Million Veteran Program Return of Actionable Results
Phase: NA
Conditions: Cardiovascular Disease
Sponsor: VA Office of Research and Development

 
Million Veteran Program Return Of Actionable Results – Familial Hypercholesterolemia 
(MVP-ROAR-FH)
Funding Agency: VA Office of Research and Development
Principal Investigator: Jason L. Vassy, MD, MPH, SM
Version Number 6
August 26, 2022
 
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Effective Date:
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Abstract
Background
In the last 5 years, the genomics research and clinical communities have developed some 
consensus about which disease-associated genetic results are “actionable” for patients and 
their healthcare providers. At the same time, professional variant interpretation standards and 
increased data sharing have increased the validity of genetic variant interpretation. Familial 
hypercholesterolemia (FH) is an example of an actionable monogenic disease, and validated 
FH variants are now being identified among participants of the Million Veteran Program (MVP). 
However, it remains uncertain whether patients and their healthcare providers will use such 
genetic results to change clinical management.
Objectives
The purpose of the MVP-ROAR-FH (Return Of Actionable Results) study is to develop a 
process to return medically actionable genetic results to living MVP participants and to 
determine the impact of doing so on medical management and outcomes and Veteran quality of 
life. 
Methods
This a randomized controlled trial of immediate vs. delayed (after 6 months) return of FH variant 
results. After first being given the opportunity to opt out of participating from the MVP Core study 
team, living MVP participants with an actionable FH variant are contacted by the MVP-ROAR-
FH genetic counselor (GC). The GC discusses the fact that MVP researchers have identified a 
genetic result that might give the participant and his/her healthcare providers information about 
his/her risk of heart disease from cholesterol but that this is a research result and would have to 
be confirmed in a clinical laboratory. After consenting to participate in the study, the participant 
completes a baseline survey and presents to his/her local VA facility for a blood draw or 
provides a saliva sample using a self-collection kit. After confirmed biospecimen collection by 
study staff, participants are randomly allocated to the Immediate Results or Delayed Results 
arm. Baseline cholesterol values from all participants are measured from blood specimens or, in 
the absence of a blood draw, are obtained from the medical record. Biospecimens (blood or 
saliva) from participants in the Immediate Results arm are sent for FH variant confirmation. 
Upon receiving the variant confirmation results, the GC calls participants in the Immediate 
Results arm to deliver the study intervention at baseline. Briefly, the GC lets the participant 
know the results of the FH variant confirmation and delivers standard post-test genetic 
counseling, including the provision of FH-related resources and other information and facilitation 
of cascade genetic testing of family members, if appropriate. The GC also sends the results and 
physician-level materials about FH to the participant’s primary care provider (PCP). Participants 
in the Delayed Results group receive only their cholesterol results at baseline. During the 6 
months after enrollment, participants in both arms continue receiving usual care from their PCPs 
and other healthcare providers as usual. After 6 months, participants in both arms complete a 
follow-up survey and undergo an end of study blood draw for repeat cholesterol panel testing 
and, for participants in the Delayed Results arm, FH variant confirmation testing using either 
blood or saliva. After their end-of-study data collection is complete, the GC contacts participants 
in the Delayed Results arm to deliver the same study intervention the Immediate Results arm 
received. A subset of PCPs whose patients received results from MVP-ROAR will be invited to 
participate in qualitative interviews about their experience with the project and to identify 
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facilitators and barriers to effective genetic return of results in Veteran healthcare.  The primary 
hypothesis is that the reduction in low-density lipoprotein cholesterol after 6 months will be 
greater in the Immediate Results arm compared to the Delayed Results arm. Secondary 
outcomes include changes in medications, cascade genetic testing among family members, 
quality of life, and healthcare costs.
Anticipated Impact on Veteran Healthcare
This project has the potential to improve the health care and health outcomes for MVP 
participants with FH variants while also generating generalizable knowledge about the 
processes and outcomes of returning genetic results to research participants. The processes 
developed and studied in this project could inform best practices for the return of genetic results 
in MVP participants in the VA for other conditions.
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List of Abbreviations
ACC
American College of Cardiology
ACMG
American College of Medical Genetics and Genomics
AE
Adverse event
AHA
American Heart Association
AMP
Association of Molecular Pathology 
APOB
Apolipoprotein B gene
B
Benign
CHD
Coronary heart disease
CLIA
Clinical Laboratory Improvement Amendments 
CVD
Cardiovascular disease
FDA
Food & Drug Administration
FH
Familial hypercholesterolemia
GC
Genetic counselor
GMS
Genomic Medicine Service
HERC
Health Economics Resource Center
III
Individually identifiable information
LB
Likely benign
LDL-C 
Low-density lipoprotein cholesterol 
LDLR
Low-density lipoprotein receptor gene
LP
Likely pathogenic
MCA
Managerial Cost Accounting
MOU
Memorandum of Understanding
MVP
Million Veteran Program
P
Pathogenic
PCP
Primary care provider
PCSK9
Proprotein convertase subtilisin/kexin type 9 gene
PHI
Protected health information
RCT
Randomized controlled trial
ROAR
Return of actionable results
ROR
Return-of-results
SAE
Serious adverse event
SLCO1B1
Solute carrier organic anion transporter family member 1B1 gene
SOP
Standard operating procedure
UP
Unanticipated problem
VA
Veterans Affairs
VUS
Variant of uncertain significance
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Table of Contents
1.0 
Study Personnel
7
2.0 
Introduction
8
3.0 
Objectives
10
4.0 
Resources and Personnel
12
5.0 
Study Procedures
14
5.1 Study Design
14
5.2. Recruitment Methods
21
5.3 Informed Consent Procedures
22
5.4 Inclusion/Exclusion Criteria
23
5.5 Study Evaluations
23
5.6 Data Analysis
26
5.7 Withdrawal of Subjects
27
6.0 
Reporting
27
7.0
Privacy and Confidentiality
29
8.0 
Communication Plan
31
9.0 
References
32
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Appendices
Living MVP Participants with FH Variants (LDLR)
MVP-ROAR-FH Informed Consent Letter
MVP-ROAR-FH Informational Sheet
MVP-ROAR-FH Informational Sheet (Pilot)
MVP-ROAR-FH GC IC Phone Script
MVP-ROAR-FH Instructions for Saliva Collection
MVP-ROAR-FH Baseline Survey
MVP-ROAR-FH Survey Cover Letter
MVP-ROAR-FH Loss to Follow-Up Letter (General / Result version)
MVP-ROAR-FH Baseline Letter to Delayed Results Arm
MVP-ROAR-FH Physician Letter (Delayed Results)
MVP-ROAR-FH 6-Month Survey (Immediate Results version)
MVP-ROAR-FH 6-Month Survey (Delayed Results version)
MVP-ROAR-FH Immediate Results 6-Month Letter
MVP-ROAR-FH Physician Immediate Results 6-Month Letter
Sample Lipid Report
MVP-ROAR-FH GC Result Delivery Process
MVP-ROAR-FH Patient Results Letter (Positive / Negative version)
Clinical Variant Report
MVP-ROAR-FH Family Letter
MVP-ROAR-FH Physician Letter (Immediate Results) (Positive / Negative version)
MVP-ROAR-FH Sample Post-counseling CPRS Note
MVP-ROAR-FH Study Withdrawal Letter
MVP-ROAR-FH PCP Email Invitation
MVP-ROAT-FH Draft Interview Guide
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Protocol Title:  
Million Veteran Program Return Of Actionable Results (MVP-ROAR-FH)
1.0 
Study Personnel
1.1 Principal Investigator:
●Jason Vassy, MD, MPH, SM
Clinician-Investigator, Section of General Internal Medicine, 
VA Boston Healthcare System
Associate Professor of Medicine, Harvard Medical School
1.2 Executive committee for the study:
The executive committee will conduct ongoing scientific and operational review of study 
activities. This committee includes an interdisciplinary collection of clinicians and researchers 
with expertise in FH, clinical cardiology, genomic medicine, epidemiology, biostatistics, genetic 
return-of-results, genetic counseling, and econometrics. This committee will meet virtually 
biweekly, chaired by Dr. Vassy. Members of the executive committee:  
●Themistocles (Tim) L. Assimes, MD, PhD
Associate Director, Epidemiology Research and Information Center for Genomics, 
VA Palo Alto Health Care System 
Associate Professor of Medicine, Stanford University 
●Charles A. Brunette, PhD
Health Science Specialist
VA Boston Healthcare System
●Kurt D. Christensen, MPH, PhD 
Instructor of Medicine, Harvard Medical School and Brigham and Women’s Hospital
●Morgan Danowski, MS, LCGC
Genetic Counselor
VA Boston Healthcare System
●
Qin Hui, MS
Genetic Data Analyst, Rollins School of Public Health, Emory University
●Joshua W. Knowles, MD, PhD
Chief Research Advisor, FH Foundation  
Assistant Professor of Medicine, Stanford University 
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●Pradeep Natarajan, MD, MMSc 
Director of Preventive Cardiology at Massachusetts General Hospital
Assistant Professor of Medicine, Harvard Medical School 
●Amy Sturm, MS, LCGC 
Professor and Director, Cardiovascular Genomic Counseling, Geisinger Health
●Yan Sun, PhD
Associate Professor of Epidemiology, Emory University
●Virginia Morrison, MS, LCGC
Genetic Counselor, Genomic Medicine Service, 
VA Salt Lake City Health Care System
●Peter Wilson W.F. Wilson, MD
Director of Epidemiology and Genomic Medicine, Atlanta VA Medical Center
Professor of Medicine, Division of Cardiology, Emory University
1.3 Potential participating sites
Because eligible participants for this study include Million Veteran Program (MVP) participants 
found to have potentially actionable genetic variants, participants and their PCPs may be drawn 
from more than 50 VA locations, primarily but not limited to those with high MVP enrollment (see 
Living MVP Participants with FH Variants (LDLR)). Study procedures, including recruitment, 
consent, delivery of the intervention, and data collection will be conducted centrally by the MVP-
ROAR study team. MVP local site investigators will be notified each time a participant is 
enrolled from their site. Recruitment start-up will be graduated. A non-randomized pilot trial will 
be conducted among 10 eligible MVP participants from the VA Boston Healthcare System and 
1-2 other VA locations before initiation of the larger randomized controlled trial (RCT) across the 
entire MVP cohort. 
2.0 
Introduction
2.1 Return of results to research biobank participants
Since 2011, MVP has enrolled participants who receive clinical care in the VA healthcare 
system to understand role of genetics in health1. Participants provide broad consent to use their 
samples and survey and healthcare data for research and consent to be contacted in the future 
about additional research opportunities. One of the opportunities afforded by biobanks linked to 
integrated healthcare systems is the ability to screen for genetic risk factors that, if reported to 
participants and their healthcare providers, may inform their health care and improve health 
outcomes. Biobank participants routinely state that they would desire and expect actionable 
medical findings to be returned for their benefit2,3. The ethics and practicalities of such return are 
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complicated, but there is an emerging consensus that biobanks should consider reporting 
clinically validated results in genes deemed medically actionable4-8. 
2.2 Familial hypercholesterolemia: A medically actionable genetic diagnosis
A common monogenic condition, familial hypercholesterolemia (FH) is an ideal test case for 
piloting genetic return of results in MVP. Cardiovascular disease, including coronary heart 
disease (CHD) is the leading cause of death in Veterans. Elevated low-density lipoprotein 
cholesterol (LDL-C) level is an important, prevalent, and modifiable CHD risk factor9. 
Characterized by extreme LDL-C elevation, FH occurs in approximately 1 in 250 in the US10-12 
and markedly raises premature CHD risk, independent of cross-sectional LDL-C values10,13,14. 
Familial hypercholesterolemia can be caused by variants in the low-density lipoprotein receptor 
(LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and 
low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes. In current practice, FH 
may be identified through routine lipid testing, but only 1 in 50 individuals with severe 
hypercholesterolemia have FH mutations and some FH mutation carriers may not have severely 
elevated LDL-C. However, across LDL-C values, even when not markedly elevated, FH 
mutation status portends increased risk of premature CHD. Cholesterol values seen in common 
hypercholesterolemia can overlap considerably with those seen in FH, particularly in middle-
aged and older adults15,16. As a result, an estimated 90% of FH cases in the US remain 
undiagnosed17.
Compared to common hypercholesterolemia, an FH diagnosis changes prognosis and 
management, as FH individuals have much greater CHD risk than would be predicted by usual 
risk models and require earlier and more aggressive therapy and surveillance. Individuals with 
FH have a 10 to 20-fold higher lifetime CHD risk than those without. Even compared to 
individuals with equivalent LDL-C levels at a single measurement, FH heterozygotes have a 3-
fold higher of CHD compared to matched patients without an FH variant14,18,19. Contemporary 
observational analyses indicate a greater relative and absolute clinical benefit of LDL-C-
lowering with statins among those with FH mutations20. Thus, the American Heart Association 
and American College of Cardiology recommend intensive LDL-C lowering (<100 mg/dL or <70 
mg/dL, depending on other risk factors) when FH is present, which might necessitate statin 
dose escalation or the addition of ezetimibe or a PCSK9 inhibitor to high-dose statin therapy21,22. 
Diagnosing FH among MVP participants and distinguishing it from common 
hypercholesterolemia thus has the potential to improve the healthcare of the Veteran. 
Considerable data suggest that many patients with FH are undiagnosed and undertreated, 
resulting in many potentially preventable myocardial infarctions and deaths23-28. Indeed, in 
preparatory-to-research analyses for this proposal, only 240/642 (37%) MVP participants with a 
potential FH variant in one of the 3 FH genes have a most recent LDL-C <100mg/dL, and only 
397/642 (62%) have been prescribed a statin of any dose in the last year. This is consistent with 
observations in other healthcare settings29,30. Moreover, some healthcare providers remain 
skeptical that a genetic diagnosis of FH should change clinical management over and above 
non-genetic approaches to risk prediction and management. 
Identifying an FH variant in an individual also carries family implications. National registry 
projects demonstrated the benefits of systematic FH case-finding with genetic screening and 
cascade testing in family members and show that such an approach may lead to more complete 
capture, earlier treatment of undiagnosed FH, and cost-effective CHD risk reduction15,17,31-34. 
Thus, several professional organizations and the Centers for Disease Control and Prevention 
endorse cascade screening among first-degree relatives of patients with an FH variant as an 
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effective genomic medicine intervention with high evidence of clinical utility17,21. Because of its 
actionability, FH is on the American College of Medical Genetics and Genomics (ACMG) list of 
reportable monogenic conditions35. Thus, identification of MVP participants has the potential to 
improve the lives not only of the Veteran but also their children, siblings and other family 
members.
2.3 Emerging consensus around FH variant interpretation and management
Clinical laboratories currently use American College of Medical Genetics and Genomics 
(ACMG) - Association for Molecular Pathology (AMP) standards and guidelines to classify 
individual genetic variants into one of five pathogenicity categories for a given disease: benign 
(B), likely benign (LB), variant of uncertain significance (VUS), likely pathogenic (LP), or 
pathogenic (P)36. In clinical testing, it is standard of care to report only P and LP variants back to 
ordering providers and patients when unexpected actionable genetic variants are identified35,37. 
The ACMG-AMP standards ask laboratories to apply a set of 28 criteria to classify each variant, 
using evidence such as population data, computational data, functional data, and segregation 
data. Once a laboratory interprets a given variant, it is encouraged to share that interpretation in 
a publicly accessible database such as ClinVar38, along with any criteria it used to make its 
determination of pathogenicity. Because there is some subjectivity in how laboratories apply the 
ACMG-AMP criteria39, some variants have conflicting interpretations in ClinVar. ClinVar uses a 
4-star rating system for the variant interpretations in its database, corresponding to the level of 
evidence behind each variant classification. Recognizing that content expertise is required to 
adjudicate the application of ACMG-AMP criteria to specific disease-gene associations, the NIH-
funded Clinical Genome Resource (ClinGen) was created in part to implement evidence-based 
disease expert consensus for curating genes and variants40. ClinGen organizes expert curation 
groups for individual diseases, such as FH. These expert curation groups develop consensus 
for applying ACMG-AMP criteria in classifying variant pathogenicity for specific diseases and 
their associated genes. Only variants that are classified by such expert panels can achieve a 3- 
or 4-star interpretation in ClinVar.
This project will use ClinVar data and the ongoing curation work of the ClinGen Cardiovascular 
Familial Hypercholesterolemia Variant Curation Expert Panel41,42 (co-led by Dr. Knowles) to 
ensure that only variants with high-quality LP or P classifications are returned to participants. As 
of May 2019, the panel’s FH-specific variant criteria have been finalized and are awaiting 
ClinGen approval, after which the panel will begin to systematically review the >2000 LDLR 
variants listed in ClinVar. We will only consider returning FH variants classified as LP or P 
according to ACMG-AMP for this project. Thus, it is important to note that, although these are 
research-derived results, their interpretation will meet clinical standards. Indeed, in December 
2018 the US Food and Drug Administration (FDA) formally recognized genetic variant 
information from the ClinGen Expert Curated Human Genetic Database as a source of valid 
scientific evidence that can be used to support clinical validity in premarket submissions for 
diagnostics tests, the first database to receive such recognition. 
 
