Screening Performance and Costs of Different Strategies in Prenatal Screening for Trisomy 21.
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ABSTRACT:
SUBMITTER: Kagan KO
PROVIDER: S-EPMC4397935 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Non-invasive prenatal tests for the detection of fetal aneuploidies are predominantly based on the analysis of cell-free DNA (cfDNA) from the plasma of pregnant women by next-generation sequencing. The development of alternative tests for routine genetic laboratories is therefore desirable. Multiplex digital droplet PCR was used to detect 16 amplicons from chromosome 21 and 16 amplicons from chromosome 18 as the reference. Two fluorescently labeled lock nucleic acid probes were used for the detection of reaction products. The required accuracy was achieved by examining 12 chips from each patient using Stilla technology. The plasma cfDNA of 26 pregnant women with euploid pregnancies and 16 plasma samples from pregnancies with trisomy 21 were analyzed to determine the cutoff value for sample classification. The test was validated in a blind study on 30 plasma samples from pregnant patients with a risk for trisomy 21 ranging from 1:4 to 1:801. The results were in complete agreement with the results of the invasive diagnostic procedure (sensitivity, specificity, PPV, and NPV of 100%). Low cost, and speed of analysis make it a potential screening method for implementation into the clinical workflow to support the combined biochemical and ultrasound results indicating a high risk for trisomy 21.
| S-EPMC10746715 | biostudies-literature
Project description:BackgroundMolecular size determination of circulating free fetal DNA in maternal plasma is an important detection method for noninvasive prenatal testing (NIPT). The fetal DNA molecule is the primary factor determining the overall performance of NIPT and its clinical interpretation. The proportion of cell-free fetal DNA molecules is expressed as the fetal DNA fraction in the plasma of pregnant women.MethodsWe proposed an effective method to deduce fetal chromosomal aneuploidy based on the proportion of a certain range of DNA fragment lengths from maternal plasma. We gradually narrowed the range of the upper and lower boundary via a traversing algorithm.ResultsWe explored the optimal range of the upper and lower boundary by using size-based DNA fragment length. Using this range, the accuracy of the sensitivity and specificity could be improved by up to 100% for detecting the three most common autosomal aneuploidies, namely trisomy 13, trisomy 18, trisomy 21 in the sample set.ConclusionsNumerical experiments demonstrate that our method is effective and efficient. The program is available upon request.
| S-EPMC6461288 | biostudies-literature
Project description:Down syndrome (DS), also known as trisomy 21 (T21), is the most common human chromosomal anomaly. Although DS can affect many organ systems, lung and heart disease are the leading causes of death. An abundance of existing data suggests that lung abnormalities originate postnatally in DS. However, a single report of branching insufficiency in DS has inferred a potential prenatal origin. The histology of T21 fetal lungs (n = 15) was assessed by an experienced pathologist. Spatial differences in cellular phenotypes were examined using immunohistochemistry (IHC). Comprehensive gene expression in prenatal T21 lungs (n = 19), and age-matched controls (n = 19), was performed using high-throughput RNA sequencing (RNAseq) and validated by RT-qPCR. Histopathological abnormalities were observed in approximately half of T21 prenatal lung samples analyzed, which included dilated terminal airways/acinar tubules, dilated lymphatics, and arterial wall thickening. IHC for Ki67 revealed significant reductions in epithelial and mesenchymal cell proliferation, predominantly in tissues displaying pathology. IHC demonstrated that airway smooth muscle was reduced and discontinuous in the proximal airway in conjunction with reduced SOX2. RNAseq identified 118 genes significantly dysregulated (FDR < 0.05) in T21 lung when unadjusted and 316 genes when adjusted for age. Ontology analysis showed that IFN pathway genes were appreciably upregulated, whereas complement and coagulation cascades and extracellular matrix pathway genes were downregulated. RT-qPCR confirmed the changes in genes associated with these pathways in prenatal T21 lungs. Our data demonstrate that specific histological, cellular, and molecular abnormalities occur prenatally in different compartments of human T21 lung, which could be representative of premature stage progression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC9109699 | biostudies-literature
Project description:ObjectiveTo compare costs and efficacy of reflex and recall prenatal DNA screening for trisomy 21, 18 and 13 (affected pregnancies). In both methods women have Combined test markers measured. With recall screening, women with a high Combined test risk are recalled for counselling and offered a DNA blood test or invasive diagnostic testing. With reflex screening, a DNA analysis is automatically performed on plasma collected when blood was collected for measurement of the Combined test markers.MethodsPublished data were used to estimate, for each method, using various unit costs and risk cut-offs, the cost per woman screened, cost per affected pregnancy diagnosed, and for a given number of women screened, numbers of affected pregnancies diagnosed, unaffected pregnancies with positive results, and women with unaffected pregnancies having invasive diagnostic testing.ResultsCost per woman screened is lower with reflex v recall screening: £37 v £38, and £11,043 v £11,178 per affected pregnancy diagnosed (DNA £250, Combined test markers risk cut-off 1 in 150). Reflex screening results in similar numbers of affected pregnancies diagnosed, with 100-fold fewer false-positives and 20-fold fewer women with unaffected pregnancies having invasive diagnostic testing.ConclusionsReflex DNA screening is less expensive, more cost-effective, and safer than recall screening.
