Study of Awareness and Detection of Familial Hypercholesterolemia

The FH Foundation CASCADE-FH Registry will implement an enrollment framework which is
characterized by three possible points of contact: 1) Clinic enrollment 2) Self-enrollment
through an online patient portal, and 3) Electronic Health Record (EHR) identification.

Pathway 1: Clinic-Based Screening and Enrollment During the initial study phase, a number of
specialized lipid clinics across the US will participate in the CASCADE-FH registry. FH
patients at these sites who meet inclusion will enroll. Each site will be required to receive
IRB approval and obtain patient consent. Once the initial set of specialized lipid clinics
has demonstrated acceptable feasibility for patient enrollment and engagement, additional
sites will be recruited into the registry.

Pathway 2: Patient Self-Enrollment Potential registry participants will have the opportunity
to self-enroll in the CASCADE-FH Registry through an online screening mechanism. A link on
the FH Foundation website (http://www.thefhfoundation.org) will direct potential participants
to a brief screening questionnaire see inclusion criteria.

Pathway 3: Electronic Health Record (EHR) Screening System-wide searches of EHR to identify
potential FH patients based on LDL lab values and clinical FH criteria. Following
identification, the primary care provider of the potential FH patient is sent a notification
letter describing the patient's high LDL level, at-risk status and need for additional
screening. The patient may then undergo additional clinical or genetic testing and be
provided information about CASCADE-FH and registry participation.

Data collection For data entered at clinical sites, the primary source of information will be
the patient's medical record. Baseline data will elements to be abstracted and entered.

Data elements entered by self-enrolled patients in the online patient portal will include a
subset of clinical information as well as questions on quality of life, disease-related
anxiety, and depression. A short survey to assess patient understanding of FH health risks,
available treatment options, and family member screening will also be included. The patient
questionnaire was designed to be free of clinical jargon and pilot-tested by FH patient
volunteers to ensure ease of use by participants.

Followup data collection For patients enrolled at clinical sites, providers will be asked to
update information at yearly intervals. Medical records will be reviewed to assess changes in
medications, occurrence of major adverse cardiovascular events, hospitalizations, genetic
testing, and laboratory values updated since the last date of data entry. Follow-up data will
be collected yearly for 3 years following initial enrollment. Self-enrolled patients may
update data at any time by accessing the patient portal. Updated information on current
medication regimens, clinical events, and quality of life will be collected. However,
reminder emails will be sent to all self-enrolled patients on an annual basis to ensure
uniform entry of follow up information.

Patient-Reported Data Validation To ensure collection of high-quality data on FH
patient-reported outcomes, an annual validation of a proportion of self-enrolled patient
records will be conducted to assess concordance between information entered in the online
patient portal with data from their medical record. Following baseline data entry,
self-enrolled patients will be asked to provide contact information for their physicians and
to sign a medical release for validation of patient reported data. Of patients signing this
medical release, a randomly generated 10% sample will be selected for validation on a yearly
basis. Patient responses to questions regarding medication regimens, comorbid conditions,
clinical events and lab results will be compared to determine concordance between patient-
and physician-reported data. Overall agreement, sensitivity, specificity, and kappa
statistics will be evaluated to determine concordance between responses. Based on prior
validation analyses of patient-reported data, we expect moderate to good agreement between
the two data sources (Κ=0.40-0.80)19,20 Data elements with low rates of concordance will be
assessed for clarity and may be refined to enhance sensitivity and specificity. Supplemental
educational material may be provided for variables with low concordance to further promote
valid data capture.

Longitudinal Outcomes Serial lipid values will be a key outcome of interest and will be
examined to assess the adequacy of lipid modifying therapies to achieve target LDL values.
Longitudinal outcomes of interest will include medication changes, occurrence of major
adverse cardiovascular events, and mortality. Primary patient-reported outcomes of interest
will include notification and screening of family members, treatment satisfaction,
disease-related perceptions, and quality of life measurements.

Statistical Considerations The CASCADE-FH Registry will collect patient-reported and
clinician-reported information to characterize treatment patterns and outcomes among FH
patients. Because this study is not-hypothesis driven and no specific medical therapies or
treatment interventions are being compared, formal prospective calculations of sample sizes
are not necessary. However, we will periodically assess variations in lipid management,
clinical events, and patient-reported outcomes to evaluate temporal changes in these
variables. Standard statistical approaches commonly used in observational analyses will be
utilized.

Data Feedback and Quality Improvement Sites participating in the CASCADE-FH Registry will
receive annual data feedback reports that will highlight treatment patterns, serial lipid
values, and clinical outcomes for their enrolled patients compared with the national results.
These reports will be designed to facilitate quality improvement interventions at
participating sites designed to improve the treatment and outcomes of FH patients.
Self-enrolled patients will have the opportunity to download their reported data directly as
well as through pre-programmed self-feedback, electronic reports that can be accessed at any
time.

Inclusion Criteria:

Online Patient Enrollment Inclusion Criteria:

- Patients with existing clinical diagnosis of FH;

- Patients with genetic mutation of FH;

- Patients with an initial (pretreatment) LDL level >190 mg/dL or total cholesterol >300
mg/dL;

- Patients currently taking a lipid-lowering medication and have an LDL >124 mg/dL or
total cholesterol >195 mg/dL.

Clinic Patient Enrollment Inclusion Criteria:

- Patients with existing clinical diagnosis of FH using one of the three clinical
diagnostic (US MedPed Program Criteria, Simon Broome Register Criteria with diagnosis
of "Probable", Dutch Lipid Clinic Network Diagnostic Criteria with diagnosis of
"Probable")tools for FH; or

- Patients with genetic mutation of FH

Exclusion Criteria:

- Patients will be excluded from participation in the registry when a known medical
condition other than FH that is thought to contribute to hyperlipidemia (i.e.,
untreated hypothyroidism, nephrotic syndrome, cholestasis hypopituitarism).