The accuracy of cell-free DNA screening for fetal segmental copy number variants: A systematic review and meta-analysis

Background: The performance of cell-free DNA (cfDNA) screening for microscopic copy number variants (CNVs) is unclear.Objectives: This was a systematic review and meta-analysis to investigate the sensitivity, specificity and positive predictive value (PPV) of cfDNA screening for CNVs.Search Strategy: Articles published in EMBASE, PubMed or Web of Science before November 2022 were screened for inclusion. This protocol was registered with PROSPERO (23 March 2021, CRD42021250849) prior to initiation.Selection Criteria: Articles published in English, detailing diagnostic outcomes for at least 10 high-risk CNV results with cfDNA were considered for inclusion.Data Collection and Analysis: The PPV was calculated and pooled with random-effects models for double-arcsine transformed proportions, using cases with diagnostic confirmation. Overall sensitivity, specificity and a summary receiver-operating characteristics (ROC) curve were calculated using bivariate models. The risk of bias was assessed using QUADAS-2.Main Results: In all, 63 articles were included in the final analysis, detailing 1 591 459 cfDNA results. The pooled PPV was 37.5% (95% confidence interval [CI] 30.6-44.8), with substantial statistical heterogeneity (I-2 = 93.9%). Bivariate meta-analysis estimated sensitivity and specificity to be 77.4% (95% CI 65.7-86.0) and 99.4% (95% CI 98.0-99.8), respectively, with an area under the summary ROC curve of 0.947 (95% CI 0.776-0.984).Conclusions: Approximately one-third of women who screen high-risk for CNVs with cfDNA will have an affected fetus. This value is of importance for screening counselling.