| S-EPMC6658079 | biostudies-literature
Project description:A universal biomarker panel with the potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptome analysis is a powerful tool to capture differentially expressed genes (DEG), which can be used as biomarker-diagnostic-predictive tool for various conditions in prenatal setting. In search of biomarker set for predicting high-risk pregnancies, we performed global expression profiling to find DEG in Ts21. Subsequently, we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using expression microarrays. Datasets from Ts21 transcriptomic studies from GEO repository were incorporated. DEG were discovered using linear regression modelling and validated using RT-PCR quantification on an independent sample of 16 cases with Ts21 and 32 controls. The classification performance of Ts21 status based on expression profiling was performed using supervised machine learning algorithm and evaluated using a leave-one-out cross validation approach. Global gene expression profiling has revealed significant expression changes between normal and Ts21 samples, which in combination with data from previously performed Ts21 transcriptomic studies, were used to generate a multi-gene biomarker for Ts21, comprising of 9 gene expression profiles. In addition to biomarker's high performance in discriminating samples from global expression profiling, we were also able to show its discriminatory performance on a larger sample set 2, validated using RT-PCR experiment (AUC=0.97), while its performance on data from previously published studies reached discriminatory AUC values of 1.00. Our results show that transcriptomic changes might potentially be used to discriminate trisomy of chromosome 21 in the prenatal setting. As expressional alterations reflect both, causal and reactive cellular mechanisms, transcriptomic changes may thus have future potential in the diagnosis of a wide array of heterogeneous diseases that result from genetic disturbances.
| S-EPMC3774664 | biostudies-literature
Project description:The trials performed worldwide toward noninvasive prenatal diagnosis (NIPD) of Down's syndrome (or trisomy 21) have shown the commercial and medical potential of NIPD compared to the currently used invasive prenatal diagnostic procedures. Extensive investigation of methylation differences between the mother and the fetus has led to the identification of differentially methylated regions (DMRs). In this study, we present a strategy using the methylated DNA immunoprecipitation (MeDiP) methodology in combination with real-time quantitative PCR (qPCR) to achieve fetal chromosome dosage assessment, which can be performed noninvasively through the analysis of fetal-specific DMRs. We achieved noninvasive prenatal detection of trisomy 21 by determining the methylation ratio of normal and trisomy 21 cases for each tested fetal-specific DMR present in maternal peripheral blood, followed by further statistical analysis. The application of this fetal-specific methylation ratio approach provided correct diagnosis of 14 trisomy 21 and 26 normal cases.
| S-EPMC3977039 | biostudies-literature
Project description:BackgroundScreening tests for Trisomy 21 (T21), also known as Down syndrome, are routinely performed for the majority of pregnant women. However, current tests rely on either evaluating non-specific markers, which lead to false negative and false positive results, or on invasive tests, which while highly accurate, are expensive and carry a risk of fetal loss. We outline a novel, rapid, highly sensitive, and targeted approach to non-invasively detect fetal T21 using maternal plasma DNA.Methods and findingsHighly heterozygous tandem Single Nucleotide Polymorphism (SNP) sequences on chromosome 21 were analyzed using High-Fidelity PCR and Cycling Temperature Capillary Electrophoresis (CTCE). This approach was used to blindly analyze plasma DNA obtained from peripheral blood from 40 high risk pregnant women, in adherence to a Medical College of Wisconsin Institutional Review Board approved protocol. Tandem SNP sequences were informative when the mother was heterozygous and a third paternal haplotype was present, permitting a quantitative comparison between the maternally inherited haplotype and the paternally inherited haplotype to infer fetal chromosomal dosage by calculating a Haplotype Ratio (HR). 27 subjects were assessable; 13 subjects were not informative due to either low DNA yield or were not informative at the tandem SNP sequences examined. All results were confirmed by a procedure (amniocentesis/CVS) or at postnatal follow-up. Twenty subjects were identified as carrying a disomy 21 fetus (with two copies of chromosome 21) and seven subjects were identified as carrying a T21 fetus. The sensitivity and the specificity of the assay was 100% when HR values lying between 3/5 and 5/3 were used as a threshold for normal subjects.ConclusionsIn summary, a targeted approach, based on calculation of Haplotype Ratios from tandem SNP sequences combined with a sensitive and quantitative DNA measurement technology can be used to accurately detect fetal T21 in maternal plasma when sufficient fetal DNA is present in maternal plasma.
