scholarly journals Not all low fetal fraction cell‐free DNA screening failures are at increased risk for aneuploidy

2021 ◽  
Author(s):  
Samantha Caldwell ◽  
Eyad Almasri ◽  
Lindsey Schmidt ◽  
Chen Xu ◽  
Brittany Dyr ◽  
...  
Keyword(s):  
Cell Free Dna ◽  
Free Dna ◽  
Increased Risk ◽  
Fetal Fraction

scholarly journals Noninvasive Fetal Genotyping by Droplet Digital PCR to Identify Maternally Inherited Monogenic Diabetes Variants

2020 ◽  
Vol 66 (7) ◽  
pp. 958-965 ◽  
Author(s):  
Richard C Caswell ◽  
Tristan Snowsill ◽  
Jayne A L Houghton ◽  
Ali J Chakera ◽  
Maggie H Shepherd ◽  
...  
Keyword(s):  
At Risk ◽  
Digital Pcr ◽  
Monogenic Diabetes ◽  
Droplet Digital Pcr ◽  
High Birth Weight ◽  
Cell Free Dna ◽  
Pathogenic Variants ◽  
Free Dna ◽  
Increased Risk ◽  
Fetal Fraction

Abstract Background Babies of women with heterozygous pathogenic glucokinase (GCK) variants causing mild fasting hyperglycemia are at risk of macrosomia if they do not inherit the variant. Conversely, babies who inherit a pathogenic hepatocyte nuclear factor 4α (HNF4A) diabetes variant are at increased risk of high birth weight. Noninvasive fetal genotyping for maternal pathogenic variants would inform pregnancy management. Methods Droplet digital PCR was used to quantify reference and variant alleles in cell-free DNA extracted from blood from 38 pregnant women heterozygous for a GCK or HNF4A variant and to determine fetal fraction by measurement of informative maternal and paternal variants. Droplet numbers positive for the reference/alternate allele together with the fetal fraction were used in a Bayesian analysis to derive probability for the fetal genotype. The babies’ genotypes were ascertained postnatally by Sanger sequencing. Results Droplet digital PCR assays for GCK or HNF4A variants were validated for testing in all 38 pregnancies. Fetal fraction of ≥2% was demonstrated in at least 1 cell-free DNA sample from 33 pregnancies. A threshold of ≥0.95 for calling homozygous reference genotypes and ≤0.05 for heterozygous fetal genotypes allowed correct genotype calls for all 33 pregnancies with no false-positive results. In 30 of 33 pregnancies, a result was obtained from a single blood sample. Conclusions This assay can be used to identify pregnancies at risk of macrosomia due to maternal monogenic diabetes variants.

Low Fetal Fraction and Birth Weight in Women with Negative First-Trimester Cell-Free DNA Screening

2019 ◽  
Vol 37 (01) ◽  
pp. 086-091
Author(s):  
Mark A. Clapp ◽  
Margaret Berry ◽  
Lydia L. Shook ◽  
Penelope S. Roberts ◽  
Ilona T. Goldfarb ◽  
...  
Keyword(s):  
Birth Weight ◽  
First Trimester ◽  
Cell Free Dna ◽  
Free Dna ◽  
Increased Risk ◽  
Trimester Screening ◽  
Future Work ◽  
Primary Variable ◽  
Cfdna Screening ◽  
Fetal Fraction

Abstract Objective To determine the association between low fetal fraction and birth weight among women with a negative cell-free DNA (cfDNA) result for common aneuploidies in the first trimester. Study Design This is a retrospective cohort of women who delivered a singleton between July 2016 and June 2018 at a single institution and had normal cfDNA testing in the first trimester. The primary variable of interest was “low fetal fraction,” which was defined as fetal fractions less than 5th percentile among all fetal fractions in the cohort (fetal fraction < 5.34%). The primary outcomes were birth weight ≤ 5th and ≤ 10th percentiles. Multivariable logistic regressions assessed for the association between low fetal fraction and birth weight. Results A total of 7,478 women delivered a singleton at ≥24 weeks' gestation, of which 2,387 (32%) underwent genetic screening through cfDNA; the majority were in the first trimester (n = 2,052 [86%]). 2,035 met the inclusion criteria. Birth weight ≤ 5th percentile was significantly higher in the low fetal fraction group (6.9 vs. 3.2%; p = 0.04). A low fetal fraction was associated with higher odds of an infant with a low birth weight: adjusted odds ratio (aOR) of 2.32 (95% CI 1.15–4.67) for birth weight ≤ 10th percentile (p = 0.02) and aOR of 3.73 (95% CI 1.40–9.03) for birth weight ≤ 5th percentile (p = 0.004). Conclusion Low fetal fractions of ≤ 5th percentile were associated with an increased risk of birth weights ≤ 5th and ≤ 10th percentiles in women with negative cfDNA screening in the first trimester. Future work is needed to further investigate this relationship and to determine the potential clinical implications, such as third-trimester screening for growth restriction in women with low fetal fractions and negative cfDNA screening results.

