Assessing Non-Inferiority of Scalable eConsent for Genomics

识别患有医学上可操作的遗传性综合征(如林奇综合征(LS))的个人可能会导致 减少发病率和死亡率。然而，先前对子宫内膜LS筛查方案的评估 癌症背景发现，按数量级计算，他们成功的最大威胁是非癌症患者的高比率 同意测序。很大程度上是由于未经同意，要求进行以下测序的协议 免疫组织化学(IHC)阳性筛查估计漏掉了58%的LS索引病例，而直接针对 测序筛查方案预计会遗漏30%。然而，目前尚不清楚为什么会出现不同意的情况： 也许人们误解了基因测序的某些重要方面，或者他们有顾虑 (例如，遗传隐私)可以在同意过程中得到更好或更彻底的解决。 传统的面对面同意测序面临着两个额外的挑战：接触到农村和 其他医疗服务不足的地区，并确保筛查方案具有成本效益。电子同意 (电子会议)在克服访问和成本障碍方面表现出了希望，并已开始在 重要的基因组学项目，包括我们所有人的研究计划，从来没有严格 与传统的同意相比，以确保不会自卑。与Sage Bionetworks合作，我们改编了 他们为我们所有人开发的电子同意框架，以支持盖辛格的MyCode社区健康倡议，该倡议 涉及临床上可操作的变异的人群筛查，包括LS。我们提出了一个务实的、非 与传统同意相比，智者电子同意的自卑感RCT--我们已经试行过了。在……里面 除了确定eConsent在确保患者理解方面是否不逊色(目标1)外，这项研究 将有助于确定患者难以理解的基因组筛查方面，或他们表达的 倾向于了解更多，这将为电子同意和传统同意流程提供信息，以及 潜在地提高筛查摄取率(目标2)。与在仅LS筛查中进行这项研究相比 人口，大的MyCode人口将提供足够的样本量来支持非劣势试验 一小段时间。此外，随着测序成本的持续下降，群体基因组筛选 本身将成为一种可行的、经济高效的方法来识别患有LS和其他遗传性疾病的个体 综合症。事实上，多个医疗系统已经在试行这样的项目，这将需要可扩展的、 可获得的、成本效益高的同意方法。这项研究的结果将极大地有利于 IMPULSS实施工具包，旨在帮助机构实施、评估和适应LS 随着时间的推移筛选计划，特别是在机构转移计划变得具有成本效益的情况下 癌症患者的直接测序方案或人群筛查。包括有关的数据 用于测序的可扩展eConent的成本和有效性将是IMPULSS工具包的宝贵补充 这有助于减少识别具有遗传性癌症风险的个人的障碍，以预防癌症。

Identifying individuals with medically actionable, hereditary syndromes such as Lynch Syndrome (LS) can lead to reduced morbidity and mortality. However, prior evaluations of LS screening programs in the endometrial cancer context find that the biggest threat to their success, by orders of magnitude, is the high rate of non- consent for sequencing. Largely due to non-consent, protocols that call for sequencing following immunohistochemistry (IHC)–positive screens are estimated to miss 58% of LS index cases, while direct-to- sequencing screening protocols are expected to miss 30%. It is not known, however, why non-consent occurs: perhaps people misunderstand some important aspect of genetic sequencing, or perhaps they have concerns (e.g., genetic privacy) that could be better or more thoroughly addressed during the consent process. Traditional, in-person consent for sequencing faces two additional challenges: reaching patients in rural and other medically underserved areas and ensuring that screening protocols are cost-effective. Electronic consent (eConsent) shows promise in overcoming barriers of both access and cost and has begun to be used in important genomics projects, including the All of Us Research Program, yet has never been rigorously compared to traditional consent to ensure non-inferiority. Working with Sage Bionetworks, we adapted the eConsent framework they developed for All of Us to Geisinger's MyCode Community Health Initiative, which involves population screening for clinically actionable variants, including LS. We propose a pragmatic, non- inferiority RCT—which we have already piloted—of Sage eConsent compared to traditional consent. In addition to determining whether eConsent is non-inferior in ensuring patient comprehension (Aim 1), this study will help identify aspects of genomic screening that are difficult for patients to understand or that they express a preference to learn more about, which will inform both eConsent and traditional consent processes, and potentially improve screening uptake (Aim 2). Compared to conducting this study in a LS-only screening population, the large MyCode population will provide sufficient sample size to power a non-inferiority trial over a short period of time. Moreover, as the cost of sequencing continues to decline, population genomic screening will itself become a viable, cost-effective approach to identifying individuals with LS and other hereditary syndromes. Indeed, multiple health systems are already piloting such programs, which will require scalable, accessible, and cost-effective approaches to consent. The results of this study will greatly benefit the IMPULSS implementation toolkit that will be designed to help institutions implement, evaluate, and adapt LS screening programs over time, particularly as it becomes cost-effective for institutions to move their programs towards a direct-to-sequencing protocol in cancer patients or to population screening. Including data on the costs and effectiveness of scalable eConsent for sequencing will be a valuable addition to the IMPULSS toolkit that can help reduce barriers to identifying individuals with hereditary cancer risk in order to prevent cancer.