MDisrupt, San Jose, California.
Veritas Genetics, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
J Mol Diagn. 2020 May;22(5):599-609. doi: 10.1016/j.jmoldx.2020.01.014. Epub 2020 Feb 22.
Testing asymptomatic individuals for unsuspected conditions is not new to the medical and public health communities. Protocols to develop screening tests are well established. However, the application of screening principles to inherited diseases presents unique challenges. Unlike most screening tests, the natural history and disease prevalence of most rare inherited diseases in an unselected population are unknown. It is difficult or impossible to obtain a truth set cohort for clinical validation studies. As a result, it is not possible to accurately calculate clinical positive and negative predictive values for likely pathogenic variants, which are commonly returned in genetic screening assays. In addition, many of the genetic conditions included in screening panels do not have clinical confirmatory tests. All these elements are typically required to justify the development of a screening test, according to the World Health Organization screening principles. Nevertheless, as the cost of DNA sequencing continues to fall, more individuals are opting to undergo genomic testing in the absence of a clinical indication. Despite the challenges, reasonable estimates can be deduced and used to inform test design strategies. Herein, we review basic test design principles and apply them to genetic screening.
对无症状个体进行未知状况的检测，对医学和公共卫生领域来说并非新鲜事。制定筛查测试的方案已经很成熟。然而，将筛选原则应用于遗传疾病会带来独特的挑战。与大多数筛查测试不同，大多数未经选择的人群中罕见遗传疾病的自然史和疾病流行率是未知的。很难或不可能为临床验证研究获得真实的队列。因此，无法准确计算遗传筛查检测中常见的致病性变异的临床阳性和阴性预测值。此外，筛查面板中包含的许多遗传疾病都没有临床确认测试。根据世界卫生组织的筛选原则，所有这些要素通常都需要证明筛选测试的合理性。然而，随着 DNA 测序成本的持续下降，越来越多的人在没有临床指征的情况下选择进行基因组检测。尽管存在挑战，但可以进行合理的估计，并用于告知测试设计策略。在此，我们回顾了基本的测试设计原则，并将其应用于遗传筛查。