Although FH may go undiagnosed in routine care, the risk of hypercholesterolemia for CHD in 
general is widely appreciated in the medical community and among patients. As a result, gaps 
in genetic literacy may pose less of a barrier for FH return-of-results versus other monogenic 
conditions. Professional FH guidelines and educational resources exist to help patients and 
providers manage an FH diagnosis, and these resources will be used in this project to support 
the responsible and clinically meaningful return of genetic results to MVP participants. 
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For all the reasons above, FH is the ideal test case for piloting genetic return-of-results in MVP.  
Although the ACMG lists FH among its actionable conditions and there is emerging expert 
consensus about how to interpret and manage FH variants, it is unknown whether participants 
in a biobank study like MVP and their healthcare providers will be receptive to the information 
and change clinical management accordingly. Moreover, the return-of-results process may bring 
unanticipated harms, such as distress or anxiety, that would be important to quantify and 
address. Thus, there is equipoise in whether actionable genetic results should be returned to 
biobank participants. This study will use a randomized design to test the hypothesis that 
returning FH variants to MVP participants and their providers will result in lower LDL cholesterol 
levels. If the return-of-results process described in this protocol does not change clinical 
management or results in undue participant distress, further study will be needed to improve the 
process and achieve net benefit to patient-participants. 
3.0 
Objectives
3.1 Study purpose/aims
The purpose of this study is to develop a process to return medically actionable genetic results 
to living MVP participants and determine the impact of doing so on medical outcomes, Veteran 
quality of life, and healthcare costs. We will determine this impact by using an RCT of reporting 
Immediate Results vs. Delayed Results (after 6 months) to test the hypotheses in Section 3.2.  
3.2 Study outcomes and hypotheses
3.2.1. Primary outcome
The primary outcome will be the change in LDL-C from study baseline to the end of study (6 
months after enrollment). We will test the hypothesis that the LDL-C reduction after 6 months 
will be greater in the Immediate Results arm compared to the Delayed Results arm.
3.2.2. Secondary outcomes
We will test the following secondary hypotheses:
1.
The proportion of participants meeting clinically significant LDL-C targets (< 100mg/dL for 
primary prevention and <70 mg/dL for secondary prevention) at 6 months will be greater in 
the Immediate Results arm than in the Delayed Results arm.
2.
The proportion of participants with an intensification of lipid-lowering pharmacotherapy will 
be greater in the Immediate Results arm than in the Delayed Results arm. This composite 
outcome will include prescription of new monotherapy, dose escalation of existing 
pharmacotherapy, and addition of one or more medications to existing pharmacotherapy.
3.2.3. Exploratory outcomes
We will test the following exploratory hypotheses:
1.
Medication adherence at 6 months will be higher in the Immediate Results arm than in the 
Delayed Results arm.
2.
Participants in the Immediate Results arm will report a greater number of first-degree 
relatives having undergone genetic testing at 6 months than in the Delayed Results arm.
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3.
A greater proportion of participants in the Immediate Arm will have healthy lifestyle 
behaviors (smoking, physical activity, and saturated fat intake) at 6 months than in the 
Delayed Results arm. 
3.2.4. Economic outcomes
We will perform a budget impact analysis of the intervention alongside the randomized trial, as 
described in Section 5.6 Data Analysis below.
3.2.5 Provider outcomes
We will describe VHA primary care providers’ perceptions of the facilitators and barriers of 
return of actionable genetic results to MVP participants nationwide. 
3.3 Relevance to Veterans and VA
This project has the potential to improve the health care and health outcomes for MVP 
participants with FH variants while also generating generalizable knowledge about the 
processes and outcomes of returning genetic results to research participants. 
The reporting of potentially pathogenic FH variants to MVP participants and their healthcare 
providers might impact participants’ clinical outcomes in the following ways. First, for Veterans 
without prior cholesterol testing, receipt of such a variant could prompt them and their providers 
to initiate routinely recommended healthcare screening. Given the high rates of cholesterol 
screening in the VA, a small proportion of participants are likely to fall into this category43. 
Second, for Veterans with prior elevated cholesterol results not already on therapy, disclosure of 
an FH variant result might prompt initiation of statin therapy after discussion with their 
healthcare provider. Third, an FH variant result will identify participants who are already on lipid-
lowering therapy but are undertreated for their level of CHD risk per current guidelines. These 
participants and their providers might intensify current lipid-lowering regimens, by maximizing 
statin intensity (medication and dose) or adding additional agents such as ezetimibe or a 
PCSK9 inhibitor as necessary. The end result for all of these pathways would be an overall 
reduction in LDL-C values among participants receiving FH variant results, mediated by a 
change in therapy. Since LDL-C is a well-recognized causal mediator of CHD, LDL-C reduction 
is an established surrogate endpoint for CHD risk reduction. Beyond the MVP participants 
themselves, an important additional benefit of reporting FH variants may be a greater uptake of 
family-based screening among these Veterans’ family members. 
Moreover, the processes developed and studied in this project could inform best practices for 
the return of genetic results in MVP participants in the VA for other conditions.
4.0 
Resources and Personnel
4.1 
 
