The Experts below are selected from a list of 402 Experts worldwide ranked by ideXlab platform

K H Nicolaides - One of the best experts on this subject based on the ideXlab platform.

  • clinical performance of non invasive prenatal testing nipt using targeted cell free dna analysis in maternal plasma with microarrays or next generation sequencing ngs is consistent across multiple controlled clinical studies
    Prenatal Diagnosis, 2015
    Co-Authors: Renee Stokowski, Eric Wang, Karen White, Annette Batey, Bo Jacobsson, Herb Brar, Madhumitha Balanarasimha, Desiree Hollemon, Andrew B Sparks, K H Nicolaides
    Abstract:

    Objective To evaluate the clinical performance of non-invasive prenatal testing for trisomy 21, 18, and 13 using targeted cell-free DNA (cfDNA) analysis. Methods Targeted cfDNA analysis using DANSR™ and FORTE™ with microarray quantitation was used to evaluate the risk of trisomy 21, 18, and 13 in blinded samples from 799 singleton, twin, natural, and IVF pregnancies. Subjects either had fetal chromosome evaluation by karyotype, FISH, QF-PCR, or karyotype for newborns with suspected aneuploidy at birth. The results of targeted cfDNA analysis were compared to clinical genetic testing outcomes to assess clinical performance. Results Targeted cfDNA analysis with microarray quantification identified 107/108 trisomy 21 cases (99.1%), 29/30 trisomy 18 cases (96.7%), and 12/12 trisomy 13 cases (100%). The specificity was 100% for all three Trisomies. Combining this data with all published clinical performance studies using DANSR/FORTE methodology for greater than 23 000 pregnancies, the sensitivity of targeted cfDNA analysis was calculated to be greater than 99% for trisomy 21, 97% for trisomy 18, and 94% for trisomy 13. Specificity for each trisomy was greater than 99.9%. Conclusion Targeted cfDNA analysis demonstrates consistently high sensitivity and extremely low false positive rates for common Autosomal Trisomies in pregnancy across quantitation platforms. © 2015 Ariosa Diagnostics Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

  • validation of targeted sequencing of single nucleotide polymorphisms for non invasive prenatal detection of aneuploidy of chromosomes 13 18 21 x and y
    Prenatal Diagnosis, 2013
    Co-Authors: Argyro Syngelaki, M M Gil, K H Nicolaides, V Atanasova, Desislava Markova
    Abstract:

    Objective To assess the performance of cell-free DNA (cfDNA) testing in maternal blood for detection of fetal aneuploidy of chromosomes 13, 18, 21, X, and Y using targeted sequencing of single-nucleotide polymorphisms. Methods Prospective study in 242 singleton pregnancies undergoing chorionic villus sampling at 11 to 13weeks. Maternal blood was collected before chorionic villus sampling and sent to Natera (San Carlos, CA, USA). cfDNA was isolated from maternal plasma, and targeted multiplex PCR amplification followed by sequencing of 19488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y was performed. Sequencing data were analyzed using the NATUS algorithm that determines the copy number and calculates a sample-specific accuracy for each of the five chromosomes tested. Laboratory personnel were blinded to fetal karyotype. Results Results were provided for 229 (94.6%) of the 242 cases. Thirty-two cases were correctly identified as aneuploid, including trisomy 21 [n=25; sensitivity=100% (CI: 86.3–100%), specificity=100% (CI: 98.2–100%)], trisomy 18 (n=3), trisomy 13 (n=1), Turner syndrome (n=2), and triploidy (n=1), with no false positive or false negative results. Median accuracy was 99.9% (range: 96.0–100%). Conclusions cfDNA testing in maternal blood using targeted sequencing of polymorphic loci at chromosomes 13, 18, 21, X, and Y holds promise for accurate detection of fetal Autosomal Trisomies, sex chromosome aneuploidies, and triploidy. © 2013 John Wiley & Sons, Ltd.

Peter Benn - One of the best experts on this subject based on the ideXlab platform.

