Comparing Direct and Indirect Methods for Cascade Screening in Familial Hypercholesterolemia (FH) and Long QT Syndrome (LQTS)

比较家族性高胆固醇血症 (FH) 和长 QT 综合征 (LQTS) 的直接和间接级联筛查方法

• 批准号: 10416668
• 负责人: AMBER L BEITELSHEES
• 金额: $ 71.47万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416668
• 关键词: Address; Affect; Amish; Anxiety; Arrhythmia; Centers for Disease Control and Prevention (U.S.); Communication; Communities; Consolidated Framework for Implementation Research; Coupled; Decision Making; Disease; Ethics; Familial Hypercholesterolemia; Family; Family member; First Degree Relative; Founder Effect; Founder Generation; Frequencies; Genetic; Genomic medicine; Genomics; Goals; Intervention; Knowledge; Laws; Long QT Syndrome; Malignant Neoplasms; Mental Depression; Methods; Minority Groups; Modeling; Morbidity - disease rate; National Cancer Institute; Outcome; Participant; Pathogenicity; Patient Self-Report; Patient-Focused Outcomes; Patients; Population; Privacy; Procedures; Provider; Randomized Controlled Trials; Reach Effectiveness Adoption Implementation and Maintenance; Recording of previous events; Relative Risks; Research; Resource-limited setting; Risk; Rural; Rural Population; Social Impacts; Sudden Death; Target Populations; Testing; Training; Underserved Population; Variant; Work; actionable mutation; arm; base; care providers; community engagement; comparative efficacy; comparison group; cost; design; efficacy outcomes; genetic information; geographic barrier; implementation evaluation; implementation framework; implementation outcomes; implementation process; implementation science; improved; insight; interest; mortality; outreach; pilot test; population health; pressure; proband; process evaluation; randomized controlled design; screening; skills; stem; trial comparing; uptake

PROJECT SUMMARY An important aspect of successful genomic medicine implementation is developing effective approaches for screening at-risk family members after probands are identified, also known as cascade screening. Most cascade screening studies conducted to date have been conducted outside the US, and very few studies have used a rigorous approach involving a comparator group or randomized controlled design. As such, a critical gap exists in our knowledge of the most effective delivery strategies of cascade screening and their ethical acceptability. The goal of the research we propose is to compare direct (i.e., contacting relatives of probands directly by study team) vs indirect (i.e., traditional, proband-initiated contact) implementation of cascade screening using familial hypercholesterolemia (FH) and Long QT Syndrome (LQTS) as model cases. We will focus on screening two pathogenic variants, KCNQ1 Met224Thr, which causes LQTS, and APOB Arg3527Gln, a variant known to cause FH. Both variants have a high carrier frequency (2% and 12%, respectively) in the Amish due to founder effects. Cascade screening for FH is recommended as a tier 1 condition by the Centers for Disease Control and Prevention. This very large number of subjects carrying the same actionable variants for LQTS and FH, coupled with our history of engagement in the Amish community, provides an outstanding opportunity to address the knowledge gap. Specifically, we will conduct a randomized controlled trial of participants with pathogenic variants causing LQTS and FH to compare direct vs indirect methods for cascade screening coupled with implementation evaluation outcomes to assess the ethical and social impacts of the intervention. We hypothesize that, compared to traditional proband-initiated contact, direct contact will lead to greater efficiency of cascade screening, greater patient knowledge, and promote autonomous decision-making by relatives, while still maintaining acceptable levels of privacy and autonomy. In Aim 1 we will assess efficacy of the cascade screening strategies by comparing uptake in the direct versus indirect arms. In Aim 2 we will assess the mode of contact on self-reported alignment with ethical principles, anxiety, perceived pressure to undergo testing, and knowledge of disease. Aim 3 will characterize implementation evaluation outcomes such as reach, fidelity, and cost of the two contact approaches based on the RE-AIM Framework (reach, effectiveness, adoption, implementation, maintenance) and CFIR (Consolidated Framework for Implementation Research).

项目摘要 成功的基因组医学实施的一个重要方面是开发有效的方法 鉴定出探针后，筛查处于危险的家庭成员，也称为级联筛选。大多数级联 迄今为止进行的筛查研究已在美国以外进行，很少有研究使用 严格的方法涉及比较组或随机控制设计。因此，存在关键的差距 在我们了解级联筛查及其道德可接受性的最有效的交付策略中。 我们提出的研究的目的是比较直接（即直接通过研究与概率的亲属联系 团队）与间接（即传统的，概率提出的联系）实施级联筛查 高胆固醇血症（FH）和长QT综合征（LQT）作为模型病例。我们将专注于筛选两个 致病变体，KCNQ1 Met224THR，导致LQTS和APOB ARG3527GLN，这是已知引起的变体 FH。由于创始人效应，这两种变体在阿米什人的载体频率分别为2％和12％）。 建议通过疾病控制中心和 预防。携带LQT和FH的相同可行变体的大量受试者，耦合 鉴于我们参与阿米什人社区的历史，为解决这个问题提供了一个绝佳的机会 知识差距。具体而言，我们将对具有致病性的参与者进行随机对照试验 引起LQT和FH的变体比较了直接与间接方法的级联筛选方法 实施评估结果以评估干预的道德和社会影响。我们 假设，与传统的概率发起的接触相比，直接接触将提高效率 级联筛查，更多的患者知识和促进亲戚的自主决策，而 仍保持可接受的隐私和自治水平。在AIM 1中，我们将评估级联的功效 通过比较直接和间接臂的吸收来筛选策略。在AIM 2中，我们将评估模式 自我报告的一致性与道德原则，焦虑，经过测试的压力以及 疾病知识。 AIM 3将表征实施评估结果，例如覆盖范围，忠诚度和 基于RE-AIM框架的两种联系方法的成本（覆盖，有效性，采用， 实施，维护）和CFIR（实施研究的合并框架）。