 Study personnel
 
 
All study personnel listed below will have access to protected health information.
4.1.1 Principal investigator
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The principal investigator (PI) supervises all aspects of the study. The PI takes ultimate 
responsibility for the conduct of the study, including meeting study goals, monitoring of 
participant safety, and dissemination of findings.   
4.1.2 Project manager
The project manager (PM) oversees the day-to-day operations of the study, under the 
supervision of the PI. The PM, in conjunction with the PI and relevant study personnel, 
develops and maintains study-related standard operating procedures (SOPs). The PM is 
the primary point of contact between the study personnel and the IRB and works with the 
IRB to maintain approval for the study protocol and associated documents, including 
relevant correspondence for protocol modifications, continuing reviews, regulatory 
audits, and event reporting. The PM coordinates and leads regular meetings among the 
study personnel and collaborators, including preparing meeting agendas and minutes. 
The PM oversees the study budget and is the primary point of contact between the study 
and vendors. The PM oversees records management for all study-related documents 
and materials. The PM may delegate some of these tasks to the research assistant as 
appropriate. The PM escalates study-related problems to the PI, including any 
participant safety concerns identified.
4.1.3 Genetic counselor
The genetic counselor (GC) designs and delivers the study intervention to participants 
and their PCPs. The GC works with the PI and PM to develop the genetic counseling-
related materials for review by the IRB. The GC works with the PM to develop the SOP 
for each step in the return-of-results process, including the ordering of variant 
confirmation testing, sample acquisition and shipping for variant confirmation testing, 
receipt of variant confirmation results, reporting of results and associated supportive 
information to participants and their PCPs, and entry of genetic results into the 
participants’ medical record. The GC describes the study to participants and obtains 
informed consent. The GC may administer the baseline survey, if conducted at the same 
time as informed consent. The GC delivers the post-test genetic counseling intervention 
and works with participants to facilitate cascade genetic testing of family members, as 
appropriate. The GC is available for follow-up questions by participants and their 
healthcare providers. The GC is the primary point of contact between the study and the 
VA-approved, CLIA-certified laboratory used for FH variant confirmation. The GC 
escalates clinical questions/concerns to the PI, including any participant safety concerns, 
and escalates research-related questions to the PM.    
4.1.4 Senior genetic counselor
The senior GC is a practicing genetic counselor in the VA healthcare system. As 
applicable, the senior GC guides the use of existing clinical genomic medicine services 
to facilitate the clinical variant confirmation testing and reporting. 
4.1.5. Research assistant
The research assistant (RA) performs study tasks under the supervision of the PM. 
These include literature reviews; drafting and formatting of IRB and other regulatory 
documents; preparation of materials for study meetings; formatting of data tables and 
figures; and drafting of research posters and presentations. The RA performs initial 
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participant eligibility screening by chart review, escalating any questions to the GC. 
Under the direction of the PM, the RA sends participant mailings at appropriate times. In 
collaboration with the GC, the RA communicates with local sites to make arrangements 
for participant blood draws, to facilitate entry of genetic results into the medical record, 
and to prepare letters and accompanying materials for patients, their families, and PCPs. 
The RA administers the baseline and end-of-study participant surveys. The RA facilitates 
the distribution of participation incentives to participants. The RA escalates clinical 
questions to the GC and research questions to the PM.
4.1.6. Statistician
The statistician advises the study team on the appropriate study design and statistical 
analyses for the study outcomes. The statistician conducts sample size and power 
calculations and supervises the data analyst in performing statistical analysis of study 
data.   
4.1.7 Data analyst
The data analyst (DA) creates and maintains the database housing the study data. The 
DA creates a data capture system to collect and merge data from participant surveys, 
medical records, and other VA databases. The DA ensures that data capture and 
management systems comply with required data security standards. The DA prepares 
summary data tables for study planning, reporting, monitoring, and dissemination of 
results. Under the direction of the statistician, the DA performs statistical analyses of 
study outcomes.
4.2 Services
The study staff will partner with VA Genomic Medicine Service (GMS) to facilitate clinical 
genetic confirmation testing and report processing for the MVP-ROAR-FH Study. The 
GMS will provide services and support for FH variant confirmation testing as arranged 
for MVP-ROAR-FH participants by study staff. GMS uses the VA’s telehealth 
infrastructure to provide clinical genetic services to Veterans in over 90 facilities 
throughout the country. Part of their service includes an ability to order germline genetic 
tests for Veterans, with an established process to facilitate testing with commercial 
laboratories. As applicable, study staff will use established GMS processes to carry out 
clinical confirmation testing with a VA-approved CLIA-certified laboratory. Biospecimen 
samples will be labeled with participant name, date of birth, gender, and relevant variant 
for clinical confirmation, and shipped to the VA Boston Healthcare System clinical 
laboratory for lipid testing and dissemination to the VA-approved CLIA-certified 
laboratory for genetic confirmation testing.
5.0 
Study Procedures
5.0.1 Study timeline
 
 
Year 1
Year 2
Year 3
 
Q1
Q2
Q3
Q4
Q
1
Q2
Q3
Q4
Q1
Q2
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Non-randomized pilot testing of study intervention                  
(10 eligible MVP participants)                         
 
 
 
 
 
 
 
 
 
Patient recruitment and enrollment                                            
(20-21 patients per month x 12 months = 244)
 
 
 
 
 
 
 
 
 
 
Return of results to patients in immediate results arm             
 
 
 
 
 
 
 
 
 
 
Return of results to patients in delayed results arm                 
 
 
 
 
 
 
 
 
 
 
Patient data collection                                                                  
(6-month outcomes; EHR and survey data)
 
 
 
 
 
 
 
 
 
 
Data preparation and analysis for clinical outcomes
 
 
 
 
 
 
 
 
 
 
Report on primary outcomes to ORD
 
 
 
 
 
 
 
 
 
 
Data preparation and analysis for economic outcomes
 
 
 
 
 
 
 
 
 
 
Participant and provider qualitative interviews and analysis
 
 
 
 
 
 
 
 
 
 
Dissemination of results
 
 
 
 
 
 
 
 
 
 
5.1 Study Design
5.1.1. Study overview
This project is an RCT of immediate versus delayed (after 6 months) reporting of clinically 
confirmed FH variants among 244 MVP participants. In an initial non-randomized pilot phase of 
the project, the below procedures will be piloted among 10 eligible participants, all of whom will 
receive their results immediately at baseline. 
Figure 1 illustrates the RCT study design, which is further described in the relevant sections 
below. In brief, the study procedures include the following:
●
Living MVP participants with an eligible FH variant are mailed a letter from the MVP Core 
study team, introducing this new MVP-related study and giving participants the opportunity 
to opt out of further contact about the study by returning a prepaid opt out postcard or by 
calling the MVP Call Center.
●
To any participant who does not opt out within 2 weeks of this initial mailing, the MVP-
ROAR-FH study team mails a letter giving more detail about the study, including all 
necessary informed consent information (see MVP-ROAR-FH Informed Consent Letter and 
MVP-ROAR-FH Informational Sheet). Participants in the non-randomized pilot of the study 
procedures will be mailed a letter introducing the study as well as an informational 
document including all elements of informed consent (see MVP-ROAR-FH Informed 
Consent Letter and MVP-ROAR-FH Informational Sheet (Pilot)).
●
Two weeks after this mailing, the study genetic counselor calls the participant to review the 
informed consent information, answers any questions about the study, and documents 
verbal consent or decline (see MVP-ROAR-FH GC IC Phone Script). Study staff also 
conduct the baseline survey (see MVP-ROAR-FH Baseline Survey) on this phone call or on 
another call scheduled at a convenient time for the participant. Participants may complete 
the baseline survey in paper form by request (see MVP-ROAR-FH Survey Cover Letter). 
Potentially eligible participants not reached after at least three contact attempts by phone 
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will be sent a loss to follow-up letter (MVP-ROAR-FH Loss to Follow-Up Letter) via certified 
mail.   
●
The genetic counselor works with each consented participant and local laboratory staff to 
facilitate the collection of biospecimen(s). Two tubes of blood will be collected at baseline, 
one for baseline lipid panel testing and a second for potential CLIA-certified FH variant 
confirmation (performed by a commercial genetic laboratory). Alternatively, a saliva sample 
may be collected remotely from the participant for FH variant confirmation using a self-
collection kit. Participants may utilize this option if they have undergone lipid testing at their 
local VA facility within the last 6 months and without a subsequent change in lipid-lowering 
medications. 
●
After the MVP-ROAR-FH study staff confirms baseline biospecimen collection, participants 
in the RCT are randomly assigned to the Immediate Results arm or the Delayed Results 
arm. (Participants in the non-randomized pilot will receive their results immediately at 
baseline).
●
Immediate Results arm
 
