt out will continue on to receive the 
implementation strategy.  
 
R33 Aim 2.  
• 
Probands. We will recruit a purposive sample of R33 Aim 1 probands via the same methods used 
in the RCT (i.e., text, email, patient portal, and/or phone) to invite them to complete a one-time 
qualitative interview. 
• 
Family Heart Foundation members. We will recruit FHF staff / leadership via email to invite them 
to participate in a one-time qualitative interview. 
 
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 

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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). 
○ 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 Foundation 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 

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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 Foundation 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. The ‘no cost’ test will be provided by reimbursing 
the participant for the cost of the LabCorp lipid test (via ClinCard; $59); we give them 
instructions on how to obtain the test via LabCorp. Although this implementation strategy is 
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. 
• 
R33 Aim 1 (RCT). We plan to conduct this study as a pragmatic trial. First, we will randomize 
participants to one of the 3 study arms (n=100 per arm). Participants randomized to the Penn and 
Family Heart Foundation arms will be asked to confirm their identity through the Way To Health 
platform (text and/or email) and via phone and/or patient portal if initial Way To Health outreach 
is unsuccessful. They will also be given information about how to opt-out. All participants who do 
not opt-out will receive further engagement via the Penn or Family Heart Foundation strategies 
(described below). Participants randomized to the FHF arm will be given the opportunity to opt 
out of having their information shared with FHF. Participants randomized to the usual care arm 
will not receive outreach at baseline. The first outreach will be done via Way To Health (text 
and/or email) and via phone and/or patient portal if initial Way To Health outreach is 
unsuccessful, ahead of the 6-month Follow-Up survey (described below). Probands in this arm will 
be asked to confirm their identity and will be given information about how to opt-out (using the 
same messaging as is used for the Penn and Family Heart Foundation arms) before they are invited 
to complete the survey.  

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○ Penn (health system)-mediated. After confirming the proband’s identity and giving 
information about how to opt-out, the Penn and/or Northwestern research teams will 
conduct the Penn Medicine (health system-mediated) study activities with probands who 
didn’t opt out. Probands receive a series of automated SMS messages, patient portal 
messages, and/or emails through the Way to Health platform containing information about 
FH and cascade screening from Penn Medicine. Participants may also receive a phone call 
informing them of the program and directing them to the text and/or email messages. 
Probands will be invited to complete a genetic test for FH if they haven’t had genetic testing 
previously. They will have multiple options for completing genetic testing: requesting the test 
from their PCP or having the study clinician order a genetic test via a testing company called 
LabCorp. Test completion and results will be shared with the study team via self-report by the 
proband (via REDCap survey) and/or will be received directly from LabCorp by the study 
clinician who ordered the test. Tests ordered by the study clinician will be offered at no cost 
to the participant (i.e., the cost of the test will be covered by LabCorp and/or paid to LabCorp 
from study funds; the participant will not be charged). Participants will be informed before 
they sign up for LabCorp testing that for tests ordered by the study clinician, their results will 
be shared directly back with the study clinician. Probands will also receive a request for them 
to identify first-degree biological relatives. We provide an opportunity for customization 
whereby probands have a choice of whether to contact family members themselves or share 
contact information so that automated text / email messages can be sent directly by Penn 
Medicine via Way to Health; and what communication modalities to use (e.g., text message 
or email). If participants opt to contact family directly, they receive tips on how to do this 
effectively (e.g., committing to a date/time to make contact) and informational materials that 
they can share. If the proband selects health system-mediated outreach, identified family 
members will be asked to confirm their identity through the Way To Health platform (text 
and/or email) or via phone if initial Way To Health outreach is unsuccessful, and will be given 
information about how to opt-out. They will also receive a link to an opt-out letter containing 
passive informed consent language and reiterating information about how to opt-out. Then, 
family members who don’t opt out will receive educational information about FH and 
instructions for obtaining lipid and/or genetic testing. To mimic real world settings, we will 
allow family members to select how they would like to complete their screening from a range 
of mechanisms. This includes sharing results from a recent lipid panel and/or genetic test, 
requesting a lipid panel and/or genetic test from their PCP, or having the study clinician order 
the test for them (testing via this option will be free for family members). Test completion 
and results will be shared with the study team via self-report by the family member (during a 
phone call or telemedicine visit with study clinician; and/or via REDCap survey) or will be 
received directly by the study clinician if they ordered the test. Family members will be 
informed before they sign up for LabCorp testing that for tests ordered by the study clinician, 
their results will be shared directly back with the study clinician. Family members that 
complete lipid and/or genetic testing (or are willing to share recent test results) will be invited 
to complete a follow-up phone call or telemedicine visit with the health system arm’s study 
clinician to review their results. If a proband’s initial choice of pathway is not successful (e.g., 
proband chose to contact relatives directly and they did not respond), they will have the 
option of initiating the other contact approach. Probands will receive an invitation to 
complete a REDCap survey at approximately 6 months post-randomization to report on the 
outcomes of their program participation (i.e., whether their family members received FH 
testing and/or were diagnosed with FH; 6-month Follow-Up Survey). 
○ Family Heart Foundation-mediated. After confirming the proband’s identity and giving 
information about how to opt-out, probands randomized to this arm (and who didn’t opt out) 
will be given the opportunity to opt out of having their information shared with FHF (as 