  • review of epidemiological factors other than maternal age that determine the prevalence of common Autosomal Trisomies
    Prenatal Diagnosis, 2021
    Co-Authors: Howard Cuckle, Peter Benn
    Abstract:

    The birth prevalence of each common Autosomal trisomy (21, 18 and 13) increases with advancing maternal age and this is the most important epidemiological risk factor. Prevalence during pregnancy is also dependent on gestational age. Other factors claimed to influence prevalence include paternal age, ethnicity, family history, premature reproductive aging, parity, twinning, smoking, environmental exposures, maternal medical conditions, and predispositions. We review the evidence for these associations since they may provide insights into causal mechanisms. When investigating potential co-factors it is important to adequately allow for maternal age and minimize its confounding contribution. This is well illustrated by reports of an inverse paternal age effect where there is strong correlation between parental ages. Gestational age at diagnosis, availability of prenatal screening, diagnostic testing, and elective termination of affected pregnancies and healthcare disparities also confound the studies on ethnicity, medical conditions, and predispositions or environmental factors. Data from twin zygosity studies demonstrate the importance of differences in fetal viability for affected pregnancies. We conclude that existing epidemiological evidence for most of the co-factors discussed should currently be considered tenuous; history of Down syndrome, albeit biased, may be an exception. The co-factors may yet provide clues to hitherto poorly understood causal pathways.

  • rare Autosomal Trisomies comparison of detection through cell free dna analysis and direct chromosome preparation of chorionic villus samples
    Ultrasound in Obstetrics & Gynecology, 2019
    Co-Authors: Peter Benn, Francesca Malvestiti, Beatrice Grimi, Federico Maggi, G Simoni, Francesca Romana Grati
    Abstract:

    Objective Direct chromosome preparations of chorionic villus samples (CVS) and cell-free DNA (cfDNA) testing both involve analysis of the trophoblastic cell lineage. The aim of this study was to compare the spectrum of rare Autosomal Trisomies (RATs) detected by these two approaches and assess the available information on their clinical significance. Methods Data from 10 reports on genome-wide cfDNA testing were pooled to determine which chromosomes were most frequently involved in RAT-positive cases, and pregnancy outcome information was reviewed. CVS information was obtained from an updated database of 76 102 consecutive CVS analyses performed over a period of 18 years at TOMA laboratory, in which trophoblastic and mesenchymal layers were analyzed and amniotic fluid cell analysis was recommended for RAT-positive cases. Chromosomes involved and presence of confined placental mosaicism, true fetal mosaicism and uniparental disomy (UPD) for imprinted chromosomes were assessed. Also evaluated were the frequency and types of RATs in products of conception. Results RATs were present in 634 of 196 662 (0.32%) cfDNA samples and 237 of 57 539 (0.41%) CVS trophoblast samples (P 9% each. Conclusions Although there are strong parallels between RATs ascertained through cfDNA analysis and direct chromosome preparation of CVS, caution is needed in applying conclusions from CVS analysis to cfDNA testing, and vice versa. RATs identified through genome-wide cfDNA tests have uncertain risks for fetal loss, growth restriction or fetal abnormality. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

  • cell free dna screening for fetal aneuploidy as a clinical service
    Clinical Biochemistry, 2015
    Co-Authors: Howard Cuckle, Peter Benn, Eugene Pergament
    Abstract:

    Non-invasive prenatal testing (NIPT) through the analysis of cell free (cf)DNA is revolutionizing prenatal screening for fetal aneuploidy. Current methods used in clinical practice include shotgun massively parallel sequencing (s-MPS); targeted (t-MPS); and an approach that takes advantage of single nucleotide polymorphism (SNP) differences between mother and fetus. Efficacy of cfDNA testing for the common Autosomal Trisomies far exceeds that of conventional screening. Depending on the methodology used, reasons for discordancy between cfDNA results and fetal karyotype can include true fetal mosaicism, confined placental mosaicism, presence of a maternal karyotype abnormality, insufficient counting due to low fetal fraction, and a vanishing twin. Among the possible cfDNA strategies a Primary test has the highest performance but is expensive, while a Contingent cfDNA test can achieve high performance at a relatively low cost. Practicalities to be considered in the provision of testing include pretest counseling about the scope and accuracy of the testing, the interpretation of results when there is a low fetal fraction and follow-up studies for positive test results. The role of first trimester nuchal translucency measurement and conventional biochemical testing needs to be reassessed in the context of the use of cfDNA.

Diana W Bianchi - One of the best experts on this subject based on the ideXlab platform.

