Clinical experience across the fetal-fraction spectrum of a non-invasive prenatal screening approach with low test-failure rate

Objective To describe our clinical experience across the entire range of fetal‐fraction (FF) measurements of a non‐invasive prenatal screen (NIPS) that uses whole‐ genome sequencing (WGS). Methods We analyzed retrospectively results from 58 105 singleton pregnancies that underwent NIPS on a customized WGS platform during an 8‐month period and assessed clinical test performance for trisomy 21, trisomy 18 and trisomy 13. Pregnancy outcomes were sought for all screen‐positive patients and for 18% of screen‐negative patients. As differences in outcome‐collection response rates could artificially impact test‐performance calculations, we computed inferred sensitivity, specificity, positive predictive values (PPV) and negative predictive values adjusted for ascertainment bias. Results The screening test yielded a result for 99.9% (n = 58 048) of patients, meaning that approximately 1 in 1000 patients received a test failure (i.e. test failure rate = 0.1%). Of pregnancies with a test result, 572 (1%) screened positive for one of the common aneuploidies (362 for trisomy 21, 142 for trisomy 18 and 68 for trisomy 13). Informative outcomes were received for 237 (41.4%) patients with a screen‐positive result and 3258 (5.7%) of those with a screen‐negative result. In the full cohort, inferred sensitivities for trisomy 21, trisomy 18 and trisomy 13 were 99.7%, 96.8% and 94.3%, respectively, and PPVs were 93.1%, 85.2% and 48.4%, respectively. If a FF threshold of 4% had been employed to guard against false negatives, calculated sensitivities for the three aneuploidies would not have changed significantly, yet, importantly, the overall test‐failure rate would have increased to 6.6% (n = 3829), impacting 1 in 15 women. Conclusions Our clinical experience demonstrates that a customized WGS‐based NIPS without a FF threshold achieves high accuracy while maintaining a low test‐failure rate of 0.1%. As such, alternative strategies to ensure high accuracy of detection of common aneuploidies in samples with low FF (such as redraw after test failure, redrawing at a later gestational age, risk scoring based on FF) are not necessary for this screening approach. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
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