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described above). For probands who do not opt out of having their contact information 
shared, FHF will be provided with the proband’s name and contact information securely via 
REDCap. (This data sharing is covered under the Master Collaboration Agreement between 
FHF, Penn, and Northwestern.) Then, FHF will reach out directly via an FHF-employed 
navigator, making multiple contact attempts if needed. The navigator is trained and 
supervised by FHF leadership (Dr. McGowan) and a genetic counselor. During an initial call, 
the navigator introduces the proband to navigation services, conducts a social history, obtains 
contact information for family members the proband gives permission to contact, and 
initiates a plan for contacting family members. Probands will also be invited to complete a 
free genetic test for FH if they haven’t had genetic testing already; details and logistics of this 
testing will mirror those described for the Penn Medicine arm above. As with the health 
system-mediated approach, probands will choose whether to contact family members 
themselves or have FHF contact relatives directly, with similar choice architecture and the 
same consent procedures as described above. Those who choose to contact family members 
themselves receive personalized coaching to address barriers and concerns, including follow-
up calls as needed. They also receive informational materials that they can share with their 
relatives. If family contacts are successful, the family member will be offered FH screening 
(lipid and/or genetic test) at no cost; the details and logistics of this testing will mirror those 
described above for the Penn Medicine arm. Family members that complete lipid and/or 
genetic testing will be invited to complete a follow-up phone call or telemedicine visit with 
the FHF arm’s study clinician or genetic counselor to review their results. If a proband 
participant’s initial choice of pathway is not successful (e.g., proband chose to contact 
relatives directly and they did not respond), they will have the option of initiating the other 
contact approach. Probands will receive an invitation to complete a REDCap survey at 
approximately 6 months post-randomization to report on the outcomes of their program 
participation (i.e., whether their family members received FH testing and/or were diagnosed 
with FH; 6-month Follow-Up Survey). 
○ Usual Care. Probands randomized to the usual care arm will not receive outreach at baseline. 
At approximately 6 months post-randomization, we will reach out to the proband via Way To 
Health (text/email) and patient portal and/or phone if Way To Health outreach is unsuccessful 
(as described above), to confirm identity and give the option to opt-out. Participants who 
confirm their identity and do not opt out will be sent an invitation to complete a survey via 
REDCap (i.e., 6-month Follow-Up Survey). The survey will ask questions about whether they 
have participated in family cascade screening and if so, the results (i.e., whether their family 
members received FH testing and/or were diagnosed with FH). 
○ 12-month LDL-C levels. At approximately 10 months after initial randomization, probands in 
all arms will be invited to complete lipid testing at no cost to them. Lipid testing logistics and 
procedures will mirror those described above for proband genetic testing and family member 
genetic/lipid testing in the Penn and Family Heart Foundation arms. Probands who complete 
lipid testing and share their results with the study team either by a) self-report via REDCap; 
and/or b) having their test ordered by a study clinician, which automatically sends the test 
results back to the ordering clinician, will receive a letter from Penn Medicine summarizing 
and interpreting their results and encouraging them to discuss their results with their primary 
care provider. Participants in all arms will also be asked to report results from their last lipid 
panel before randomization (obtained as part of their routine care) via a REDCap survey, so 
we can compare their lipid panel numbers before and after program participation as part of 
study data analyses. 
• 
R33 Aim 2 (Interviews).  
○ We will invite probands who participated in the RCT and Family Heart Foundation staff / 
leadership to complete a one-time qualitative interview. Interviews will be conducted by the 

