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

Yvette C. Raymond; Melissa L. Acreman; Sofia Bussolaro; Ben W. Mol; Shavi Fernando; Melody Menezes; Fabricio Da Silva Costa; Ilaria Fantasia; Daniel Lorber Rolnik

doi:10.1111/1471-0528.17386

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

Yvette C. Raymond^* (Corresponding Author), Melissa L. Acreman, Sofia Bussolaro, Ben W. Mol, Shavi Fernando, Melody Menezes, Fabricio Da Silva Costa, Ilaria Fantasia, Daniel Lorber Rolnik

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

3 Citations (Scopus)

Abstract

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 (I² = 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.

Original language	English
Pages (from-to)	549-559
Number of pages	11
Journal	BJOG: An International Journal of Obstetrics and Gynaecology
Volume	130
Issue number	6
Early online date	8 Feb 2023
DOIs	https://doi.org/10.1111/1471-0528.17386
Publication status	Published - May 2023

Bibliographical note

Funding Information:
BWM is supported by a NHMRC Investigator grant (GNT1176437). BWM reports consultancy for ObsEva and Merck and travel support and research grants from Merck. MM is employed as a genetic counsellor at a private genetic testing provider. DLR has received research grants from NHMRC and Norman‐Beischer Medical Research Foundation. The authors declare no competing interests. Completed disclosure of interest forms are available to view online as supporting information.

Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.

Data Availability Statement

The datasets and code supporting the current study have not been deposited in a public repository but are available from the corresponding author on request.

Keywords

cell-free DNA
cell-free DNA screening
segmental copy number variants

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Raymond, Y. C., Acreman, M. L., Bussolaro, S., Mol, B. W., Fernando, S., Menezes, M., Da Silva Costa, F., Fantasia, I., & Rolnik, D. L. (2023). The accuracy of cell-free DNA screening for fetal segmental copy number variants: A systematic review and meta-analysis. BJOG: An International Journal of Obstetrics and Gynaecology, 130(6), 549-559. https://doi.org/10.1111/1471-0528.17386

The accuracy of cell-free DNA screening for fetal segmental copy number variants: A systematic review and meta-analysis. / Raymond, Yvette C. (Corresponding Author); Acreman, Melissa L.; Bussolaro, Sofia et al.
In: BJOG: An International Journal of Obstetrics and Gynaecology, Vol. 130, No. 6, 05.2023, p. 549-559.

Research output: Contribution to journal › Review article › peer-review

Raymond, YC, Acreman, ML, Bussolaro, S, Mol, BW, Fernando, S, Menezes, M, Da Silva Costa, F, Fantasia, I & Rolnik, DL 2023, 'The accuracy of cell-free DNA screening for fetal segmental copy number variants: A systematic review and meta-analysis', BJOG: An International Journal of Obstetrics and Gynaecology, vol. 130, no. 6, pp. 549-559. https://doi.org/10.1111/1471-0528.17386

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abstract = "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 (I2 = 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.",

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author = "Raymond, {Yvette C.} and Acreman, {Melissa L.} and Sofia Bussolaro and Mol, {Ben W.} and Shavi Fernando and Melody Menezes and Fabricio Da Silva Costa and Ilaria Fantasia and Rolnik, {Daniel Lorber}",

note = "Funding Information: BWM is supported by a NHMRC Investigator grant (GNT1176437). BWM reports consultancy for ObsEva and Merck and travel support and research grants from Merck. MM is employed as a genetic counsellor at a private genetic testing provider. DLR has received research grants from NHMRC and Norman‐Beischer Medical Research Foundation. The authors declare no competing interests. Completed disclosure of interest forms are available to view online as supporting information. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.",

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T1 - The accuracy of cell-free DNA screening for fetal segmental copy number variants

T2 - A systematic review and meta-analysis

AU - Raymond, Yvette C.

AU - Acreman, Melissa L.

AU - Bussolaro, Sofia

AU - Mol, Ben W.

AU - Fernando, Shavi

AU - Menezes, Melody

AU - Da Silva Costa, Fabricio

AU - Fantasia, Ilaria

AU - Rolnik, Daniel Lorber

N1 - Funding Information: BWM is supported by a NHMRC Investigator grant (GNT1176437). BWM reports consultancy for ObsEva and Merck and travel support and research grants from Merck. MM is employed as a genetic counsellor at a private genetic testing provider. DLR has received research grants from NHMRC and Norman‐Beischer Medical Research Foundation. The authors declare no competing interests. Completed disclosure of interest forms are available to view online as supporting information. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.

PY - 2023/5

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N2 - 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 (I2 = 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.

AB - 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 (I2 = 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.

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

Access to Document

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