 : The participant’s baseline specimen for variant confirmation is 
shipped to the reference laboratory for clinical variant confirmation of their research results. 
The laboratory returns these results to the genetic counselor, who schedules a telephone 
or video visit with the participant, to deliver the intervention described in Section 5.1.3 
below. Briefly, he/she lets the participant know the results of the FH variant confirmation 
and delivers standard post-test genetic counseling, including the provision of FH-related 
resources and other information. This genetic counseling session is neither audio- nor 
video-recorded. If the Veteran has living family members, he/she will also educate and 
provide resources for cascade genetic testing of those family members. The genetic 
counselor also sends the genetic and cholesterol results and physician-level materials 
about FH to the participant’s PCP. Participants not reached after at least three contact 
attempts by phone will be sent a loss to follow-up letter (MVP-ROAR-FH Loss to Follow-Up 
Letter_Result) via certified mail.   
o
Delayed Results arm
 
 : The participant’s baseline blood specimen for variant confirmation 
is discarded. If collected using saliva, the participant’s baseline specimen will be stored 
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in a locked and secure cabinet for six months, at which time the sample may be shipped 
to the laboratory for variant confirmation The study staff sends the participant a letter 
letting them know that they were assigned to the delayed results group and that they will 
be contacted in 6 months to have their research result confirmed (see MVP-ROAR-FH 
Baseline Letter to Delayed Results Arm). This letter also includes the participant’s 
baseline cholesterol results. A copy of this letter is also sent to the participant’s PCP 
(see MVP-ROAR-FH Physician Letter (Delayed Results)). 
●
During the 6 months after enrollment, participants will continue receiving usual care from 
their PCPs and other healthcare providers. As discussed below in Section 5.1.3, PCPs of 
patients in the Immediate Results arm may choose to change the patient’s treatment or 
refer the patient to a specialist. 
●
Six months after randomization, study staff will contact each participant to conduct an end-
of-study telephone survey (see MVP-ROAR-FH 6-Month Survey (Immediate Results 
version) and MVP-ROAR-FH 6-Month Survey (Delayed Results version)) and arrange for 
the participant to have end-of-study fasting lipid panel testing at their local laboratory. A 
second specimen, either blood or saliva, will be collected from participants in the Delayed 
Results arm for clinical variant confirmation testing. Participants may complete the follow-
up survey in paper form by request (see MVP-ROAR-FH Survey Cover Letter).
●
After their end-of-study data collection is complete, the genetic counselor contacts 
participants in the Delayed Results arm to deliver the same study intervention the 
Immediate Results arm received at baseline. Participants not reached after at least three 
contact attempts by phone will be sent a loss to follow-up letter (MVP-ROAR-FH Loss to 
Follow-Up Letter_Result) via certified mail.   
●
After their end-of-study data collection is complete, participants in the Immediate Results 
arm receive a letter with their follow-up cholesterol results (see MVP-ROAR-FH Immediate 
Results 6-Month Letter, MVP-ROAR-FH Physician Immediate Results 6-Month Letter, and 
MVP-ROAR-FH Sample Lipid Report) 
●
Study staff will recruit participant’s VA PCPs for interviews about the barriers and benefits 
they perceive in genetic return-of-results. The interviews will be conducted, recorded, and 
transcribed via Microsoft Teams, a VA-approved system.  
5.1.2. Usual care
In this project, usual care is defined as the current approach to screening and management of 
hypercholesterolemia across the VA healthcare system. Currently, VA locations already achieve 
high rates of cholesterol screening in their general patient population43. Using guidelines such 
as the 2014 VA/DoD Clinical Practice Guideline for the Management of Dyslipidemia for 
Cardiovascular Risk Reduction or the 2018 ACC/AHA Multisociety Guideline on the 
Management of Blood Cholesterol, VA clinicians use cholesterol results, along with other risk 
factors including blood pressure, diabetes status, and smoking status, to determine whether a 
Veteran’s CVD risk is high enough to merit consideration of treatment with a statin medication. 
Without other CVD risk factors, VA guidelines do not recommend treating based on elevated 
LDL-C levels alone unless they are ≥190 mg/dL. Depending on a Veteran’s CVD risk, a VA 
clinician might recommend dietary modification and/or initiate therapy with a statin, such as 
atorvastatin, simvastatin, or rosuvastatin. Current guidelines recommend that providers repeat 
cholesterol testing periodically after initiation of therapy to monitor LDL-C reduction. For patients 
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for whom maximum-dose statin therapy is not tolerated or does not achieve sufficient LDL-C 
reduction, providers might replace or add other medications such as ezetimibe or a PCSK9 
inhibitor. 
As discussed in Section 2.2, the guidelines for cholesterol management differ significantly for 
individuals with FH, although most of these individuals go clinically unrecognized. FH can be 
clinically recognized without genetic testing using varying definitions, such as the Simon 
Broome Register criteria, Dutch Lipid Clinic Network criteria, and Make Early Diagnosis to 
Prevent Early Deaths criteria19. However, clinical definitions of FH rely on data that are not 
necessarily collected systematically in busy clinical practice, such as a detailed family history of 
hypercholesterolemia or coronary heart disease and the presence of tendinous xanthomata or 
arcus cornealis on physical examination19,20. Recently, an expert consensus panel 
recommended that genetic testing for FH variants in the LDLR, APOB, and PCSK9 genes be 
performed for any patient meeting a clinical definition for “probable” or “definite” FH34, but these 
recommendations have not been widely adopted. Moreover, not all FH patients have an LDL-C 
≥190 mg/dL at a given measurement in time. In a recent analysis of data from the Geisinger 
Healthcare System, only 55% of patients with an FH variant had a maximum LDL-C ≥190 mg/dL 
in their medical record. Nonetheless, we know that such individuals have a 3-fold higher of CHD 
compared to matched patients without an FH variant and would thus be recommended to be 
treated with lipid-lower therapy to a target LDL-C <100mg/dL. Among 325 living MVP 
participants with a potentially pathogenic LDLR variant, 177 (54%) have a most recent LDL-C > 
100 mg/dL.  
In this context, usual care in this project includes the following:
●VA clinicians, most commonly PCPs, order periodic cholesterol testing for their patients.
●Based on cholesterol results, plus other risk factors including age, sex, blood pressure, 
diabetes status, prior CVD, and smoking status, PCPs consider initiating treatment with 
lifestyle modification with or without pharmacotherapy, including statins or other agents.
●PCPs follow these patients at regular intervals, periodically repeating cholesterol testing to 
monitor for medication adherence and appropriate LDL-C response. PCPs may escalate 
therapy (e.g. increasing the dose of statin therapy or adding ezetimibe to statin therapy) for 
patients not meeting their LDL-C goals. 
●There is significant variability in patients’ willingness to take statin or other medications.
●Depending on individual and regional practice patterns and availability, PCPs may refer 
certain patients to a preventive cardiology or lipid clinic, if cholesterol results are particularly 
abnormal or if there is some other concerning feature relevant to the patient’s CVD risk. 
●The astute PCP or specialist may perform a detailed physical examination and family history 
relevant to FH and apply FH clinical criteria to determine whether the patient has a clinical 
diagnosis of FH.
●For patients meeting clinical criteria for FH, some providers may consider genetic testing for 
FH variants to make a specific molecular diagnosis of FH (e.g. identifying the specific LDLR 
variant causing their disease). This would typically be performed with pre- and post-test 
genetic counseling, to discuss test results interpretation and implications for family 
members.   
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5.1.3. Intervention
In contrast to usual care, participants enroll in the MVP-ROAR-FH study with the knowledge that 
analysis of their MVP research sample potentially included information about their heart disease 
risk that might be useful for them, their healthcare providers, and their family members. 
Participants randomly assigned to the Immediate Results arm receive the following study 
intervention at baseline:
●Participants receive the results of their FH variant confirmation from the research genetic 
counselor (GC) via telephone or videoconferencing (see MVP-ROAR-FH GC Result Delivery 
Process). This genetic counseling session includes a detailed family history assessment and 
specific information about FH, including management guidelines, information about local 
specialists who treat patients with FH, recommendations for family members, and facilitation 
of genetic cascade testing of family members.
●A follow-up mailing or encrypted email to participants, corresponding to the variant 
confirmation result, reiterates the clinical implications (see MVP-ROAR-FH Patient Results 
Letter Positive or Negative).This mailing also includes a clinical variant report (see Clinical 
Variant Report), a family letter (see MVP-ROAR-FH Family Letter) that the participant may 
choose to share with family members, and available FH patient resources, as applicable.
●The GC also sends the participants’ PCPs a clinical variant report along with physician-level 
information about FH treatment guidelines and a list of specialists in the area who treat 
patients with FH (see MVP-ROAR-FH Physician Letter (Immediate Results) Positive or 
Negative), as applicable. This letter provides the contact information for the GC, who is 
available to answer additional questions from providers.
●The clinical variant report is submitted to the participant’s local VA for scanning into the 
medical record (See Clinical Variant Report). The genetic counselor also enters a clinical 
note in the local medical record summarizing the result (See Sample Post-counseling CPRS 
Note).
o
In the event the reference laboratory changes the classification of the 
result (e.g. likely pathogenic to pathogenic variant) the GC will send the 
participant a letter explaining the change (MVP-ROAR-FH 
Reclassification Letter). The updated result will also be shared with the 
participant’ PCP and entered into the medical record. 
●The essence of the study intervention is a genetic test result and supporting information 
about its clinical significance. Participants and providers may act on this information as they 
see fit. The study intervention does not include a specific treatment regimen or other 
protocolized management strategy.
●If the participant’s VA PCP contacts the GC for additional guidance, the GC can offer to 
facilitate a consultation between the PCP and a cardiologist associated with the study, who 
can provide management recommendations to the PCP.
Participants randomly assigned to the Delayed Results arm receive a letter informing them of 
their randomization status and including their cholesterol results (see MVP-ROAR-FH Baseline 
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Letter to Delayed Results Arm). They and their PCPs receive the above intervention 6 months 
after enrollment, after completing the end-of-study data collection procedures.  
5.1.4. Study population
The eligible study population includes any living MVP participant with a FH-associated genetic 
variant categorized as Pathogenic or Likely Pathogenic using ACMG-AMP variant interpretation 
criteria. Among the first >700,000 MVP participants genotyped, approximately 750 meet these 
criteria. We will enroll approximately 254 participants (10 for the pilot study and 244 for the 
randomized trial). Per standard clinical practice, the genetic counselor will facilitate cascade 
genetic testing among family members of participants found to have a clinically confirmed FH 
variant, but family members will not be considered research subjects, and no research data will 
be collected about them.
Upon completion of end of study data collection, study staff will invite patient-participants’ VHA 
PCPs to participate in a brief interview about their experience. 
5.1.4.1 Potentially vulnerable subjects
The MVP-ROAR-FH study population, including Veteran participants and PCP participants, may 
include some subjects considered vulnerable, including students, economically and/or 
educationally disadvantaged persons, or patients with debilitating or terminal illness. As a result, 
all potential participants will be informed during the consent process that participation in the 
study is entirely voluntary and that a decision to not participate or to withdraw from the study at 
any time has no bearing on the provision of medical care or the receipt of benefits to which the 
participant is otherwise entitled. Moreover, all participants will be provided opportunities to ask 
questions of the study staff as well as to consult others, including their families and/or providers, 
prior to participation. During the study, all participant primary care providers within VA will be 
provided information regarding their patients’ engagement in the study. The study will not 
include potentially vulnerable participants who are pregnant, incarcerated, or are unable to 
adequately understand study procedures and provide verbal consent to participate in the study. 
If it is suspected by the study staff that a participant meets vulnerable subject criteria during 
recruitment or enrollment, such information will be reported to the study PI for further 
assessment, action (i.e. study withdrawal), and/or required reporting.
5.1.5. Risks to participants
5.1.5.1. Anticipated risks
A principal risk of genetic testing is a breach of confidentiality, in which sensitive information 
concerning a patient’s genetic risk for disease becomes known. Moreover, the return of a 
