Improving Single-Nucleotide Polymorphism-Based Fetal Fraction Estimation of Maternal Plasma Circulating Cell-Free DNA Using Bayesian Hierarchical Models

2018 ◽  
Vol 25 (9) ◽  
pp. 1040-1049 ◽  
Author(s):  
Nicholas B. Larson ◽  
Chen Wang ◽  
Jie Na ◽  
Ross A. Rowsey ◽  
William Edward Highsmith ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Hierarchical Models ◽  
Bayesian Hierarchical Models ◽  
Maternal Plasma ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Cell Free Dna ◽  
Bayesian Hierarchical ◽  
Free Dna ◽  
Fetal Fraction

scholarly journals Cell‐free DNA fetal fraction in twin gestations in single‐nucleotide polymorphism‐based noninvasive prenatal screening

2019 ◽  
Vol 40 (2) ◽  
pp. 179-184 ◽  
Author(s):  
Herman Hedriana ◽  
Kimberly Martin ◽  
Daniel Saltzman ◽  
Paul Billings ◽  
Zachary Demko ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prenatal Screening ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Cell Free Dna ◽  
Noninvasive Prenatal Screening ◽  
Free Dna ◽  
Fetal Fraction

Noninvasive Cell-Free DNA-Based Prenatal Detection of Microdeletions Using Single Nucleotide Polymorphism–Targeted Sequencing

2014 ◽  
Vol 123 ◽  
pp. 167S
Author(s):  
Matthew Rabinowitz ◽  
Melissa Savage ◽  
Barbara Pettersen ◽  
Styrmir Sigurjonsson ◽  
Matthew Hill ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Targeted Sequencing ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Cell Free Dna ◽  
Prenatal Detection ◽  
Free Dna

scholarly journals Cell-Free DNA Analysis of Targeted Genomic Regions in Maternal Plasma for Non-Invasive Prenatal Testing of Trisomy 21, Trisomy 18, Trisomy 13, and Fetal Sex

2016 ◽  
Vol 62 (6) ◽  
pp. 848-855 ◽  
Author(s):  
George Koumbaris ◽  
Elena Kypri ◽  
Kyriakos Tsangaras ◽  
Achilleas Achilleos ◽  
Petros Mina ◽  
...  
Keyword(s):  
Trisomy 21 ◽  
Dna Analysis ◽  
Prenatal Testing ◽  
Cost Effective ◽  
Maternal Plasma ◽  
Trisomy 13 ◽  
Cell Free Dna ◽  
Free Dna ◽  
Genomic Regions ◽  
Fetal Fraction

Abstract BACKGROUND There is great need for the development of highly accurate cost effective technologies that could facilitate the widespread adoption of noninvasive prenatal testing (NIPT). METHODS We developed an assay based on the targeted analysis of cell-free DNA for the detection of fetal aneuploidies of chromosomes 21, 18, and 13. This method enabled the capture and analysis of selected genomic regions of interest. An advanced fetal fraction estimation and aneuploidy determination algorithm was also developed. This assay allowed for accurate counting and assessment of chromosomal regions of interest. The analytical performance of the assay was evaluated in a blind study of 631 samples derived from pregnancies of at least 10 weeks of gestation that had also undergone invasive testing. RESULTS Our blind study exhibited 100% diagnostic sensitivity and specificity and correctly classified 52/52 (95% CI, 93.2%–100%) cases of trisomy 21, 16/16 (95% CI, 79.4%–100%) cases of trisomy 18, 5/5 (95% CI, 47.8%–100%) cases of trisomy 13, and 538/538 (95% CI, 99.3%–100%) normal cases. The test also correctly identified fetal sex in all cases (95% CI, 99.4%–100%). One sample failed prespecified assay quality control criteria, and 19 samples were nonreportable because of low fetal fraction. CONCLUSIONS The extent to which free fetal DNA testing can be applied as a universal screening tool for trisomy 21, 18, and 13 depends mainly on assay accuracy and cost. Cell-free DNA analysis of targeted genomic regions in maternal plasma enables accurate and cost-effective noninvasive fetal aneuploidy detection, which is critical for widespread adoption of NIPT.

