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

项目摘要 成功实施基因组医学的一个重要方面是开发有效的方法， 在先证者确定后筛查高危家庭成员，也称为级联筛查。最级联 迄今为止进行的筛查研究都是在美国以外进行的，很少有研究使用 涉及对照组或随机对照设计的严格方法。因此， 我们对级联筛查最有效的实施策略及其伦理可接受性的了解。 我们提出的研究目标是直接比较（即，通过研究直接联系先证者亲属 团队）与间接（即，传统的，先证者发起的接触）使用家族性级联筛查的实施 高胆固醇血症（FH）和长QT综合征（LQTS）作为模型病例。我们将重点筛选两个 致病性变体，KCNQ 1 Met 224 Thr，其导致LQTS，和APOB Arg 3527 Gln，已知导致LQTS的变体， FH。由于创始人效应，这两种变体在阿米什人中具有高载波频率（分别为2%和12%）。 FH的级联筛查被疾病控制中心推荐为1级条件， 预防携带LQTS和FH的相同可操作变体的这一非常大量的受试者， 与我们在阿米什社区的参与历史，提供了一个很好的机会，以解决 知识差距。具体来说，我们将进行一项随机对照试验， 导致LQTS和FH的变异，比较级联筛选的直接与间接方法， 实施评价结果，以评估干预措施的道德和社会影响。我们 假设与传统先证者主动接触相比，直接接触将导致更高的效率 级联筛查，更多的患者知识，并促进亲属的自主决策， 仍然保持可接受的隐私和自主权水平。在目标1中，我们将评估级联的功效 通过比较直接与间接臂中的摄取来筛选策略。在目标2中，我们将评估模式 自我报告的与伦理原则一致的接触，焦虑，感知的接受测试的压力， 疾病的知识。目标3将描述实施评估的结果，如覆盖范围、保真度和 基于RE-AIM框架的两种接触方法的成本（覆盖范围、有效性、采用率， 实施研究综合框架（CFIR）。

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).