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Penn and/or Northwestern research teams, and will occur either by phone or 
videoconference to maximize convenience and participant preference. We will obtain verbal 
informed consent before beginning the interview (the consent form will be submitted for IRB 
approval before interviews begin). Interviews will be audio-recorded with the participant’s 
permission. During interviews, participants will be asked questions from an interview guide 
that will be submitted for IRB approval before interviews begin. Interviews will last 
approximately 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.  
• 
R33 Aim 1 6-month Follow-Up Surveys. Probands in all arms will be offered a $25 e-ClinCard for 
completing the 6-month Follow-Up Survey in REDCap. Probands (usual care arm only) who 
complete part 2 of the 6-month Follow-Up survey will be offered an additional $25 e-ClinCard. 
• 
R33 Aim 1 12-month LDL-C. Probands in all arms who complete a 12-month lipid panel (and share 
results via self-report in a REDCap survey or via the study clinician ordering the test, which sends 
the results directly to the study clinician) and share pre-randomization lipid panel results (via 
REDCap survey) will be compensated $25 via e-ClinCard. 
• 
R33 Aim 2 interviews. Probands will be compensated via $25 e-ClinCard for participating in the 
qualitative interview. FHF staff/leadership will not be compensated for completing an interview. 
 
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.  
• 
R33 Aim 1. For testing hypotheses related to our primary clinical and implementation outcomes 
of reach (yes/no) we will conduct two-sample Z-tests and report the proportion of reach and 95% 
confidence interval in each arm. To assess potential imbalance in variables that we use for 
stratified sampling (e.g., race/ethnicity) on the dependent variable, we will conduct logistic 
regression analysis with reach (1 = yes, 0 = no) as the outcome and a binary variable for indicating 

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implementation strategy (1 = FHF; 0 = health system) as the covariate of interest, adjusting for 
these stratification variables. The odds ratio parameter for the binary study arm indicator 
approximates the ratio between the proportion of reach in the two arms, and we will assess 
whether the odds ratio parameter is significantly greater than one. To assess potential impact on 
results due to proband clustering within clinic, we will repeat the same logistic regression analysis 
but additionally include clinic as a random effect. As exploratory analyses, if data allow, we will 
repeat the above analysis but with “reach” redefined as “whether a proband had at least two 
family members who completed a lipid panel or FH genetic test within 6 months of proband 
randomization.” For continuous outcomes (number of family members screened, number of 
family members diagnosed with FH, proband LDL-C), we will conduct similar analyses but 
substitute a two-sample t-test and linear regression models. All tests will be two-sided at the 0.05 
significance level. For missing data, we will use multiple imputation as we have in other trials. 
• 
R33 Aim 2a (Interviews). As in previous work, we will query around specific mechanisms through 
which our implementation strategies operate (e.g., shifting responsibility from proband to 
technology or FHF, shifting engagement to non-health system related staff, changing motivation), 
using the CFIR to identify key mechanisms at multiple ecological levels. We will also include 
questions about social and structural factors that may contribute to health inequities such as 
experiences of discrimination, health care access, language barriers, and how these relate to the 
success of the implementation strategy conditions and if they differ across populations. We will 
also collect responses to quantitative measures of income and medical mistrust verbally during 
interviews. Analysis of this quantitative data will occur as part of Aim 2b, described below. We 
will interview FHF team members to understand how this approach might be scaled up at the 
national level. We will load all transcripts into QSR NVivo for data management and analysis of 
the qualitative data. 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 expert Dr. Klaiman (Co-I), 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. 
• 
R33 Aim 2b (Quantitative Analyses). This analysis is exploratory. We will conduct stratified 
analysis by repeating the Aim 1 analysis separately in subgroups defined by each candidate effect 
modifier (race/ethnicity, gender). This will allow us to examine the difference in effect sizes (e.g., 
difference in reach) between subgroups. To test the significance of such a difference, for the 
primary outcome, we will fit a logistic regression model that uses the reach status (yes/no) as the 
outcome variable and includes three covariates, a binary variable indicating the study arm (1 = 
FHF; 0 = health system), the effect modifier (e.g., race/ethnicity), and a cross term between the 
study arm and effect modifier. A significant modification effect is indicated if the p-value for the 
cross term by the Wald test is less than 0.05. We will use the same statistical methods to assess 
modification effects of the stratification variables in the comparison between the two active 
strategies and usual care. We understand that power is limited given the sample size; therefore, 
we will carefully examine the size and direction of the effect. We will perform interaction analysis 
for the secondary outcomes also, substituting linear regression models for continuous variables 
(e.g., LDL-C levels). Lastly, we will conduct exploratory, descriptive analyses to understand the 
differential effects of participant income and medical mistrust. 
 