| S-EPMC2951898 | biostudies-literature
Project description:ObjectivesTo develop and validate a nomogram based on fetal nuchal translucency thickness (NT) and ultrasonographic facial markers for screening for trisomy 21 in the first trimester of pregnancy.MethodsThis was a retrospective case-control study using stored two-dimensional midsagittal fetal profile images captured at 11 + 0 to 13 + 6 weeks' gestation in singleton pregnancies. We included images from 302 trisomy-21 pregnancies and 322 euploid pregnancies. Cases were divided into a training set (200 euploid + 200 with trisomy 21) and a validation set (122 euploid + 102 with trisomy 21) at a ratio of approximately 2:1. For each, the maternal age, gestational age, fetal NT and karyotype were noted, and 12 ultrasonographic fetal facial markers were measured. The least absolute shrinkage and selection operator (LASSO) method and multivariable analysis were used to select automatically the discriminative markers. Logistic regression was used to develop a LASSO model, based on the selected markers, to screen for trisomy 21 in the first trimester of pregnancy. Furthermore, 60 of the 624 images were selected randomly as a retest set to evaluate the model's robustness. The predictive performance of screening for trisomy 21 of a model based on fetal NT and maternal age and of the LASSO model was assessed using the area under the receiver-operating-characteristics curve (AUC). A nomogram was developed as an individualized tool to predict patient-specific probability for trisomy 21, which is a more visual presentation of the LASSO model. The performance of the nomogram was assessed using the C-index and calibration curve.ResultsInto the LASSO model were incorporated eight markers, including fetal NT, prenasal-thickness-to-nasal-bone-length ratio, facial profile line, frontomaxillary facial angle, frontonasal facial angle, mandibulomaxillary facial angle, maxilla-nasion-mandible angle and d2 (distance between the anterior edge of the prefrontal skin and the mandibulomaxillary line) (all P < 0.05). The AUCs of the LASSO model for screening for trisomy 21 were 0.983 (95% CI, 0.971-0.994) in the training set and 0.979 (95% CI, 0.966-0.993) in the validation set, and these were higher than the AUCs of all eight individual ultrasonographic markers included in the model. The AUC of the LASSO model in the retest set was 0.997 (95% CI, 0.990-1.000), indicating good robustness of the LASSO model. The AUC of the LASSO model was significantly higher than that of the model based on fetal NT and maternal age in both training and validation sets (P < 0.001 for both). The nomogram of the LASSO model showed good discrimination of trisomy 21, with C-indices of 0.983 in the training set and 0.981 in the validation set.ConclusionsWe present an individualized nomogram which incorporates fetal NT and a series of ultrasonographic facial profile markers selected by the LASSO method and multivariable analysis. This nomogram can potentially be utilized as a convenient and effective tool in screening for trisomy 21 in the first trimester of pregnancy. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
| S-EPMC8362158 | biostudies-literature
Project description:BackgroundThe first- and second-trimester screening for trisomy 21 (T21) are reimbursed for all pregnant women in Belgium. Using a cut-off risk of 1:300 for T21, about 5% of all pregnant women are referred for definitive prenatal diagnosis using an invasive test, at a sensitivity of (only) 72.5%. The sensitivity and specificity of the non-invasive prenatal test (NIPT) are over 99% but come at a cost of €460 (£373) per test. The objective is to estimate the consequences of introducing NIPT for the detection of T21.MethodsA cost-consequences analysis was performed presenting the impact on benefits, harms and costs. Context-specific real-world information was available to set up a model reflecting the current screening situation in Belgium. This model was used to construct the second and first line NIPT screening scenarios applying information from the literature on NIPT's test accuracy.ResultsIntroducing NIPT in the first or second line reduces harm by decreasing the number of procedure-related miscarriages after invasive testing. In contrast with NIPT in the second line, offering NIPT in the first line additionally will miss fewer cases of T21 due to less false-negative test results. The introduction of NIPT in the second line results in cost savings, which is not true for NIPT at the current price in the first line. If NIPT is offered to all pregnant women, the price should be lowered to about €150 to keep the screening cost per T21 diagnosis constant.ConclusionsIn Belgium, the introduction and reimbursement of NIPT as a second line triage test significantly reduces procedure-related miscarriages without increasing the short-term screening costs. Offering and reimbursing NIPT in the first line to all pregnant women is preferred in the long term, as it would, in addition, miss fewer cases of T21. However, taking into account the government's limited resources for universal reimbursement, the price of NIPT should first be lowered substantially before this can be realised.
| S-EPMC4225226 | biostudies-literature
Project description:To date, a universal biomarker panel with a potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptomic approach, a measure of gene expression levels across the genome, is a powerful tool to capture differentially expressed genes (DEG) in various conditions, including human trisomy of chromosome 21 (Ts21). DEG can be used to design a biomarker set as a diagnostic-predictive tool for various conditions of heterogeneous aetiology in a prenatal setting. In the search of novel biomarker set to predict high-risk pregnancies, we performed global expression profiling to find DEG in Ts21 used as a model. Subsequently we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using Agilent 4x44K expression microarrays. DEG were discovered using linear regression modelling implemented in limma package. Datasets from Ts21 transcriptomic studies available at GEO repository were incorporated to select our preliminary top DEG. Subsequently, selected top DEG were validated using RT-PCR quantification on independent sample of 16 cases with Ts21 and 32 controls, as well as new datasets from previously performed expression studies in Ts21. The classification was performed using support vector machine classification kernel and evaluated using leave-one-out cross validation approach. Transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using Agilent 4x44K expression microarrays.
2013-06-19 | E-GEOD-48051 | biostudies-arrayexpress