Dataset Information

Fetal fraction evaluation in non-invasive prenatal screening (NIPS).

ABSTRACT: An important factor in quality control of non-invasive prenatal screening (NIPS) or testing (NIPT) is a sufficient percentage of fetal DNA to avoid false-negative results. Here we evaluate 14,379 shallow whole-genome sequenced diagnostic NIPS samples, as well as negative controls, for both technical and biological factors that can influence fetal fraction and its assessment. Technically, bioinformatics analyses can have a profound impact on fetal fraction determination. We found best performance for fetal fraction determination with the Y chromosome based tool DEFRAG for male fetuses and the count based tool SeqFF for female fetuses. Biologically, gestational age of up to 21 weeks and maternal age had no influence on fetal fraction, while an increase in weight and BMI had a negative influence on fetal fraction. While a trend was observed, no statistically significant difference in fetal fraction was found between trisomy and normal samples. Overall, these results confirm the influence of biological factors and give insight into technical factors that can affect fetal fractions in NIPS.

SUBMITTER: Hestand MS

PROVIDER: S-EPMC6336813 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Fetal fraction evaluation in non-invasive prenatal screening (NIPS).

Hestand Matthew S MS Bessem Mark M van Rijn Peter P de Menezes Renee X RX Sie Daoud D Bakker Ingrid I Boon Elles M J EMJ Sistermans Erik A EA Weiss Marjan M MM

European journal of human genetics : EJHG 20180925 2

An important factor in quality control of non-invasive prenatal screening (NIPS) or testing (NIPT) is a sufficient percentage of fetal DNA to avoid false-negative results. Here we evaluate 14,379 shallow whole-genome sequenced diagnostic NIPS samples, as well as negative controls, for both technical and biological factors that can influence fetal fraction and its assessment. Technically, bioinformatics analyses can have a profound impact on fetal fraction determination. We found best performance ...[more]

PMID: 30254213

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Project description:ObjectiveTo 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).MethodsWe 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.ResultsThe 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.ConclusionsOur 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.

Project description:ObjectiveTo identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF).MethodsA FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively.ResultsThe evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%).ConclusionsFor pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Dataset Information

Fetal fraction evaluation in non-invasive prenatal screening (NIPS).

Publications

Fetal fraction evaluation in non-invasive prenatal screening (NIPS).

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