genetic test result may lead to the diagnosis of a genetic condition and placement of such 
information into the medical record. As a result, there may be a risk that genetic information 
collected from participants during this study is used for the purposes of discrimination with 
regard to their health insurance or their job. Such recognition of genetic disease risk and/or 
diagnosis may affect their future insurance costs and/or coverage, such as denial of health, life, 
disability, or long-term care coverage. There are state, federal, and VA protections that prevent 
health insurance companies, group health plans, and most employers from discriminating 
against participants based on their genetic information.
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It is possible that participants may be distressed by learning the results of their genetic test. It is 
also possible that participants may feel anxious or distressed about being randomized to the 6-
month Delayed Results arm. Patient assessments including surveys and blood draws may also 
involve some risk. Some patients may experience distress or discomfort when answering 
questions about personal demographic and/or medical issues. Common risks associated with 
venipuncture include minor discomfort, lightheadedness, infection, or bruising at the site of the 
blood draw. 
VHA primary care providers will be contacted to participate in semi-structured interviews to 
explore the facilitators and barriers to return of genetic results within MVP. Interviews pose 
minimal risk to VA PCPs. They may experience embarrassment during the interview if they feel 
they do not know the “correct” answers to questions about genetic testing. They may also 
perceive coercion to participate in the study as a VA employee. There is also the unlikely risk to 
privacy of a breach of study data. 
5.1.5.2. Minimization of risks 
Prior to participation, all participants will undergo a detailed informed consent process by a 
genetic counselor (see section 5.3 Informed Consent Procedures). The genetic counselor will 
explain the risks and benefits of genetic confirmation testing and the risks and benefits of 
participation in this randomized control trial. The informed consent document will include all 
required elements of consent for study participation, including an explanation of the purposes of 
genetic testing, a description of known risks associated with genetic testing, a description of any 
benefits to the patient or others (e.g., familial cascade testing) that may reasonably be expected 
from genetic testing, and a statement describing the extent, if any, to which confidentiality of 
patient medical records, data, and/or samples identifying the patient or their genetic test results 
will be maintained. At any time, patients may elect not to participate. 
High levels of distress during patient survey assessments and blood draws are uncommon and 
staff will be trained to navigate such occurrences. Clinical blood samples will be collected by 
trained phlebotomists at patients’ local VA sites. 
Genetic testing results and related clinical information will be returned to participants and their 
PCPs, for the purposes of medical follow-up, by a trained GC. This information will be 
documented in the VA medical record, accessible to VA clinicians and others providing routine 
and/or specialty (e.g. cardiology, lipidology, genetics) care. 
Participants and their healthcare providers will have access to a dedicated GC throughout the 
entirety of the study, who will provide pre- and post-genetic test counseling and as-needed 
consultation. The GC will serve as a resource for both participants and their providers, and, in 
addition to genetic counseling, may provide education, make appropriate clinical referrals, and 
be available for additional support, questions, and concerns as necessary. Participants who are 
noted to be anxious, either by their genetic test result or randomization to the 6-month Delayed 
Results arm, will be identified by the GC and cases will be discussed with the principal 
investigator. The GC and principal investigator will use their best clinical judgment to determine 
the safest path forward for the participant which could include 1) engaging the participant ‘s 
provider 2) referral for additional clinical care (e.g., mental health or specialty care), and/or 3) 
withdrawal from the study (see section 5.7 Withdrawal of Subjects).
There may be other risks that are currently unknown. We will inform participants if any new 
information is discovered about the risks of taking part in this study and take steps to mitigate 
them as needed. Any adverse event or reaction experienced by participants in this study, 
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including those associated with genetic testing and/or survey or clinical assessment, will be 
reported by study staff to the VA Central IRB (see Section 6.0 Reporting). 
For the PCP interview study, VA PCPs may experience embarrassment during the interview if 
they feel they do not know the “correct” answers to questions about genetic testing. This will be 
minimized by the use of skilled interviewers. They may also perceive coercion to participate in 
the study as a VA employee. This will be minimized by a clear statement in the recruitment 
email and at the beginning of the interview that participation or non-participation will in no way 
impact their VA employment or performance evaluation. There is also the unlikely risk to privacy 
of a breach of study data. This will be minimized through use of VA-approved methods, 
including: collection of data via Microsoft Teams, storage of data in VINCI behind the VA firewall 
accessible only to approved study staff, and removal of all personal identifiers before the 
presentation or publication of data. The study is performed under a Certificate of Confidentiality.
5.1.5.3. Benefits
Potential benefits to participants include the acquisition of clinical information important to their 
current and future medical care. Specifically, awareness of FH risk by participants and their 
providers may aid in the management of a yet unknown, suspected, or current FH diagnosis or 
for identifying risk of future disease. This information would allow participants to collaborate with 
their providers to develop improved treatment, surveillance, and/or prevention options related to 
their FH risk. Early studies also show benefits of family cascade screening as a mechanism to 
identify at risk family members after known cases of FH are discovered34.
Benefits to society include an improved understanding of FH genetic testing and return of FH 
genetic test results. Very limited data exist regarding the benefits or harms of disclosing FH 
mutations to individuals and their families, especially individuals identified through population-
level screening, such as MVP, rather than those who are selected for genetic testing due to their 
own personal or family history of high cholesterol or FH. Population screening for FH genetic 
variants is not currently the standard of care. This study will allow us to obtain outcomes to 
explore how participant and provider knowledge of FH impacts medical care compared with 
currently accepted standards of care. This information may inform future policy, screening, and 
management guidance for FH, and for the use of genetic testing and the return of results more 
generally. 
VA PCPs participants may learn important information about the genetic testing process, but 
they will otherwise gain no direct benefit from participation. As a healthcare organization, VHA 
will benefit from applying the insights learned from this research to its care of the Veteran 
population. 
5.1.5.4. Comparison of risks and anticipated benefits to patients and society
The risks associated with genetic testing and the return of FH genetic test results in this study 
are minimal and not dissimilar to what may occur in routine medical care. The potential benefits 
for confirming and returning FH genetic test results may lead to enhanced awareness of FH and 
improved treatment for patients with known FH risk. Without rigorously assessing the value of 
returning FH genetic test results compared to currently accepted standards, the true benefits 
are unknown. The risk/benefit ratio for the conduct of this study is favorable to the proposed 
intervention.
5.2. Recruitment Methods
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5.2.1. Identification and recruitment of subjects
MVP Core study staff queries MVP databases for living participants with an eligible FH variant. 
The MVP Core study team mails eligible participants a letter introducing this new MVP-related 
study and giving participants the opportunity to opt out of further contact about the study by 
returning a prepaid opt out postcard or by calling the MVP Call Center. To any participant who 
does not opt out within 2 weeks of this initial mailing, the MVP-ROAR study team mails a letter 
giving more detail about the study, including all necessary informed consent information (see 
MVP-ROAR-FH Informed Consent Letter and MVP-ROAR-FH Informational Sheet). Participants 
in the non-randomized pilot of study procedures will receive a letter introducing the study and an 
informational document including all elements of informed consent (see MVP-ROAR-FH 
Informed Consent Letter and MVP-ROAR-FH Informational Sheet (Pilot)).Two weeks after this 
mailing, the study genetic counselor calls the participant to review the informed consent 
information, answers any questions about the study, and documents verbal consent or decline 
(see MVP-ROAR-FH GC ICF Phone Script).
Upon completion of the return of results, PCPs who provide care for a participant enrolled in the 
trial (n~ 250) will be recruited for interviews. Study staff will first contact the PCPs via email, 
sent to their VA email address, introducing the interview study and providing the option to opt 
out of future contact (see MVP-ROAR-FH PCP Email Invitation). A maximum of three emails will 
be sent. If no response is received, a maximum of three additional total attempts by phone or 
Microsoft Teams will be made to contact the PCP. Study staff will schedule an interview date 
and time with interested PCPs. Before the interview, staff will review the informed consent 
information, answer any questions about the interview study, and document verbal consent or 
decline. A total of 10-20 PCPs will be interviewed. 
5.2.2. Participant incentives
Participants will be mailed a check for $50 after completing the end-of-study survey and 
biospecimen collection. 
VA PCPs will not be provided an incentive to participate in the interview study. 
5.3 Informed Consent Procedures
5.3.1 Remote consent
We are requesting a waiver of HIPAA authorization and waiver of documentation of informed 
consent to enable remote consent by telephone or videoconferencing for eligible MVP 
participants and their VA PCPs nationwide. 
5.3.2 Procedure
The study staff will mail eligible participants a letter including all elements necessary for 
informed consent (see MVP-ROAR-FH Informed Consent Letter, MVP-ROAR-FH Informational 
Sheet, MVP-ROAR Informational Sheet (Pilot)). The informed consent letter will describe the 
study, the study procedure, the risks and benefits of participation in the study, confidentiality, 
data security, and collection and use of health data. Upon receipt of this letter, participants may 
contact the study staff to ask questions about the study and to arrange a time for the study GC 
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to follow-up for the formal review of informed consent information. If a participant does not 
contact the study staff after a period of two weeks, the study GC will call the participant to 
confirm receipt of the informed consent letter and ask whether the participant would like to 
consent to study participation. Participants uncertain of study participation during this call will be 
permitted as much time as needed to review the document and to consider enrollment. If the 
patient is interested in study participation and demonstrates an understanding of the nature of 
the study and consent process, the GC will formally review the informed consent information 
with the participant by phone (see MVP-ROAR-FH GC IC Phone Script). The GC will log 
participant consent in a data file, which will include the date letters are mailed, the dates of 
participant phone contact, and the date phone consent is obtained. Upon verification of consent, 
the study staff will conduct the baseline study survey and arrange for the collection of 
biospecimen during this call or on another call scheduled at a convenient time for the 
participant. If a participant cannot be reached after at least three attempts to contact them by 
phone, they will be considered lost to follow-up. These individuals will be sent a letter, including 
a brief description of the study and study team contact information in the event they become 
interested or have questions (see MVP-ROAR-FH Loss to Follow-Up Letter or MVP-ROAR-FH 
Loss to Follow-Up Letter_General). This letter will be sent via certified mail.   
For the PCP interview study, study staff will document informed consent by asking the PCP to 
state their full name and date of the interview and that they agree to participate in the study and 
have the interview recorded.
5.3.3 Human subjects protection training
The PI and research staff will maintain up-to-date required human subjects training certificates, 
including Good Clinical Practice, Privacy and HIPAA Focused Training, VA Privacy and 
Information Security Awareness and Rules of Behavior, and Research Compliance. 
5.4 Inclusion/Exclusion Criteria
A participant is eligible for enrollment in this study if he/she meets the following criteria:
●Is a living enrollee in MVP
●Is identified to have a Pathogenic or Likely Pathogenic variant in an FH-associated gene in 
their MVP genotype data (see Section 2.3)
●Has not previously undergone genetic testing for familial hypercholesterolemia. Study staff 
first ascertain this by review of the medical record and then confirm during the informed 
consent call by asking the participants about any prior genetic testing he/she has undergone 
(see MVP-ROAR-FH GC IC Phone Script).
●Is not incarcerated
●Is not pregnant
A PCP participant is eligible for enrollment in the interview study if they meet the following 
criteria:

