Evaluation of Array Comparative genomic Hybridisation in prenatal diagnosis of fetal anomalies: a multicentre cohort study with cost analysis and assessment of patient, health professional and commissioner preferences for array comparative genomic hybridisation

Robson, Stephen C., Chitty, Lyn S., Morris, Stephen, Verhoef, Talitha, Ambler, Gareth, Wellesley, Diana G., Graham, Ruth, Leader, Claire, Fisher, Jane and Crolla, John A. (2017) Evaluation of Array Comparative genomic Hybridisation in prenatal diagnosis of fetal anomalies: a multicentre cohort study with cost analysis and assessment of patient, health professional and commissioner preferences for array comparative genomic hybridisation. Efficacy and Mechanism Evaluation, 4 (1). pp. 1-104. ISSN 2050-4365

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Official URL: https://doi.org/10.3310/eme04010


Current pathways for testing fetuses at increased risk of a chromosomal anomaly because of an ultrasound anomaly involve karyotyping after rapid aneuploidy exclusion. Chromosomal microarray (CMA) may detect more clinically significant chromosomal imbalances than karyotyping but evidence to guide UK health service providers on whether or not CMA should replace karyotyping is limited.

(1) To compare detection rates of copy number variants (CNVs) and laboratory turnaround times (TATs) by karyotyping and CMA in fetuses with ultrasound anomalies, (2) to calculate test costs and the cost per additional pathogenic CNV detected by CMA relative to karyotyping and (3) to determine what factors influence parents’ and health professionals’ choice and decision-making about CMA.

A multicentre experimental research cohort study with an additional cost analysis.

A total of 20 fetal medicine units and nine cytogenetic laboratories across England and Wales.

Women with a fetus undergoing quantitative fluorescent polymerase chain reaction (QF-PCR) and karyotyping for clinical indications with (1) one or more structural anomalies identified on ultrasound or (2) an isolated nuchal translucency (NT) of ≥ 3.5 mm.

Karyotyping and CMA after exclusion of major chromosomal anomalies by QF-PCR. The array design consisted of 8-plex 60,000 60-mer oligonucleotides with a backbone resolution of ≈75 kb.

Main outcome measures
Rates of abnormal karyotypes and pathogenic CNVs and variants of unknown significance on CMA. Laboratory TATs for karyotyping and CMA. Costs of karyotyping and CMA and cost per additional pathogenic CNV detected by CMA. Parent and health professional attitudes to CMA.

Out of the 1718 probands recruited, 1123 cases with normal QF-PCR and both karyotype and CMA were available for analysis. In the group with structural anomalies (n = 629), CMA detected more CNVs [6.8%, 95% confidence interval (CI) 4.4% to 9.3%] and more pathogenic CNVs (3.5%, 95% CI 1.5% to 5.5%) than karyotyping. In the increased NT group (n = 494), CMA detected more CNVs (4.5%, 95% CI 1.8% to 7.1%) than karyotyping but not more pathogenic CNVs. Compared with karyotyping, median TAT was 3 days [interquartile range (IQR) 0–13 days] longer with CMA but when actual set-up to reporting times were compared, CMA was 5 days (IQR 2–8 days) quicker. Cost calculations of the respective pathways indicated that, per patient, CMA is on average £113 more costly than karyotyping. The incremental cost per extra pathogenic CNV detected by CMA was greater in the increased NT than the structural anomaly group (£9439 vs. £3635). Qualitative evaluation suggested that parents find CMA acceptable, despite the uncertainties it may introduce, and that in the main it is acceptable to health professionals and commissioners.

CMA is a robust, acceptable and probably cost-effective method to detect more clinically significant chromosomal imbalances in the anomalous fetus. The results suggest that CMA should replace karyotyping in these care pathways.

Future work
The application of CMA (and exome sequencing) on cell-free DNA in maternal plasma.

Trial registration
Current Controlled Trials ISRCTN01058191.

This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and NIHR partnership. The funder had no role in the identification, design and conduct of the study and the reporting of the analysis. The funder did recommend the inclusion of the cell-free DNA aspects of the EACH study. Funding was also received from the Great Ormond Street Biomedical Research Centre.

Item Type: Article
Additional Information: Copyright © Queen’s Printer and Controller of HMSO 2017. This work was produced by Robson et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.
Subjects: A300 Clinical Medicine
B200 Pharmacology, Toxicology and Pharmacy
B700 Nursing
B900 Others in Subjects allied to Medicine
Department: Faculties > Health and Life Sciences > Nursing, Midwifery and Health
Depositing User: Elena Carlaw
Date Deposited: 13 Aug 2019 13:59
Last Modified: 01 Aug 2021 10:50
URI: http://nrl.northumbria.ac.uk/id/eprint/40336

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