Noninvasive prenatal screening for patients with high body mass index: Evaluating the impact of a customized whole genome sequencing workflow on sensitivity and residual risk

Abstract

Objective Women with high body mass index (BMI) tend to have reduced fetal fraction (FF) during cell‐free DNA‐based noninvasive prenatal screening (NIPS), causing test failure rates up to 24.3% and prompting guidelines that recommend aneuploidy screening other than NIPS for patients with significant obesity. Because alternatives to NIPS are only preferable if they perform better, we compared the respective sensitivities at different BMI levels of traditional aneuploidy screening and a customized whole‐genome sequencing NIPS. Method The relationship between FF, aneuploidy, and BMI was quantified from 58 105 patients screened with a customized NIPS that does not fail samples because of low FF alone. Expected analytical sensitivity as a function of aneuploidy and BMI (eg, trisomy 18 sensitivity when BMI = 35) was determined by scaling the BMI‐ and aneuploidy‐specific FF distribution by the FF‐ and aneuploidy‐specific sensitivity calculated from empirically informed simulations. Results Across all classes of obesity and assuming zero FF‐related test failures, analytical sensitivity for the investigated NIPS exceeded that of traditional aneuploidy screening for trisomies 13, 18, and 21. Conclusion Relative to traditional aneuploidy screening, a customized NIPS with high accuracy at low FF and a low test‐failure rate is a superior screening option for women with high BMI.

High-throughput fetal fraction amplification increases analytical performance of noninvasive prenatal screening

“…All samples were from patients who had consented to de-identified research and received testing with the Prequel NIPS (Myriad Women’s Health, South San Francisco, CA; as described 9 , 34 , 35 ). The study was granted an institutional review board (IRB) exemption by Advarra (Pro00042194).…”

“…Consolidated libraries were sequenced on the Illumina HiSeq 4000 and processed via a custom bioinformatics pipeline characterized previously. 35 , 36 …”

High-throughput fetal-fraction amplification increases analytical performance of noninvasive prenatal screening

“…All samples were from patients who had consented to de-identified research and received testing with the Prequel NIPS (Myriad Women's Health, South San Francisco, CA; as described 9,34,35 ). The study was granted an IRB exemption by Advarra (Pro00042194).…”

Is there an optimal gestational age for cell-free DNA testing in maternal obesity?

“…Another concern is that it is not known whether maternal obesity will diminish the sensitivity of cfDNA screening, which could lead to false negatives because of a low fetal fraction. 4 The authors did not report the detection rates of common trisomies in their study. Finally, for women with a negative cfDNA result who were tested at 9 to 10 weeks' gestation, would they still be offered a nuchal translucency (NT) ultrasound at 11 to 14 weeks' gestation?…”