Has received genetic testing results for a Veteran enrolled in MVP-ROAR
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
Is actively practicing at a VHA location
5.5 Study Evaluations
Study data will come from the following sources and procedures:
5.5.1. MVP database
The MVP Core study staff will provide the MVP Return study staff a data file with the following 
information about potentially eligible participants:
●Name, date of birth, and last 4 digits of Social Security Number (SSN)
●Genotype in the APOB, LDLR, LDLRAP1, PCSK9, and SLCO1B1 genes from their MVP 
genetic data
●Race and ethnicity
●VA station where participant enrolled in MVP and VA station(s) where participant currently 
receives health care
5.5.2. Medical record review
Study staff will review each potentially eligible participant’s medical records to confirm the 
absence of a prior positive genetic test result for FH and to abstract the participant’s list of 
medications.
5.5.3. Informed consent call
At the beginning of the informed consent call (see MVP-ROAR-FH GC IC Phone Script), 
the GC confirms the participant’s name, date of birth, and last 4 SSN digits. He/she then 
also asks whether the participant has had prior genetic testing and, if so, what kind. 
Participants whose responses indicate, in the clinical judgement of the GC, a prior 
positive genetic test result for FH are ineligible. During this call the GC will collect or 
confirm participant contact information including preferred phone number, mailing 
address, and an email address. 
5.5.4. Baseline telephone survey
The baseline survey (see MVP-ROAR-FH Baseline Survey) may occur on the same 
phone call as the informed consent process or on a separate call. Participants may 
complete the baseline survey in paper form by request (see MVP-ROAR-FH Survey 
Cover Letter). The survey collects the following information from the consented 
participant:  
●Name and station of participant’s VA PCP
●Name and contact information of any PCP outside of VA, if applicable
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●Confirmation of baseline VA medication list, as assessed from medical record review
●Medication name and dose for any over-the-counter medications or medications prescribed 
by a provider outside VA
●Beliefs about medications: Beliefs About Medicines Questionnaire (BMQ)44
●Patient activation: Patient Activation Measure (PAM)45
●Quality of life: Veterans RAND 12-item Health Survey (VR-12)46
●Race and ethnicity
5.5.5. Baseline biospecimen collection
Participants present to their local laboratory for a fasting blood draw for two tests:
●Baseline lipid panel testing
 
 : This is performed by a clinical laboratory at a VA facility. 
●FH variant confirmation
 
 : For participants randomized to the Immediate Results arm, this is 
performed by an external Clinical Laboratory Improvement Amendments (CLIA)-certified, 
College of American Pathologists (CAP)-accredited laboratory. This laboratory uses 
standard clinical techniques to sequence FH-associated genes and confirm the presence or 
absence of the suspected FH variant from the MVP genetic data. The laboratory sends a 
typical clinical report back to the study staff (see Clinical Variant Report). For participants in 
the Delayed Results arm, the second baseline blood specimen will be discarded.
Participants for whom it is not feasible to visit their local VA facility for a blood draw may 
provide a self-collected at-home saliva sample for FH variant confirmation. To utilize this 
option, participants must have:

A documented LDL-C level in their VA health record not older than 6 months from their 
date of enrollment

Absence of a statin prescription change within the time from the most recent 
documented LDL value to enrollment 
For participants in the Immediate Results arm, the saliva sample will be returned to the 
study staff and shipped to the CLIA-certified laboratory for FH variant confirmation. For 
participants in the Delayed Results arm, the saliva sample will be returned to the study staff 
and stored in a locked and secure cabinet for six months, at which time the sample may be 
shipped to the laboratory for variant confirmation or discarded if the participant is able to visit 
their local VA facility for a blood draw.  
5.5.6. End-of-study telephone survey
Six months after enrollment, the study staff calls each enrolled participant to administer the end-
of-study survey (see MVP-ROAR 6-Month Survey (Immediate Results version) and MVP-
ROAR-FH 6-Month Survey (Delayed Results version)). Participants may request to complete 
the follow-up survey by paper (see MVP-ROAR-FH Survey Cover Letter). The follow-up survey 
includes the following questions and instruments:
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●Confirmation of current VA medication list, as assessed from chart review
●Medication name and dose for any current over-the-counter medications or medications 
prescribed by a provider outside VA
●Beliefs about medications: Beliefs About Medicines Questionnaire (BMQ)
●Health behaviors: Smoking status47, saturated fat intake48, physical activity49
●Quality of life: Repeated measurement of VR-1246
●Healthcare utilization, including laboratory tests, office visits to PCP and specialists, and 
hospitalization50
●Veteran time demands and transportation costs to attend CHD-related medical 
appointments51
●Whether and how many first-degree family members underwent cascade genetic testing
●Feelings about genomic testing results: End-of-study measurement of FACToR52
●Preferences for receiving genetic test results
5.5.7. End-of-study biospecimen collection
After the end-of-study survey, participants present to their local laboratory for an end-of-study 
fasting blood draw: 

End-of-study lipid panel testing: This is performed by VA clinical laboratory.

