Sugunaraj J P, Brosius H M, Murray M F, Manickam K, Stamm J A, Carey D J, Mirshahi U L
Department of Pulmonary and Critical Care Medicine, Geisinger, Danville, PA USA.
2Department of Genetics, Yale School of Medicine, New Haven, CT USA.
NPJ Genom Med. 2019 Sep 4;4:21. doi: 10.1038/s41525-019-0095-6. eCollection 2019.
Doubts have been raised about the value of DNA-based screening for low-prevalence monogenic conditions following reports of testing this approach using available electronic health record (EHR) as the sole phenotyping source. We hypothesized that a better model for EHR-focused examination of DNA-based screening is Cystic Fibrosis (CF) since the diagnosis is proactively sought within the healthcare system. We reviewed variants in 50,778 exomes. In 24 cases with bi-allelic pathogenic variants, there were 21 true-positives. We considered three cases "potential" false-positives due to limitations in available EHR phenotype data. This genomic screening exhibited a positive predictive value of 87.5%, negative predictive value of 99.9%, sensitivity of 95.5%, and a specificity of 99.9%. Despite EHR-based phenotyping limitations in three cases, the presence or absence of pathogenic variants has strong predictive value for CF diagnosis when EHR data is used as the sole phenotyping source. Accurate ascertainment of the predictive value of DNA-based screening requires condition-specific phenotyping beyond available EHR data.
在有报告称使用现有的电子健康记录（EHR）作为唯一的表型来源来测试这种方法后，人们对基于DNA的低患病率单基因疾病筛查的价值提出了质疑。我们假设，对于基于EHR的DNA筛查检查，更好的模型是囊性纤维化（CF），因为在医疗系统中会主动进行诊断。我们回顾了50778个外显子组中的变异。在24例具有双等位基因致病性变异的病例中，有21例为真阳性。由于现有EHR表型数据存在局限性，我们将3例视为“潜在”假阳性。这种基因组筛查的阳性预测值为87.5%，阴性预测值为99.9%，敏感性为95.5%，特异性为99.9%。尽管在3例病例中基于EHR的表型存在局限性，但当将EHR数据作为唯一的表型来源时，致病性变异的存在与否对CF诊断具有很强的预测价值。准确确定基于DNA的筛查的预测价值需要超越现有EHR数据的特定疾病表型分析。
