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Q&A

Genetics

Poster Session 1

(143) Accuracy of fetal fraction measurements in SNP-based non-invasive prenatal testing (NIPT)

Tuesday, February 13, 2024

10:30 AM – 12:00 PM

Location: Prince George's Exhibit Hall CDE, Lower Atrium Level

Coauthor(s)

DL

Daniel Lyons, PhD

Natera, Inc.
Austin, TX, United States
JZ

Jingwen Zhang, PhD

Natera, Inc.
Austin, TX, United States
WX

Wenbo Xu, MD, PhD

Natera, Inc.
Austin, TX, United States

Presenting Author(s)

ZD

Zachary Demko, PhD (he/him/his)

Senior Director of Scientific Communications
Natera, Inc.
SAN CARLOS, CA, United States

Primary Author(s)

PB

Peter Benn, DSc

University of Connecticut Health Center
Farmington, CT, United States

Objective: Measuring fraction of cell free-DNA (cfDNA) that is fetal/placental in origin (fetal fraction (FF)) is an important, guideline-supported, quality assurance metric in non-invasive prenatal testing (NIPT). We assessed the accuracy of FF measurements for a SNP-based NIPT using measures of Y-chromosome DNA as a reference standard.

Study Design: We reviewed a total of 3,046 pregnancies (1,886 low-risk by SNP-based NIPT singleton male fetus cases with reported FF>2.8%, and 1,150 cases with low FF (< 2.8%)). Each cohort was from randomly selected referrals between March-May 2022. A published maximum likelihood method, considering 9,267 SNPs exclusively from autosomal chromosomes, provided the “Reported FF”. FF was also assessed by considering 277 SNPs from homologous non-recombinant regions (HNRs) of the Y chromosome that must be fetal in origin (“YchrFF”). We calculated the Pearson correlation coefficient between the ReportedFF and YchrFF; the accuracy standard deviation (SD) defined as SD (ReportedFF-YchrFF); and bias defined as mean (ReportedFF-YchrFF).

Results: Linear regression showed a very strong correlation between ReportedFF and YchrFF across the YchrFF range of 0.6% to 20% (r squared = 0.996). The accuracy standard deviation was 0.14% for samples with a Reported FF between 0.6%-2.8%; 0.19% for FF between 2.8%-5.0%%; 0.20% for FF between 5.0-7.0%; 0.26% for FF between 7.0-10.0%; and 0.38% for FF >10%.

Conclusion: Using Y-chromosome DNA as a reference standard, this SNP-based NIPT had reported FF’s that were substantially more accurate (accuracy SD=0.14-0.38%) than those previously reported for other NIPT methods (accuracy SD 1.3%-2.5%) (Persson and Prensky, Clin Chem 2021;67:863-6). Reported FF for the SNP-based NIPT can be reliably interpreted at values as low as 0.6% which is well below the 2.8% FF threshold used by this laboratory for interpreting SNP data. FF is an important quality assurance metric and all laboratories should be held to a high standard in its measurement.