FH variant confirmation: For participants randomized to the Delayed Results arm, a 
second blood specimen is drawn or self-collected saliva sample obtained for FH variant 
confirmation at an external reference laboratory, as described in Section 5.5.5 above. 
5.5.8. End-of-study VA database review
Study staff will review each enrolled participants’ medical record, Corporate Data Warehouse 
data, and other VA databases for the following clinical processes and outcomes related to FH:
●Lipid panel results prior to enrollment and during the study period
●Other clinical tests or procedures related to CVD, such as coronary computed tomography 
scan, C-reactive protein, lipoprotein(a), electrocardiogram (ECG), transthoracic 
echocardiogram, stress test, angiography, coronary artery bypass surgery
●All prescriptions of lipid-lowering medications prior to enrollment and during the study period
●Diagnoses related to hypercholesterolemia, FH, CHD, ischemic stroke, peripheral artery 
disease
●Healthcare utilization and cost data from the Health Economics Resource Center (HERC) 
and Managerial Cost Accounting System (MCA) datasets.
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5.5.9. Intervention cost accounting
The costs of the intervention, including materials and personnel time, will be collected to enable 
the budget impact analysis described in Section 5.6.2. 
5.5.10 PCP interviews
After participants receive their genetic testing results and complete the end of study survey, 
study staff will contact the participants’ VA PCPs to complete interviews. We will invite PCPs 
who have received a genetic testing result from MVP-ROAR to participate. We will conduct 
semi-structured interviews (see interview guide) to examine the facilitators and barriers to the 
return of genetic testing results to Veterans in MVP. The interviews will begin with a brief 
introduction to the MVP-ROAR Study and explore the PCP’s thoughts about genetic testing in 
general and experience with familial hypercholesterolemia. The interviewer will then explore 
potential benefits and risks of returning genetic testing results to MVP participants and the 
successes and limitations of the MVP-ROAR Study. 
5.6 Data Analysis
5.6.1. Sample size determination
We will enroll a total of 254 patient-participants: 10 for the non-randomized pilot trial and 244 for 
the RCT.
Sample size is based on the primary outcome of change in LDL-C in each arm after 6 months. 
Assuming a mean LDL-C reduction of 20% in the Immediate Results arm, a mean LDL-C 
reduction of 0% in the Delayed Results arm, and a common standard deviation of 30%53, 72 
total participants (36 per arm) are needed to have 80% power to detect a significant between-
group difference at alpha=0.05. Enrollment of twice this number (144 total) will account for an 
absence of therapy escalation in up to 50% of participants in the Immediate Results arm. 
Enrollment of 180 total participants will account for up to 20% loss to follow-up.
Change in LDL-C at 6 months
Total sample size required
Immediate Results
Delayed Results
Common SD
 
-20%
0%
30%
72
-20%
0%
40%
126
-20%
-5%
30%
126
-20%
-5%
40%
224
 
An important secondary outcome is the proportion of participants in each arm meeting accepted 
LDL-C targets at 6 months (<100 mg/dL for primary prevention and <70 mg/dL for secondary 
prevention). In preparatory-to-research analyses, only 175/322 (46%) MVP participants with a 
potentially pathogenic LDLR variant had a most recent LDL-C <100mg/dL. To have 80% power 
to detect a between-arm difference of 20% of participants meeting this LDL-C target at 
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alpha=0.05, up to 194 total participants are needed (97 per arm). To account for up to 20% loss 
to follow-up, a total of 244 participants (122 per arm) are needed.
 
Proportion of participants with LDL-C < 100mg/dL at 6 months
Total sample size required
Immediate Results
Delayed Results
 
