The Genomic Medicine at VA Study

Study Overview
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Brief Summary
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This trial will determine the clinical effectiveness of polygenic risk score testing among patients at high genetic risk for at least one of six diseases (coronary artery disease, atrial fibrillation, type 2 diabetes mellitus, colorectal cancer, breast cancer, or prostate cancer), measured by time-to-diagnosis of prevalent or incident disease over 24 months.

Detailed Description
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One of the most pressing controversies in genomics today is the clinical utility of polygenic risk scores (PRS). Broadening the scope of genomic risk testing beyond monogenic diseases, PRS combine information from hundreds or even millions of genetic loci, each with a very small effect size on the risk of common complex disease. The result is a continuous quantitative risk factor for susceptibility to conditions such as coronary artery disease (CAD), type 2 diabetes (T2D), and breast cancer. Compared to rarer monogenic disease variants, PRS have greater transformative potential for public health and healthcare in their ability to identify much larger proportions of the population at significantly elevated risk for disease, facilitating evidence-based prevention and management. Moreover, their prediction ability has vastly improved compared to earlier PRS that included only a limited number of genetic variants. However, while the associations between PRS and a wide range of common diseases are well established (clinical validity), the potential impact of this information on patient health outcomes (clinical utility) remains contested and understudied. This study will examine the effectiveness and implementation outcomes from the use of PRS for 6 common diseases that are screened for by PCPs and have established prevention strategies: CAD, AFib, T2D, colorectal cancer, prostate cancer, and breast cancer. This trial has two aims: Aim 1: Conduct a randomized controlled trial (RCT) to determine the clinical effectiveness of PRS among patients at high genetic risk for at least one disease, measured by changes in clinical management (process outcomes) and time to diagnosis of prevalent or incident disease (clinical outcome) over 24 months. Aim 2: Measure high-priority genomic medicine implementation outcomes, including primary care provider (PCP) knowledge and beliefs about PRS, patient activation in healthcare, medication adherence, and costs.

Official Title
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Pragmatic Randomized Trial of Polygenic Risk Scoring for Common Diseases in Primary Care

Conditions
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Coronary Artery Disease, Atrial Fibrillation, Type 2 Diabetes, Colorectal Cancer, Breast Cancer, Prostate Cancer

Intervention / Treatment
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* Diagnostic Test: Polygenic risk score (PRS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 50-70 years at enrollment No known diagnosis of the following conditions, initially screened by the International Classification of Disease (ICD) codes or other electronic health record (EHR) data using validated methods and then confirmed with potential patient-participants during recruitment: coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer, breast cancer, prostate cancer Exclusion Criteria: Patients will be ineligible if they: Have a known diagnosis of at least one of the six diseases of interest Are younger than age 50 or older than age 70 Are pregnant Are incarcerated or institutionalized

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized clinical trial comparing polygenic risk score (PRS) testing and reporting to delayed reporting
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Polygenic risk score (PRS) - high risk stratum<br>Patient-participants in the PRS-high arm and their providers will receive their high-PRS results at baseline, along with educational resources about the results. | Diagnostic Test: Polygenic risk score (PRS)<br>* Polygenic risk score report from a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory for coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer, breast cancer (for women only), and prostate cancer (for men only), delivered along with patient- and provider-level educational material.<br>|
| Active Comparator: Usual care (UC) - high risk stratum<br>Patient-participants in the UC-high arm and their providers will receive their high-PRS results after a 24-month observation period, along with educational resources about the results. | Diagnostic Test: Polygenic risk score (PRS)<br>* Polygenic risk score report from a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory for coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer, breast cancer (for women only), and prostate cancer (for men only), delivered along with patient- and provider-level educational material.<br>|
| Experimental: Polygenic risk score (PRS) - average risk stratum<br>Patient-participants in the PRS-average arm and their providers will receive their average-PRS results at baseline, along with educational resources about the results. | Diagnostic Test: Polygenic risk score (PRS)<br>* Polygenic risk score report from a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory for coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer, breast cancer (for women only), and prostate cancer (for men only), delivered along with patient- and provider-level educational material.<br>|
| Active Comparator: Usual care (UC) - average risk stratum<br>Patient-participants in the UC-average arm and their providers will receive their average-PRS results after a 24-month observation period, along with educational resources about the results.. | Diagnostic Test: Polygenic risk score (PRS)<br>* Polygenic risk score report from a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory for coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer, breast cancer (for women only), and prostate cancer (for men only), delivered along with patient- and provider-level educational material.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-new diagnosis of common complex disease | The primary outcome of the study is time-to-diagnosis both of undiagnosed prevalent cases of the 6 target conditions and incident cases during the study period. This composite outcome will only include clinically significant diagnoses, as adjudicated by expert clinical chart review. | 24 months after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic testing | Any evidence that the patient-participant underwent additional diagnostic testing for the six target diseases since enrollment: coronary artery disease (stress testing, cardiac CT for coronary artery calcium (CAC), coronary angiography), atrial fibrillation (ECG, heart rhythm monitoring), type 2 diabetes (hemoglobin A1c, blood glucose), colorectal cancer (colonoscopy, sigmoidoscopy, fecal blood testing, CT colonography), breast cancer (mammography, breast MRI, breast ultrasound, breast biopsy), and prostate cancer (PSA testing, prostate biopsy). | 24 months after enrollment | 
| Patient activation | Self-reported understanding, competence, and willingness to participate health care decisions and processes assessed on the baseline and end-of-study surveys, using the 13-item short form of the Patient Activation Measure (Hibbard, Health Services Research 2005). | Baseline and 24 months after enrollment | 
| Healthcare costs | A combination of administrative data and microcosting approaches will be used to estimate the costs of the intervention and the subsequent patient-level healthcare costs over the 24 months after enrollment. Estimates of the infrastructure and personnel needed to deliver the intervention will be derived empirically from the study. Healthcare costs will be abstracted from billing and administrative data. | 24 months after enrollment | 
| Medication adherence | Self-report of taking medications as prescribed assessed on the baseline and end-of-study surveys, using the 3-item Voils Medication Adherence Survey (Voils, Medical Care, 2012). | Baseline and 24 months after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polygenic risk score, Atrial fibrillation, Type 2 diabetes, Colorectal cancer, Breast cancer, Prostate cancer, Coronary artery disease