Debates on fetal fraction measurement and <scp>DNA</scp>‐based noninvasive prenatal screening: time for standardisation?

Wataganara, Tuangsit; Th, Bui; KW, Choy; Leung, Tse Ngong

doi:10.1111/1471-0528.14197

Cited by 18 publications

(20 citation statements)

References 19 publications

(31 reference statements)

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“…When a maternal blood sample is sent to different commercial providers, the estimate of fetal fraction can be quite variable, and the fetal fraction that they provide is just an estimate. There is no standardization of methods for assessment of fetal fraction [ 43 ], and so it is possible that we would have achieved a better correlation of indels with Y chromosome sequencing using a different algorithm. Achieving a definitive ‘correct’ fetal fraction will be difficult.…”

Section: Discussionmentioning

confidence: 99%

Measurement of fetal fraction in cell-free DNA from maternal plasma using a panel of insertion/deletion polymorphisms

et al. 2017

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ObjectiveCell-free DNA from maternal plasma can be used for non-invasive prenatal testing for aneuploidies and single gene disorders, and also has applications as a biomarker for monitoring high-risk pregnancies, such as those at risk of pre-eclampsia. On average, the fractional cell-free fetal DNA concentration in plasma is approximately 15%, but can vary from less than 4% to greater than 30%. Although quantification of cell-free fetal DNA is straightforward in the case of a male fetus, there is no universal fetal marker; in a female fetus measurement is more challenging. We have developed a panel of multiplexed insertion/deletion polymorphisms that can measure fetal fraction in all pregnancies in a simple, targeted sequencing reaction.MethodsA multiplex panel of primers was designed for 35 indels plus a ZFX/ZFY amplicon. cfDNA was extracted from plasma from 157 pregnant women, and maternal genomic DNA was extracted for 20 of these samples for panel validation. Sixty-one samples from pregnancies with a male fetus were subjected to whole genome sequencing on the Ion Proton sequencing platform, and fetal fraction derived from Y chromosome counts was compared to fetal fraction measured using the indel panel. A total of 157 cell-free DNA samples were sequenced using the indel panel, and informativity was assessed, along with the proportion of fetal DNA.ResultsUsing gDNA we optimised the indel panel, removing amplicons giving rise to PCR bias. Good correlation was found between fetal fraction using indels and using whole genome sequencing of the Y chromosome (Spearmans r = 0.69). A median of 12 indels were informative per sample. The indel panel was informative in 157/157 cases (mean fetal fraction 14.4% (±0.58%)).ConclusionsUsing our targeted next generation sequencing panel we can readily assess the fetal DNA percentage in male and female pregnancies.

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Section: Discussionmentioning

confidence: 99%

Measurement of fetal fraction in cell-free DNA from maternal plasma using a panel of insertion/deletion polymorphisms

et al. 2017

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“…Additionally, there is significant variation and no standardization in the way FF is measured and reported by commercial DNA laboratories, and it is reasonable to suspect variability in FF levels between tests that use different quantitation methods. 26 As all cfDNA screening tests in our study were performed at the same laboratory, the possibility for variation due to technical differences was minimized. Before developing broad clinical recommendations based on our findings, standardized measurement and reporting of the FF would have to be implemented across laboratories.…”

Section: Commentsmentioning

confidence: 99%

High Fetal Fraction on First Trimester Cell-Free DNA Aneuploidy Screening and Adverse Pregnancy Outcomes

et al. 2019

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Objective To test the hypothesis that high fetal fraction (FF) on first trimester cell-free deoxyribonucleic acid (cfDNA) aneuploidy screening is associated with adverse perinatal outcomes. Study Design This is a single-institution retrospective cohort study of women who underwent cfDNA screening at <14 weeks' gestation and delivered a singleton infant between July 2016 and June 2018. Women with abnormal results were excluded. Women with high FF (≥95th percentile) were compared with women with normal FF (5th–95th percentiles). Outcomes investigated were preterm birth, small for gestational age, and hypertensive disorders of pregnancy. Results A total of 2,033 women met inclusion criteria. The mean FF was 10.0%, and FF >16.5% was considered high (n = 102). Women with high FF had a greater chance of delivering a small for gestational age infant <fifth percentile, with an adjusted odds ratio of 2.4 (95% confidence interval: 1.1–4.8, p = 0.039). There was no significant association between high FF and either preterm birth or hypertensive disorders of pregnancy. Conclusion Women with a high FF in the first trimester are at increased risk of delivering a small for gestational age infant <fifth percentile. Further investigation into the clinical implications of a high FF is warranted.

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“…Too low FF (<4%, a common minimum threshold) may give rise to a false negative result, as the difference in the ratio of an aberrant chromosome would be insufficient to distinguish 10 . Therefore, it is important to estimate FF accurately, although currently there is a lack of standardisation in this field 11 . Several approaches for FF calculation have been proposed that differ by the target domain of the fetal-derived sequence being measured by the assay, specificity, reproducibility and the cost 11 , 12 .…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is important to estimate FF accurately, although currently there is a lack of standardisation in this field 11 . Several approaches for FF calculation have been proposed that differ by the target domain of the fetal-derived sequence being measured by the assay, specificity, reproducibility and the cost 11 , 12 . However, no large-scale comparison between different measurement methods has been done, therefore none of them can be considered a “standard” FF measurement 11 .…”

Section: Discussionmentioning

confidence: 99%

“…Several approaches for FF calculation have been proposed that differ by the target domain of the fetal-derived sequence being measured by the assay, specificity, reproducibility and the cost 11 , 12 . However, no large-scale comparison between different measurement methods has been done, therefore none of them can be considered a “standard” FF measurement 11 . Current NIPTmer version does not calculate FF, although this step should be incorporated into the analysis pipeline in the future.…”

Section: Discussionmentioning

confidence: 99%

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NIPTmer: rapid k-mer-based software package for detection of fetal aneuploidies

Sauk

Žilina

Kurg

et al. 2018

Sci Rep

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Non-invasive prenatal testing (NIPT) is a recent and rapidly evolving method for detecting genetic lesions, such as aneuploidies, of a fetus. However, there is a need for faster and cheaper laboratory and analysis methods to make NIPT more widely accessible. We have developed a novel software package for detection of fetal aneuploidies from next-generation low-coverage whole genome sequencing data. Our tool – NIPTmer – is based on counting pre-defined per-chromosome sets of unique k-mers from raw sequencing data, and applying linear regression model on the counts. Additionally, the filtering process used for k-mer list creation allows one to take into account the genetic variance in a specific sample, thus reducing the source of uncertainty. The processing time of one sample is less than 10 CPU-minutes on a high-end workstation. NIPTmer was validated on a cohort of 583 NIPT samples and it correctly predicted 37 non-mosaic fetal aneuploidies. NIPTmer has the potential to reduce significantly the time and complexity of NIPT post-sequencing analysis compared to mapping-based methods. For non-commercial users the software package is freely available at http://bioinfo.ut.ee/NIPTMer/.

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Debates on fetal fraction measurement and DNA‐based noninvasive prenatal screening: time for standardisation?

Cited by 18 publications

References 19 publications

Measurement of fetal fraction in cell-free DNA from maternal plasma using a panel of insertion/deletion polymorphisms

Measurement of fetal fraction in cell-free DNA from maternal plasma using a panel of insertion/deletion polymorphisms

High Fetal Fraction on First Trimester Cell-Free DNA Aneuploidy Screening and Adverse Pregnancy Outcomes

NIPTmer: rapid k-mer-based software package for detection of fetal aneuploidies

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