10%
30%
124
20%
40%
162
30%
50%
186
40%
60%
194
 
5.6.2. Data analysis plan
We will conduct intention-to-treat analyses to compare all outcomes in the Immediate and 
Delayed Results arms. Logistic regression will be used for dichotomous outcomes, and linear 
regression will be used for continuous outcomes. Poisson regression will be used to compare 
counts of first-degree family members undergoing cascade genetic testing between the two 
arms. Regression models will test the study hypotheses by including terms for randomization 
status. Covariates may be included if they improve model precision. Missing data will be 
imputed using fully conditional specification. 
We will perform a budget impact analysis of the intervention alongside the randomized trial, 
using International Society for Pharmacoeconomics and Outcomes Research54 and Second 
Panel on Cost-Effectiveness in Health and Medicine51 recommendations. We will use 
administrative data and microcosting and gross costing strategies55 to estimate the cost of the 
return-of-results intervention itself plus patient-level healthcare costs extracted from the VA 
Corporate Data Warehouse from the 6 months after enrollment. Mean Veteran health-related 
quality of life (VR-12) will be compared between the two study arms and used to inform cost-
effectiveness analyses by mapping scores to the VR-6D to estimate health utilities.
For the PCP interview study, we will use team-based coding and qualitative analysis to identify 
and describe emerging themes. After the team generates a priori concepts of interests, two 
team members will code a small set of transcripts independently to identify additional emergent 
concepts to be included in the codebook, develop code definitions, and align their approaches in 
applying the codebook. Disagreements will be resolved via consensus, with other team 
members’ input sought if necessary. Throughout the coding process, coders will use memos to 
capture insights on emergent themes in the data, including differences and similarities across 
the dataset. After coding is completed, coders will review data within and across codes to 
generate preliminary themes; the full team will be involved in refining and elaborating on 
themes. 
All data will be stored on encrypted, password-protected VA servers and analyzed only by 
credentialed individuals identified as study staff on the IRB protocol. 
5.7 Withdrawal of Subjects
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Study subjects will be made aware that they may withdraw from participation in this study at any 
time without penalty or loss of VA or other benefits to which they are entitled. It is expected, 
given the limited risk of the study intervention, the reporting of relevant information to 
participants’ providers, and participants’ receipt of usual care throughout their study 
participation, that subject withdrawal will be rare. If study staff develop serious concerns that a 
participant is highly distressed, anxious, depressed, or whose health and well-being may 
otherwise be immediately compromised as a result of his or her participation in the study, and at 
the discretion of the PI, the study team may inform the participant that he or she may withdraw 
from the study. Researchers may continue to use patient data collected prior to withdrawal. No 
further health data will be collected after a participant has withdrawn from the study. 
Study participants may withdraw from the study by contacting the study team by phone and 
requesting withdrawal verbally. Once a verbal request for withdrawal is received by the study 
team, participants are provided with confirmation of their withdrawal from the study (see MVP-
ROAR-FH Study Withdrawal Letter). If a participant withdraws before the baseline biospecimen 
collection, no information about the participant’s MVP research result will be provided to the 
participant. If a participant withdraws after the baseline biospecimen collection but before the 
reference laboratory has analyzed his/her sample, the study staff will contact the lab to destroy 
the sample before analysis. If a participant withdraws after the laboratory analysis but before 
receiving his/her results from the GC, he/she will be given the opportunity to receive the results 
from the GC and/or have them sent to his/her PCP, 6 months after enrollment.  
Primary care providers enrolled in the interview study may withdraw at any time by contacting 
the study team by email, phone, or Teams and requesting withdrawal. 
6.0 
Reporting
6.1. Monitoring and quality assurance
The PI will monitor the study proceedings to ensure the study is executed according to the IRB-
approved protocol, which includes ensuring the safety of participants and the validity, integrity, 
and protection of data associated with this study. The PI and research staff will be responsible 
for the day-to-day monitoring of patient safety and data quality throughout the conduct of this 
study. In addition to the regular monitoring of patient safety and data quality, the research team 
will complete any and all continuing reviews, audits, event reporting, and/or other requirements 
per the provisions and timelines set forth by VA Central IRB.
Any concerns regarding the ethical conduct of the study, the safety of participants, or a breach 
in the protection of study data made by participants, the study staff, or others will be promptly 
reported to the PI and escalated accordingly to VA Central IRB and/or other relevant oversight 
committees. 
6.2 Participant safety
Participant safety will be monitored by the PI and study staff throughout the conduct of study 
activities. All participants will have the contact information of the MVP Information Center and 
the MVP-ROAR-FH study team for any questions or concerns related to study participation. All 
participants will also have the contact information of the study GC should they have any 
concerns with their results or their delayed result disclosure. Per the study protocol the 
participant’s PCP will also receive a copy of the participant’s genetic test results. If a participant 
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experiences adverse effects or expresses emotional distress related to study participation at 
any time during their enrollment and requires medical attention based on the judgement of the 
PI, the study genetic counselor, and/or their PCP, they will be referred for clinical assessment 
and/or informed of options for study withdrawal (see Section 5.7 Withdrawal of Subjects) as 
appropriate. All serious such cases, including those requiring a referral to a mental health 
professional or other therapeutic intervention, will be reviewed and reported to VA Central IRB 
as an adverse event (AE) or serious adverse event (SAE) as necessary.
During the PCP interview study, if any PCP participant exhibits or expresses distress during any 
interview, the interviewer will offer a break to the participant and will offer the option of 
discontinuing the interview. If any PCP participant becomes overly agitated, distressed, or 
threatening the interviewer will discontinue the interview and discuss the matter with the PI. 
Throughout the conduct of the study, attention will be paid to any reports of participant 
experiences that constitute adverse events as described in Section 6.3 Adverse events and will 
be reported per Section 6.4 Event reporting. 
6.3 Adverse events
Adverse events (AEs) related to MVP-ROAR-FH procedures do not include anticipated events 
related to blood draws (e.g., pain, minor bleeding, bruising, fainting, or lightheadedness) and 
minor feelings of discomfort while answering survey questions. Pre-existing conditions or 
illnesses which are expected to exacerbate or worsen are also not considered adverse events 
and will be accounted for in the subject’s medical history. An AE may be considered any other 
unanticipated or unintended medical occurrence or worsening of a sign or symptom (including 
an abnormal laboratory finding other than the return of genetic information associated with FH) 
or disease in a study subject, which does not necessarily have a causal relationship with the 
study condition, procedure(s) or study agent(s), that occurs after participant informed consent is 
obtained. A serious adverse event (SAE) will be defined as an AE resulting in one of the 
following outcomes: death during the 6 months after study enrollment, life threatening event 
(defined as an event that places a participant at immediate risk of death), inpatient 
hospitalization, and any other condition which, in the judgment of the PI, represents a significant 
hazard, such as an important medical event that does not result in one of the above outcomes. 
An event may be considered an SAE when it jeopardizes the participant or requires medical or 
surgical intervention to prevent one of the outcomes listed above. AEs may be observed by the 
study staff or volunteered by participants, their family members, their PCPs, or others. All AEs 
and SAEs will be assessed for relationship to the study research procedures by the study PI, to 
determine whether study participation was likely to have caused the AE/SAE. 
6.4 Event reporting
Given the minimal risk of the study intervention, the study team anticipates few AEs, SAEs, or 
unanticipated problems (UPs) during the course of this study. AEs, SAEs, and UPs may be 
observed through regular monitoring by the study staff or volunteered by participants, their 
family members, their PCPs, or others throughout the conduct of the study. Any concerns 
related to patient safety or the potential occurrence of an AE, SAE, or UP in relation to the 
conduct of this study will be promptly reported to the PI for review. Upon discovery, any study-
related death will be immediately reported to the VA Central IRB. Study staff will report any 
protocol deviation that substantively affects subjects’ rights or safety, UP that poses risk to 
participants, or SAE per VA Central IRB protocols. An annual report summarizing all non-
serious adverse events and UP/protocol deviations that did not require immediate reporting will 
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be prepared and reported to the VA Central IRB at the time of continuing review. 
Acknowledgement of any AE, SAE, or UP/protocol deviation by the VA Central IRB will be 
retained by the MVP-ROAR-FH study staff. 
7.0
Privacy and Confidentiality
7.1 Use of Protected Health Information (PHI)
The MVP-ROAR-FH study team will utilize participant Protected Health Information (PHI) during 
the conduct of study activities, including in the identification and recruitment of eligible 
participants, for genetic confirmation testing, for the delivery of the study intervention, and for 
the collection of study data. Given the use of PHI, every effort will be made to ensure that the 
privacy and confidentiality of MVP-ROAR-FH participants are maintained. As with any research 
study, loss of privacy and/or confidentiality is a potential risk. To mitigate this risk, study 
personnel will take every precaution to keep participants’ PHI confidential and protect each 
participant’s privacy in all aspects in which participant data is used as part of this research 
study. This includes using coded information rather than PHI whenever possible, storing 
electronic study-related data on VA and/or VA-approved servers in accordance with appropriate 
information security policies, using only VA-approved methods for the transfer of data, and 
storing any participant-related written and/or paper documents in a secure environment (e.g., 
locked cabinet and in a locked office).
7.1.1 Biospecimens and genetic variant data
Blood specimens will be collected at participants’ local VA facilities and shipped to the VA 
Boston Healthcare System laboratory for FH variant confirmation testing at a VA-approved 
CLIA-certified laboratory. Saliva collection kits will be sent directly to participants using a 
common carrier delivery service and will be tracked with a unique reference number. Saliva 
samples will be self-collected in the participant’s home and shipped to study staff for FH variant 
confirmation testing at a VA-approved CLIA-certified laboratory. All participant data will be 
retained within the VA except the following in order to complete genetic variant confirmation 
testing: patient name, date of birth, gender, and a test requisition form will be included with the 
blood sample sent to the VA-approved CLIA-certified laboratory for genetic confirmation testing, 
using a common carrier delivery service and chain of custody. Specimens will be shipped to the 
VA-approved clinical laboratory via prepaid standard biospecimen collection kits. The shipment 
to the VA-approved CLIA-certified laboratory will not include any personal identifiers on the 
external packaging. Each shipment will be distributed for overnight delivery and will be tracked 
with a unique reference number. The VA-approved CLIA-certified laboratory will perform variant 
confirmation and then retain the sample only as long as is required by internal quality assurance 
and other regulatory procedures. The VA-approved CLIA-certified laboratory will return the 
results of variant confirmation testing to the study staff via a secure, password protected, and 
VA-approved web-interface. The study staff will transfer the clinical variant confirmation test 
results to the medical record at participants’ local VA facilities. Copies of the participants’ results 
will also be provided to their designated VA PCPs via secure VA-approved methods.
7.2 Staff training and data access
All study staff with access to PHI will complete required training and be instructed, in 
accordance with VA policy, on the requirements of Federal privacy and information laws and 
regulations, VA regulations and policies, and VHA policy. Only study personnel credentialed and 
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approved by the VA Central IRB and VA Research & Development committees will have access 
to study data stored in either physical or electronic environments. Once study team members 
are no longer a part of the research team, their access to data and research materials will be 
terminated. No unauthorized access to study servers or datasets will be permitted. All study 
staff will be trained on reporting data breaches within one (1) hour to the appropriate Information 
Security and Privacy Officers and VA Central IRB. Access to all electronic data and files (e.g., 
database, spreadsheet) containing identifiable patient information will be limited to approved 
users with a login credential. Any computer hosting such files will be password protected to 
prevent access by unauthorized users.
7.3 Data security
Risk of breach of confidentiality will be minimized through the appropriate management and 
security of participant data per VA, HIPAA, and MVP requirements. Participant PHI will be 
delinked from the final analytic dataset. All data will be retained within the VA. Data will be 
securely transmitted using VA approved methods, including FIPS 140-2 validated encryption. 
This will include transmission of PHI and other participant data, including genetic testing results, 
between VA and the commercial reference laboratory performing genetic confirmation testing. 
Participant data files (source and analytic) will be stored behind the VA firewall, on a drive 
created specifically to house the data for this research project. No PHI (including scrambled 
SSNs or dates) will be released to the public, nor will they be presented or published in the 
dissemination of study findings. All written and/or paper documents containing participant PHI 
will be filed in a locked cabinet and locked office at the VA Boston Healthcare System. Study 
data will be kept indefinitely or until the law allows their destruction in accordance with the VA 
Record Control Schedule. Electronic records will be destroyed, when allowed, in a manner in 
which they cannot be retrieved. In addition, a Certificate of Confidentiality, issued by the 
National Institutes of Health (NIH), will help to ensure the privacy of participant identities and 
data. With this certificate, researchers cannot be forced (e.g. by court subpoena) to disclose 
information that identify the participant in federal, state, or local civil, criminal, administrative, 
legal or other proceedings. 
7.3.1 Participant mailing data
A copy of patient-participant mailing data only will be downloaded outside of VINCI and stored 
on a secure, study specific SharePoint site. The SharePoint site will be housed behind the VA 
firewall and viewing of mailing data will be limited to IRB approved study personnel. This will be 
done to enable the use of Microsoft Word mail merge software to create participant letters and 
address labels for efficient printing and distribution. Participant mailing data will be in the form of 
CSV files and may include identifying variables including: participant ID, full name, gender, 
mailing address, and any associated flags (i.e. temporary address). The mail merge software 
can be used within the secure SharePoint environment. 
7.3.2 Use of encrypted emails 
The MVP-ROAR-FH Study will include the option for participants and their providers to receive 
encrypted email correspondence associated with IRB-approved study materials and study-
related appointments (i.e., local facility blood draws, remote genetic counseling appointments). 
Per VA policy, any email distributed external to the VA network and including individually 
identifiable information (III), PHI, or study specific information will be encrypted using the VA-
approved Microsoft Azure Rights Management Service (RMS). 
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Only after initiating contact by standard mail and telephone, and after participants have had the 
opportunity to opt out of contact, patient- participants will have the option to request that study 
staff send recruitment and other study materials (i.e. informational sheet, baseline survey, end-
of-study survey, delayed arm letter, VA form 10-5345, results mailings) which may contain PHI 
or study-specific information via Azure RMS encrypted email. Participants may also opt to return 
study materials (i.e. baseline survey, end of study survey, and VA form 10-5345) by scanning 
them or taking a photo and returning it to study staff via Azure RMS encrypted email. 
8.0 
Communication Plan
8.1 Notification of local facility
As an MVP-associated study, MVP local site investigators will be made aware of the conduct 
of MVP-ROAR-FH and that MVP participants from their facilities may be recruited for 
enrollment into this study. In the event a SAE or unanticipated problem occurs in conjunction 
with the conduct of MVP-ROAR-FH, the MVP local site investigator of the affected participant 
will be informed and the event will be reported in accordance with VA Central IRB procedures.
8.2 Public data set
We will share de-identified individual-level trial data (participant characteristics and outcomes) 
through a data repository housed on a secure VA server and accessible only to outside 
investigators with IRB and other regulatory approvals. In the event of a data request, approval 
for data use will be sought from the local IRB where the repository is housed.
8.3 VA MVP Central Database 
Identifiable, individual-level trial data will be shared with the MVP Program and will be stored 
in the VA MVP Central Database. 
8.4 Dissemination of study results
This trial will be registered on ClinicalTrials.gov. Communication of study progress and results 
will be the responsibility of the PI and Executive Committee. Information associated with this 
project will be communicated to VA and other stakeholders including policymakers, 
healthcare providers, patients, and the scientific community. In order to broadly disseminate 
information about this research, the MVP-ROAR-FH study team 1) will prepare scientific 
presentations and manuscripts for publication, 2) present information regarding the purpose, 
methods, and results of this research at informal meetings throughout the VA, 3) inform the 
public and policymakers of new findings through press releases and related mechanisms, 
including those currently approved through MVP, and 4) facilitate dissemination of study-
related information and findings to patients and healthcare providers through collaboration 
with MVP leadership, VA national leadership, and other centers. 
9.0 
References
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Allen NL, Karlson EW, Malspeis S, Lu B, Seidman CE, Lehmann LS. Biobank 
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Kaufman D, Murphy J, Erby L, Hudson K, Scott J. Veterans' attitudes regarding a 
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Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association Recommendations 
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Hypercholesterolemia and the Use of Genetic Testing. JAMA. 2017;318(4):381-382.
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Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is 
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the Management of Blood Cholesterol. Circulation.0(0):CIR.0000000000000625.
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Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial 
hypercholesterolaemia: a long term cohort study. BMJ. 2008;337:a2423.
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Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 
alleles conferring risk for myocardial infarction. Nature. 2015;518(7537):102-106.
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