The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies

Canick, Jacob A.; Palomaki, Glenn E.; Kloza, Edward M.; Lambert-Messerlian, Geralyn; Haddow, James E.

doi:10.1002/pd.4126

Cited by 321 publications

(330 citation statements)

References 18 publications

(45 reference statements)

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“…More recently, cell-free fetal (cff ) DNA in maternal plasma has been used to screen for fetal aneuploidies (Song et al 2013;Bianchi et al 2014). Maternal blood contains both fetal and maternal cell-free nucleic acids, but the fetal contribution to plasma cellfree DNA is a minority (Canick et al 2013;Rava et al 2014). To examine pure fetal nucleic acids, therefore, fetal sources such as chorionic villi, placenta or amniotic fluid (AF) must be obtained through a diagnostic procedure.…”

mentioning

confidence: 99%

The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease

Zwemer

Bianchi

2015

Cold Spring Harbor Perspectives in Medicine

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mentioning

confidence: 99%

The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease

Zwemer

Bianchi

2015

Cold Spring Harbor Perspectives in Medicine

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“…Both agree with earlier studies. 2,13 Gestational age accounts for 4.2% variation of log fetal fraction and maternal weight accounts for 13.9%, and combined they account for 15.4%.…”

Section: Fetal Fractionsmentioning

confidence: 99%

“…Multiple studies have pointed out that the fetal fraction plays a crucial role in the effectiveness of NIPS to detect trisomy. [13][14][15][16] The consensus for the detecting limit of the fetal fraction appears to be 4%, although theoretical studies have suggested that 2% also works, 14 and more optimistic authors have suggested that as long as GC bias is accounted for and sequence depth is unlimited, NIPS can be effective for an arbitrarily small fraction of fetal DNA. 17 The prevailing method used to analyze NIPS data sets, first outlined in ref.…”

Section: Introductionmentioning

confidence: 99%

Informative priors on fetal fraction increase power of the noninvasive prenatal screen

Huang

et al. 2018

Genetics in Medicine

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Purpose: Noninvasive prenatal screening (NIPS) sequences a mixture of the maternal and fetal cell-free DNA. Fetal trisomy can be detected by examining chromosomal dosages estimated from sequencing reads. The traditional method uses the Z-test, which compares a subject against a set of euploid controls, where the information of fetal fraction is not fully utilized. Here we present a Bayesian method that leverages informative priors on the fetal fraction.Method: Our Bayesian method combines the Z-test likelihood and informative priors of the fetal fraction, which are learned from the sex chromosomes, to compute Bayes factors. Bayesian framework can account for nongenetic risk factors through the prior odds, and our method can report individual positive/negative predictive values.Results: Our Bayesian method has more power than the Z-test method. We analyzed 3,405 NIPS samples and spotted at least 9 (of 51) possible Z-test false positives.Conclusion: Bayesian NIPS is more powerful than the Z-test method, is able to account for nongenetic risk factors through prior odds, and can report individual positive/negative predictive values.

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“…1,2,11,12 Fetal fraction results, and z-scores in Down syndrome pregnancies, were subjected to a logarithm transformation before comparison, as these data are right skewed. 13 Proportions were compared using Fisher's exact tests. Significance was two tailed at P < 0.05; no adjustment for multiple comparisons was made.…”

Section: Brief Reportmentioning

confidence: 99%

Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies

Lambert-Messerlian

Kloza

Williams

et al. 2014

Genetics in Medicine

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Advances in molecular technologies have resulted in the introduction of next-generation sequencing of maternal plasma DNA for prenatal identification of Down syndrome and other common trisomies. 1,2 Circulating cell-free (ccf) DNA of placental/fetal origin 3 in the maternal circulation is thought to be released by apoptotic cells of the placenta, 4 and the success of next-generation sequencing is dependent on the percentage of fetal (placental) DNA present in maternal plasma (the fetal fraction). The higher the fetal fraction, the more easily a trisomy or other aneuploidy can be detected. On average, 13% of ccf DNA in maternal plasma is of fetal (placental) origin, and fetal fractions of less than 4% may not be sufficient for reliable testing. 1 First and second trimester maternal serum marker levels are known to be altered in pregnancies conceived using assisted reproductive technologies (ART) versus those conceived naturally (controls). [5][6][7][8][9][10] In particular, secretory products of the placenta, such as human chorionic gonadotropin and inhibin A, are 10-30% higher in pregnancies from ART relative to control pregnancies. The cause of the increased secretion is not known. Regardless, serum marker levels can be adjusted so that screening performance in ART pregnancies is comparable with that of controls. Given that a portion of ccf DNA also is released by placental cells, albeit by a different mechanism, we sought to explore the possibility that the levels of ccf DNA also differed between ART and control pregnancies. If ART pregnancies were to release at least as much fetal-specific ccf DNA into maternal blood as do naturally conceived pregnancies, this could reassure clinicians that next-generation testing in ART pregnancies would perform at least as well as in naturally conceived pregnancies. In addition, we examined the chromosome-specific z-score and the final interpretation of the testing in the ART and control pregnancies. MATERIALS AND METHODSSamples for this study were selected from among those reported earlier as part of a multicenter international clinical validation of a next-generation sequencing test for Down syndrome. 1Purpose: We sought to compare measurements of circulating cellfree DNA as well as Down syndrome test results in women with naturally conceived pregnancies with those conceived using assisted reproductive technologies.Methods: Data regarding assisted reproductive technologies were readily available from seven enrollment sites participating in an external clinical validation trial of nested case/control design. Measurements of circulating cell-free fetal and total DNA, fetal fraction (ratio of fetal to total DNA), chromosome-specific z-scores, and karyotype results were available for analysis.Results: Analyses were restricted to 632 euploid (5.2% assisted reproductive technologies) and 73 Down syndrome (13.7% assisted reproductive technologies), including 16 twin pregnancies. No differences were found for fetal or total circulating cell-free DNA, or for the fetal fraction in ...

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The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies

Cited by 321 publications

References 18 publications

The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease

The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease

Informative priors on fetal fraction increase power of the noninvasive prenatal screen

Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies

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