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 CFTR variants in 50,778 exomes. In 24 cases with bi-allelic pathogenic CFTR 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 CFTR 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.

在使用可用的电子健康记录（EHR）作为唯一表型来源测试这种方法的报道之后，人们开始怀疑基于DNA的筛查低流行性单基因疾病的价值。我们假设针对EHR的基于DNA的筛查的更好检查模型是囊性纤维化（CF），因为在医疗保健系统中会积极寻求诊断。我们审查了50,778个外显子组中的CFTR变体。24例双等位基因致病性CFTR变体中，有21个真阳性。由于可用的EHR表型数据有限，我们考虑了三种情况的“潜在”假阳性。该基因组筛选显示阳性预测值为87.5％，阴性预测值为99.9％，敏感性为95.5％，特异性为99.9％。尽管在三种情况下基于EHR的表型存在局限性，但当将EHR数据用作唯一的表型来源时，是否存在病原体CFTR变体对CF诊断具有很强的预测价值。要准确确定基于DNA的筛查的预测价值，就需要超出可用EHR数据的特定于条件的表型。