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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.  
 
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 and Northwestern. 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.  

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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 
• 
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 
Foundation, all data saved and stored at Northwestern and FHF 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 FHF 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. 
 

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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 
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 Foundation 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 research team at Penn Medicine and/or Northwestern will reach out on behalf of Penn Medicine (via 
Way To Health, patient portal, and/or phone) to confirm probands’ identity and provide information 
about how to opt out of participation. Additionally, if randomized to the Family Heart Foundation strategy 
(and if the proband doesn’t opt out of having their contact information shared), the proband’s information 
will be shared with Family Heart Foundation so that their navigator can reach out directly to the patients 
with high cholesterol and/or FH to discuss cascade screening.  For family members who receive direct 
outreach from Penn or FHF, we will confirm their identity, and will share an opt-out consent form with 
them. Only participants who do not opt out will receive additional messaging as part of the 
implementation strategy. 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 

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confidentiality. All activities will fall under the Master Collaboration Agreement established between the 
Family Heart Foundation, Northwestern University, and the University of Pennsylvania Office of Research 
Services.  
 
Regardless of implementation strategy, probands and family members will be offered FH screening at no 
cost via a blood lipid panel or genetic test as described above. If a family member or proband 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 proband or 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.  
 
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 R61 Aim 1 and 2 interviews and R33 Aim 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. Family Heart Foundation staff will be informed that 
their decision of whether or not to participate in an interview will not impact their employment. 
 

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• 
For R61 Aim 1 and Aim 2 qualitative interviews and R33 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 R61 Aim 2 and R33 Aim 1 (RCT) family member outreach (for the Penn Medicine and Family 
Heart Foundation arms), 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. (Family members in the usual care arm will not be 
contacted by the research team or be participants in the study.) 
 
Waiver of Consent.  
For patients (probands) enrolling in Aim 2 mini-pilots and the R33 Aim 1 (RCT), 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 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 the implementation strategies or the usual care arm. 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.  
 
Similarly, for the usual care arm, our goal is to collect our study outcomes while intervening minimally on 
participants, in order to minimize the impact the data collection activities have on these participants' 
behavior. Our goal is to maintain the integrity of the care that is received by these participants as part of 
Penn Medicine's usual care for FH (i.e., our goal is for our data collection activities to have as little impact 
as possible), so we can understand the impacts and outcomes of usual care for FH at Penn Medicine. 
Similar to the active arms, 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 in the usual 
care arm. We believe additional communication in the form of a consent would affect the organic 
response of probands and alter the research results, and/or could negatively impact our ability to achieve 
the equity goals of this study. We are gathering the same information in the usual care arm as we are in 
the active arms; these research activities are all minimal risk and involve minimal collection of PHI. 
 
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.   
 

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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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