  • rare Autosomal Trisomies revealed by maternal plasma dna sequencing suggest increased risk of feto placental disease
    Science Translational Medicine, 2017
    Co-Authors: Mark D Pertile, Meredith Halksmiller, Nicola Flowers, Catalin Barbacioru, Sarah L Kinnings, Darcy Vavrek, William K Seltzer, Diana W Bianchi
    Abstract:

    Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare Autosomal Trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected “target” chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications.

Mark D Pertile - One of the best experts on this subject based on the ideXlab platform.

  • genome wide cell free dna based prenatal testing for rare Autosomal Trisomies and subchromosomal abnormalities
    2018
    Co-Authors: Mark D Pertile
    Abstract:

    Abstract Genome-wide sequencing of cell-free DNA (cfDNA) from maternal plasma enables noninvasive prenatal testing (NIPT) of all 24 chromosomes. A key advantage of the genome-wide approach is its potential to identify pathogenic copy number changes that would go unrecognized using standard methods of cfDNA-based NIPT, which screen only for aneuploidies of chromosomes 13, 18, 21, X and Y. An expanded cfDNA screening approach can identify rare Autosomal Trisomies associated with pregnancy complications that include miscarriage, true fetal mosaicism, uniparental disomy, fetal growth restriction, and fetal demise; while subchromosomal copy number imbalances such as deletions, duplications, and unbalanced chromosomal rearrangements, which have serious consequences for the normal development of the fetus, can also be identified. However, genome-wide screening for whole chromosome and segmental aneuploidies is not without its technical, biological, and interpretative challenges. This Chapter explores the rapidly expanding field of genome-wide cfDNA-based NIPT and highlights the applications, benefits, and limitations of this approach.

  • rare Autosomal Trisomies revealed by maternal plasma dna sequencing suggest increased risk of feto placental disease
    Science Translational Medicine, 2017
    Co-Authors: Mark D Pertile, Meredith Halksmiller, Nicola Flowers, Catalin Barbacioru, Sarah L Kinnings, Darcy Vavrek, William K Seltzer, Diana W Bianchi
    Abstract:

    Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare Autosomal Trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected “target” chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications.

Richard P Rava - One of the best experts on this subject based on the ideXlab platform.

  • Genome-wide Fetal Aneuploidy Detection by Maternal Plasma DNA Sequencing
    Obstetrics and gynecology, 2012
    Co-Authors: Lawrence D. Platt, Amy J Sehnert, James D. Goldberg, Alfred Abuhamad, Richard P Rava
    Abstract:

    OBJECTIVE: To prospectively determine the diagnostic accuracy of massively parallel sequencing to detect whole chromosome fetal aneuploidy from maternal plasma. METHODS: Blood samples were collected in a prospective, blinded study from 2,882 women undergoing prenatal diagnostic procedures at 60 U.S. sites. An independent biostatistician selected all singleton pregnancies with any abnormal karyotype and a balanced number of randomly selected pregnancies with euploid karyotypes. Chromosome classifications were made for each sample by massively parallel sequencing and compared with fetal karyotype. RESULTS: Within an analysis cohort of 532 samples, the following were classified correctly: 89 of 89 trisomy 21 cases (sensitivity 100%, 95% [confidence interval] CI 95.9–100), 35 of 36 trisomy 18 cases (sensitivity 97.2%, 95% CI 85.5–99.9), 11 of 14 trisomy 13 cases (sensitivity 78.6%, 95% CI 49.2–99.9), 232 of 233 females (sensitivity 99.6%, 95% CI 97.6 to more than 99.9), 184 of 184 males (sensitivity 100%, 95% CI 98.0–100), and 15 of 16 monosomy X cases (sensitivity 93.8%, 95% CI 69.8–99.8). There were no false-positive results for Autosomal aneuploidies (100% specificity, 95% CI more than 98.5 to 100). In addition, fetuses with mosaicism for trisomy 21 (3/3), trisomy 18 (1/1), and monosomy X (2/7), three cases of translocation trisomy, two cases of other Autosomal Trisomies (20 and 16), and other sex chromosome aneuploidies (XXX, XXY, and XYY) were classified correctly. CONCLUSION: This prospective study demonstrates the efficacy of massively parallel sequencing of maternal plasma DNA to detect fetal aneuploidy for multiple chromosomes across the genome. The high sensitivity and specificity for the detection of Trisomies 21, 18, 13, and monosomy X suggest that massively parallel sequencing can be incorporated into existing aneuploidy screening algorithms to reduce unnecessary invasive procedures.