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Eur J Hum Genet. 2019 Jun 23. doi: 10.1038/s41431-019-0443-0. [Epub ahead of print]

Prospective head-to-head comparison of accuracy of two sequencing platforms for screening for fetal aneuploidy by cell-free DNA: the PEGASUS study.

Author information

1
Department of Laboratory Medicine, CHU de Québec-Université Laval & Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec City, QC, Canada. francois.rousseau@fmed.ulaval.ca.
2
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada. francois.rousseau@fmed.ulaval.ca.
3
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
4
Dept. of Obstetrics & Gynecology, University of Calgary, Calgary, AB, Canada.
5
Department of Pediatrics, Mother and Child Center, University Hospital of Quebec, Laval University Research Center, Québec City, QC, Canada.
6
Centre de recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
7
Department of Obstetrics and Gynaecology, Laval University, Québec City, QC, Canada.
8
Department of Obstetrics and Gynecology, CHU Ste-Justine Research Center, Université de Montréal, Montréal, QC, Canada.
9
Department of Obstetrics & Gynecology, University of Ottawa, Ottawa, ON, Canada.
10
The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
11
School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.
12
Department of Laboratory Medicine, CISSS Chaudière-Appalaches, Lévis, QC, Canada.
13
Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
14
Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
15
Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, QC, Canada.
16
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
17
Department of Laboratory Medicine, CHU de Québec-Université Laval & Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
18
Department of Pathology & Laboratory Medicine, BC Cancer Agency, Vancouver, BC, Canada.

Abstract

We compared clinical validity of two non-invasive prenatal screening (NIPS) methods for fetal trisomies 13, 18, 21, and monosomy X. We recruited prospectively 2203 women at high risk of fetal aneuploidy and 1807 at baseline risk. Three-hundred and twenty-nine euploid samples were randomly removed. The remaining 1933 high risk and 1660 baseline-risk plasma aliquots were assigned randomly between four laboratories and tested with two index NIPS tests, blind to maternal variables and pregnancy outcomes. The two index tests used massively parallel shotgun sequencing (semiconductor-based and optical-based). The reference standard for all fetuses was invasive cytogenetic analysis or clinical examination at birth and postnatal follow-up. For each chromosome of interest, chromosomal ratios were calculated (number of reads for chromosome/total number of reads). Euploid samples' mean chromosomal ratio coefficients of variation were 0.48 (T21), 0.34 (T18), and 0.31 (T13). According to the reference standard, there were 155 cases of T21, 49 T18, 8 T13 and 22 45,X. Using a fetal fraction ≥4% to call results and a chromosomal ratio z-score of ≥3 to report a positive result, detection rates (DR), and false positive rates (FPR) were not statistically different between platforms: mean DR 99% (T21), 100%(T18, T13); 79%(45,X); FPR < 0.3% for T21, T18, T13, and <0.6% for 45,X. Both methods' negative predictive values in high-risk pregnancies were >99.8%, except for 45,X(>99.6%). Threshold analysis in high-risk pregnancies with different fetal fractions and z-score cut-offs suggested that a z-score cutoff to 3.5 for positive results improved test accuracy. Both sequencing platforms showed equivalent and excellent clinical validity.

PMID:
31231136
DOI:
10.1038/s41431-019-0443-0

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