Association of Fetal Fraction of Cell-Free DNA and Hypertensive Disorders of Pregnancy

2018 ◽  
Vol 36 (03) ◽  
pp. 311-316 ◽  
Author(s):  
Nathanael Koelper ◽  
Mary Sammel ◽  
Lorraine Dugoff ◽  
Whitney Bender
Keyword(s):  
Multinomial Logistic Regression ◽  
First Trimester ◽  
Chronic Hypertension ◽  
Hypertensive Disorders Of Pregnancy ◽  
Cell Free Dna ◽  
Free Dna ◽  
Hypertensive Disorders ◽  
Increased Risk ◽  
The Relationship ◽  
Fetal Fraction

Objective The objective of this study is to examine the relationship between fetal fraction and hypertensive disorders of pregnancy. Study Design This is a retrospective cohort study of women with singleton pregnancies who had cell-free DNA (cfDNA) screening at 10 to 20 weeks of gestation. The primary outcome was the development of gestational hypertension (gHTN), preeclampsia (PEC), and PEC with severe features. Multinomial logistic regression was performed to assess the relationship between fetal fraction and pregnancy outcomes of interest while controlling for potential confounders. Results Among 2,701 women meeting inclusion criteria, 387 (14.3%) were diagnosed with hypertensive disorders of pregnancy. First-trimester fetal fraction was significantly lower in women diagnosed with hypertensive disorders of pregnancy (10.9 vs. 12.4, p < 0.0001). An increased risk of gHTN and PEC, PEC with severe features with delivery > 34 weeks, and PEC with severe features with delivery ≤ 34 weeks was seen with lower first-trimester fetal fractions (odds ratio [OR]: 0.55, 95% confidence interval [CI] [0.36–0.83], p = 0.005; OR: 0.59, 95% CI [0.35–0.99], p = 0.048; and OR: 0.27, 95% CI [0.08–0.96], p = 0.044). The relationship between fetal fraction and hypertensive disorders of pregnancy was not statistically significant after adjusting for maternal age, race, body mass index, and chronic hypertension. Conclusion Fetal fraction of cfDNA at 10 to 20 weeks of gestation was not associated with the development of hypertensive disorders of pregnancy.

scholarly journals Deoxyribonuclease I Activity, Cell-Free DNA, and Risk of Liver Cancer in a Prospective Cohort

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Rachel M Golonka ◽  
Beng San Yeoh ◽  
Jessica L Petrick ◽  
Stephanie J Weinstein ◽  
Demetrius Albanes ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Prospective Cohort ◽  
Conditional Logistic Regression ◽  
Clinical Manifestations ◽  
Dnase I ◽  
Cancer Case ◽  
Cell Free Dna ◽  
Dnase Ii ◽  
Free Dna ◽  
Increased Risk

Abstract Background Circulating cell-free DNA (cfDNA) is a proposed latent biomarker for several cancers, including liver cancer. Deoxyribonucleases (DNases) facilitate the timely and efficient degradation of cfDNA, leading us to hypothesize that DNase I and/or II might be a more sensitive early biomarker than cfDNA. To test this hypothesis, a study was conducted in a large, prospective cohort. Methods A nested case-control study (224 liver cancer case patients and 224 matched control subjects) was conducted in a cohort of Finnish male smokers, followed from baseline (1985–1988) to 2014. The associations among DNase I activity, cfDNA, and the risk of liver cancer were assessed using multivariable-adjusted conditional logistic regression. Results DNase I activity, whether measured as radius (mm) or as units per milliliter, was statistically significantly associated with increased risk of liver cancer (Ptrend <.01). DNase I activity in the highest quartile was associated with a greater than threefold risk of developing liver cancer (DNase I activity radius >2.7 mm, hazard ratio [HR] = 3.03, 95% confidence interval [CI] = 1.59 to 5.77; DNase I activity >2.72 units/mL, HR = 3.30, 95% CI = 1.64 to 6.65). The strength of this association was not substantially altered by exclusion of cases diagnosed within the first five years of follow-up or those with hepatitis C virus (HCV) infection. In contrast, cfDNA and DNase II was not statistically significantly associated with risk of liver cancer. Conclusions DNase I activity was a superior latent biomarker of liver cancer than cfDNA. These findings advance the goal of developing a means to detect liver cancer years well before the development of clinical manifestations.

scholarly journals An online tool for fetal fraction prediction based on direct size distribution analysis of maternal cell-free DNA

BioTechniques ◽  
2020 ◽  
Author(s):  
Luca Bedon ◽  
Josef Vuch ◽  
Simeone Dal Monego ◽  
Germana Meroni ◽  
Vanna Pecile ◽  
...  
Keyword(s):  
Size Distribution ◽  
Prenatal Testing ◽  
Distribution Analysis ◽  
Blood Draw ◽  
Noninvasive Prenatal Testing ◽  
Cell Free Dna ◽  
Maternal Cell ◽  
Fetal Dna ◽  
Free Dna ◽  
Fetal Fraction

The discovery of circulating fetal DNA in the plasma of pregnant women has greatly promoted advances in noninvasive prenatal testing. Screening performance is enhanced with higher fetal fraction and analysis of samples whose fetal DNA fraction is lower than 4% are unreliable. Although current approaches to fetal fraction measurement are accurate, most of them are expensive and time consuming. Here we present a simple and cost-effective solution that provides a quick and reasonably accurate fetal fraction by directly evaluating the size distribution of circulating DNA fragments in the extracted maternal cell-free DNA. The presented approach could be useful in the presequencing stage of noninvasive prenatal testing to evaluate whether the sample is suitable for the test or a repeat blood draw is recommended.

Impact of long‐term storage of plasma and cell‐free DNA on measured DNA quantity and fetal fraction

Vox Sanguinis ◽  
2020 ◽  
Vol 115 (7) ◽  
pp. 586-594 ◽  
Author(s):  
Frederik Banch Clausen ◽  
Angela N. Barrett ◽  
Henna V. Advani ◽  
Mahesh Choolani ◽  
Morten Hanefeld Dziegiel
Keyword(s):  
Cell Free Dna ◽  
Long Term Storage ◽  
Free Dna ◽  
Term Storage ◽  
Fetal Fraction

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.

Sign in / Sign up

Export Citation Format

Share Document