Table 1 Study eligibility criteria and rationale

Penn Medicine patients diagnosed with familial hypercholesterolemia (FH; “probands”): randomized controlled trial participants

Eligibility criteria for trial enrollment

Age 18 or older

We will exclude children under age 18 from our proband participant group because the health system from which we draw our proband sample (Penn Medicine) does not have pediatric practices and thus, does not typically see children for primary care

Has clinically diagnosed FH (e.g., have ICD-10 code 78.01 documented in their electronic health record [EHR] or clinician documentation of FH diagnosis in a visit note, both confirmed via chart review)

We will require clinical diagnosis of FH but will not require prior genetic testing for FH for probands to be eligible. Although some probands will have had genetic testing to confirm FH status, we will not require this for several reasons: (a) a diagnosis of FH may be based on clinical assessment alone and does not require a genetic test; (b) up to 50% of individuals with clinically diagnosed FH may not have an identifiable genetic variant; and (c) we wish to avoid exclusion of patients who may have reservations about genetic testing even when it is provided free of charge, including minoritized populations [44, 82, 83]. Furthermore, there are low rates of genetic testing for FH in routine practice; therefore, we have opted to mirror current practice given the pragmatic nature of the study

Had a visit with a Penn Preventive Cardiology Program clinician in the prior 5 years (whether or not they are engaged in care at the start of the study)

We will limit our inclusion criteria to probands seen by a clinician within the Penn Preventive Cardiology Program—a cohort of clinicians with preventive cardiology expertise who see patients in multiple clinical sites across Penn Medicine—because these individuals are likely to be aware of their FH diagnosis prior to study outreach. In pilot work, we found that many probands with documentation of an FH diagnosis within their electronic health record were not aware of their diagnosis. It would be inappropriate for probands to be alerted to their FH diagnostic status via automated messages delivered by this study. Thus, we will focus our recruitment on individuals seen in the Penn Preventive Cardiology Program, who are likely to be aware of their FH status already. If needed to reach our intended sample size, we will expand our eligibility criteria to include patients who had a visit with other Penn Medicine clinicians (e.g., clinicians from the Penn Medicine Interventional Cardiology Program)

We estimate that 5 years would be the timespan for the inclusion of individuals in outreach for quality improvement initiatives conducted by Penn Medicine (i.e., we will mirror what might be done outside of a research context for this study)

Have an email address and/or cell phone number listed in the EHR

Email address and/or cell phone number are needed for delivery of the automated Penn Medicine-mediated implementation strategy. Based on prior Penn Medicine studies, 90% of patients have cell phones, and nearly all patients who do not have a cell phone listed in their EHR do have an email address listed

Did not participate in our R61 phase pilot (n = 27)

These participants already received an earlier version of the implementation strategies

Did not enroll a relative in a prior Penn Medicine FH cascade screening study conducted by Ajufo and colleagues (n = 28) [42]

These participants already received outreach from Penn Medicine about cascade screening and worked with a genetic counselor to enroll relatives in cascade screening

Unreachable by email or text message (i.e., delivery failure)

To ensure that health information is shared only with the intended recipient, eligible proband participants will be asked to confirm their identity via text messages and/or email prior to mention of FH. These participants who cannot be reached to confirm identity will not be randomized and thus, will not have a chance to participate

Do not positively confirm their identity when we first send them a message (i.e., respond ‘no’ or do not respond when we ask if we have reached the correct person)

Similarly, these participants who do not positively confirm identity will not be randomized and thus, will not have a chance to participate

Exclusion criteria for analyses

Proband reports that they do not have contact information for at least one living, first-degree biological relative in the USA

These probands do not have any relatives that are eligible to complete screening

Proband reports on a 6-month follow-up survey that they did not invite any first-degree biological relatives living in the USA to participate in FH screening because all of their relatives have already been screened for FH and did not wish to obtain a second opinion

We will exclude probands whose first-degree relatives have all been screened for FH (and do not wish to obtain a second opinion) because these families are not candidates for cascade screening. Because FH screening procedures may vary or evolve over time, we will not exclude relatives who have had previous FH screening but wish to obtain a second opinion

Relatives: randomized controlled trial participants

Eligibility criteria

First-degree biological relative of a participating proband

Although cascade screening ideally includes contacting and screening second-degree relatives, we will focus the finite resources for the present trial on first-degree relatives

Living in the USA

In this study, we wish to understand cascade screening within the USA context. Additionally, we anticipate that this would be an eligibility criterion for the inclusion of individuals in outreach for quality improvement initiatives conducted by Penn Medicine (i.e., we will mirror what might be done outside of a research context). Finally, the lipid testing options that we will include in this study are only available to those living in the USA

Age 2 years or older (with contact directed at the caregiver for relatives ages 2–17)

FH guidelines do not recommend lipid screening for children under age two unless both parents are known to have heterozygous FH, so children under two will not be eligible to complete screening through the study

Research team and Family Heart Foundation leadership qualitative interview participants

Eligibility criteria

All staff members involved in deploying the implementation strategies and Family Heart Foundation leadership

n/a