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

项目总结 成功实施基因组医学的一个重要方面是开发有效的方法来 在先证者被确认后对高危家庭成员进行筛查，也称为级联筛查。最级联 到目前为止，进行的筛查研究都是在美国以外进行的，很少有研究使用 涉及比较组或随机对照设计的严格方法。因此，存在着严重的差距 在我们对层叠筛查最有效的交付策略及其伦理可接受性的了解中。 我们提出的研究的目标是比较直接(即，通过研究直接联系先证者的亲属 团队)与间接(即，传统的、先证者发起的接触)实施的级联筛查使用家族式 以高胆固醇血症(FH)和长QT间期综合征(LQTS)为模型。我们将重点放映两部 致病变异体，导致LQTS的KCNQ1 Met224Thr和APOB Arg3527Gln，已知的引起LQTS的变异体 FH.由于创始人效应，这两个变种在阿米什人中都有很高的载频(分别为2%和12%)。 美国疾病控制和预防中心建议将FH的级联筛查作为一级条件 预防。这些携带LQTS和FH相同可操作变体的非常大量的受试者 与我们在阿米什社区的接触历史，提供了一个绝佳的机会来解决 知识鸿沟。具体地说，我们将对患有致病菌的参与者进行随机对照试验。 导致LQTS和FH将级联筛查的直接方法与间接方法相比较的变体 执行情况评估结果，以评估干预措施的道德和社会影响。我们 假设与传统的先证者发起的接触相比，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，同时 仍然保持可接受的隐私和自主水平。在目标1中，我们将评估级联的效果 通过比较直接臂和间接臂的摄取来筛选策略。在目标2中，我们将评估该模式 自我报告的与道德原则一致的联系，焦虑，接受测试的感知压力，以及 关于疾病的知识。目标3将描述实施情况评估结果，如REACH、FIDITY和 基于RE-AIM框架的两种联系方式的成本(覆盖范围、有效性、采用率、 (实施、维护)和CFIR(实施研究综合框架)。

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).