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

PLoS ONE ◽  
2017 ◽  
Vol 12 (10) ◽  
pp. e0186771 ◽  
Author(s):  
Angela N. Barrett ◽  
Li Xiong ◽  
Tuan Z. Tan ◽  
Henna V. Advani ◽  
Rui Hua ◽  
...  
Keyword(s):  
Maternal Plasma ◽  
Cell Free Dna ◽  
Free Dna ◽  
Fetal Fraction

scholarly journals Synergy of Total PLAC4 RNA Concentration and Measurement of the RNA Single-Nucleotide Polymorphism Allelic Ratio for the Noninvasive Prenatal Detection of Trisomy 21

2010 ◽  
Vol 56 (1) ◽  
pp. 73-81 ◽  
Author(s):  
Nancy BY Tsui ◽  
Ranjit Akolekar ◽  
Rossa WK Chiu ◽  
Katherine CK Chow ◽  
Tak Y Leung ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Real Time Pcr ◽  
Trisomy 21 ◽  
Digital Pcr ◽  
Maternal Plasma ◽  
Chromosome 21 ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Allelic Ratio ◽  
Mrna Concentration

Abstract Background: Maternal plasma mRNA encoded by the PLAC4 gene (placenta-specific 4), which is transcribed from chromosome 21 in placental cells, is a potential marker for the noninvasive assessment of chromosome 21 dosage in the fetus. We evaluated the diagnostic sensitivities and specificities of 2 trisomy 21–screening approaches that use maternal plasma PLAC4 mRNA. Methods: We studied maternal plasma samples from 153 pregnant women carrying euploid and trisomy 21 fetuses. For the samples in which the fetuses were heterozygous for the studied PLAC4 single-nucleotide polymorphism (SNP), we measured the ratio between 2 alleles of the SNP in maternal plasma PLAC4 mRNA (RNA-SNP) by mass spectrometric (MS) and digital PCR methods. For pregnancies involving fetuses homozygous for the SNP, we quantified the total PLAC4 mRNA concentration in maternal plasma by real-time PCR and digital PCR. Results: For the RNA-SNP approach, we achieved a diagnostic sensitivity and specificity of 100% (95% CI, 40.2%–100%) and 89.7% (95% CI, 78.8%–96.1%), respectively, for both the MS and the digital PCR methods. For the mRNA-quantification approach, the areas under the ROC curves were 0.859 (95% CI, 0.741–0.903) and 0.833 (95% CI, 0.770–0.923) for plasma PLAC4 mRNA concentrations measured by the real-time PCR and the digital PCR methods, respectively. Conclusions: For prenatal screening of trisomy 21, the quantification of the total PLAC4 mRNA concentration can be used in a synergistic manner with the RNA-SNP allelic ratio approach to increase the population coverage of cases in which diagnostic information can be obtained.

scholarly journals Fetal fraction of cell‐free DNA in maternal plasma in the prediction of spontaneous preterm delivery

2014 ◽  
Vol 45 (1) ◽  
pp. 101-105 ◽  
Author(s):  
M. S. Quezada ◽  
C. Francisco ◽  
D. Dumitrascu‐Biris ◽  
K. H. Nicolaides ◽  
L. C. Poon
Keyword(s):  
Preterm Delivery ◽  
Maternal Plasma ◽  
Cell Free Dna ◽  
Spontaneous Preterm Delivery ◽  
Free Dna ◽  
Fetal Fraction

scholarly journals Maternal plasma genome-wide cell-free DNA can detect fetal aneuploidy in early and recurrent pregnancy loss and can be used to direct further workup

2020 ◽  
Vol 35 (5) ◽  
pp. 1222-1229 ◽  
Author(s):  
Yuval Yaron ◽  
Montse Pauta ◽  
Celia Badenas ◽  
Anna Soler ◽  
Virginia Borobio ◽  
...  
Keyword(s):  
Cytogenetic Analysis ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Maternal Plasma ◽  
Chromosomal Anomalies ◽  
Cell Free Dna ◽  
Free Dna ◽  
Genome Wide ◽  
Competing Interest ◽  
Fetal Fraction

Abstract STUDY QUESTION Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)? SUMMARY ANSWER Genome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management. WHAT IS KNOWN ALREADY Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing. STUDY DESIGN, SIZE, DURATION This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort. MAIN RESULTS AND THE ROLE OF CHANCE Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases. LIMITATIONS, REASONS FOR CAUTION Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases. WIDER IMPLICATIONS OF THE FINDINGS cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed. STUDY FUNDING/COMPETING INTEREST(S) Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina’s Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.

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