[Show abstract][Hide abstract] ABSTRACT: To estimate performance of a single-nucleotide polymorphism-based noninvasive prenatal screen for fetal aneuploidy in high-risk and low-risk populations on single venopuncture.
[Show abstract][Hide abstract] ABSTRACT: Down syndrome screening programs lead to the prenatal diagnosis of other chromosomal abnormalities, some of which would not be detected by the secondary use of cell-free (cf)DNA testing in screen positives. This study aims to assess the number of these incidental diagnoses.
[Show abstract][Hide abstract] ABSTRACT: Objective
To evaluate performance of first trimester nuchal translucency (NT) measurement among providers (physician-sonologists and sonographers) within the Nuchal Translucency Quality Review (NTQR) program.Methods
After training and credentialing, NTQR monitored NT performance by the extent to which the median multiple of the normal median (MM) for crown-rump length (CRL), , was within the range 0.9-1.1 MoM of a published referent curve. The standard deviation (SD) of log10 MoM and slope of NT on CRL were also evaluated. We report the distribution between providers of these performance indicators and evaluate potential sources of variation.ResultsAmong the first 1.5 million scans between 2005 and 2011 there were 1,485,944 with CRL in the range 41–84 mm, from 4710 providers at 2150 sites. Among the 3463 providers with at least 30 scans, the median of the providers NT median MoMs was 0.913. Only 1901 (55%) had an NT median MoM within the expected range: 89 above 1.1 MoM, 1046 at 0.8-0.9 MoM, 344 at 0.7-0.8 MoM and 83 below 0.7 MoM. There was a small increase in the NT median MoM with the length of time in NTQR and the number of scans entered annually. On average, physician-sonologists had a higher NT median MoM than sonographers, as did those already credentialed before NTQR. The median provider SD was 0.093 and slope 13.5%. SD correlated negatively with the median MoM (r=−0.34) and positively with slope (r=0.22).Conclusion
Even with extensive training, credentialing and monitoring, there remains considerable variability between NT providers. Those with more experience had performance closer to that expected.
Ultrasound in Obstetrics and Gynecology 04/2014; · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To calculate the theoretical performance of non-invasive prenatal testing based on counting methods.Methods
The calculations were based on Gaussian distributions of the percent cell-free DNA from selected chromosome regions in affected and normal pregnancies. The means were derived from the relative genomic size of the chromosome region and the fetal fraction. The standard deviations were derived from the bivariate distributions of proportional counts. Depth of sequencing was varied from 10,000,000 to 100,000 and fetal fraction from 20% to 3%. Detection rate was estimated for a fixed 0.13% false-positive rate.ResultsWhen either depth or fetal fraction is high, expected Down syndrome screening detection rates are high. However, when fetal fraction is low, deeper sequencing is required to obtain high detection rates. For micro-deletion and micro-duplication screening, deeper sequencing is routinely required to consistently achieve high detection rates. There are small differences in the ability to detect a micro-deletion compared with a duplication of the same size.Conclusion
While the theoretical calculations do not necessarily reflect the performance of currently available NIPT tests, it confirms that fetal fraction is a key factor. Efficacy can be substantially altered depending on the abnormality under investigation and the depth of sequencing. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Objective
To determine the impact on the risk calculation of various ways of handling maternal weight when this data is provided in the first part but not the second part of a sequential screening protocol.Method
Retrospective analysis of 38,986 sequential screens in which weight was provided in both the first and second trimester. Three potential strategies for calculating MoM values when the weight is not recorded at the time of second trimester risk evaluation were evaluated. First, perform no weight adjustment. Second, use the first trimester weight. Third, use the predicted second trimester weight based on the first trimester weight. To predict the second trimester weight we used a random-effects multi-level model.ResultsThe screen positive rate for Down syndrome was 3.0% (1,151/38,986) and trisomy 18 alone 0.12% (47/38,986). The 3 strategies resulted in 196(0.50%), 41(0.11%) and 23(0.06%) patients switching risk categories with the no adjustment, first trimester weight and predicted weight strategies, respectively.Conclusion
Utilizing the first trimester weight or the predicted second trimester weight in sequential screening when second trimester weight is not provided offers an affordable alternative for laboratories to provide robust risk calculations and interpretations without requiring excessive use of resources. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: In 2004, leaders in first-trimester aneuploidy screening and a multidisciplinary group of experts established the Nuchal Translucency Quality Review Program, a national program to standardize education, credentialing, and quality monitoring of nuchal translucency. Since its inception, the program has credentialed more than 6,600 physician and ultrasonographer participants and collected more than 2.4 million nuchal translucency measurements. Ongoing quality monitoring is conducted through statistical analysis comparing the distribution and standard deviation of participants' nuchal translucency measurements against those obtained from a standard referent curve. Results of these analyses are distributed to participants quarterly and are used to track each participant's performance and to trigger performance improvement activities or mandatory remediation. This program could serve as a template for future education and credentialing programs that include partnerships with academic leaders, national professional organizations, and industry.
Obstetrics and Gynecology 01/2014; 123(1):149-54. · 4.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: The objective of this study was to provide a critical analysis of the impact of assisted conception on prenatal screening for Down syndrome (DS) in twin pregnancies and the value of various screening modalities for early detection of anomalies. Methods: The literature was searched using PubMed and the Cochrane Library focusing on prenatal screening and antenatal care of assisted-conception twin pregnancies. Results: Serum screening alone is of limited value in detecting aneuploid twins, because the unaffected cotwin can "mask" the abnormal serum results of an affected one. In addition, this test can designate the pregnancy as at high risk but not identify the affected fetus. Nuchal translucency (NT) screening is the best available modality and a highly effective screening method for twin pregnancies. Among twins, NT alone has a 69% DS detection rate, first-trimester combined NT and serum biochemistry has a 72% DS detection rate, and an integrated screen will have an 80% DS detection rate at a 5% FPR. The data in the literature concerning the effect of assisted conception on maternal serum screening markers in twin pregnancies are scarce. Conclusions: Down syndrome screening in assisted-conception twins presents clinical and technical challenges. Therefore, assisted-conception twins need close monitoring from conception to delivery, by a practitioner familiar with the available screening modalities and their relative accuracy.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 07/2013; · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-invasive prenatal testing (NIPT) for aneuploidy using cell-free DNA in maternal plasma is revolutionizing prenatal screening and diagnosis. We review NIPT in the context of established screening and invasive technologies, range of cytogenetic abnormalities detectable, costs, counseling, and ethical issues. Current NIPT approaches involve whole genome sequencing, targeted sequencing, and assessment of single nucleotide polymorphism (SNP) differences between mother and fetus. Clinical trials have demonstrated the efficacy of NIPT for Down and Edwards syndromes, and possibly Patau syndrome, in high risk women. Universal NIPT screening is not cost-effective, but when used contingently in women found at moderate risk or higher by conventional screening it is effective. Positive NIPT results must be confirmed using invasive techniques. Established screening, fetal ultrasound, and invasive procedures with microarray testing, allow the detection of a broad range of additional abnormalities not yet detectable by NIPT. NIPT approaches that take advantage of SNP information potentially allow the identification of parent of origin for imbalances, triploidy, uniparental disomy, consanguinity and separately evaluate dizygotic twins. Fetal fraction enrichment, improved sequencing, and selected analysis of the most informative sequences, should result in tests for additional chromosome abnormalities. The provision of adequate pre-test counseling poses a substantial challenge.
Ultrasound in Obstetrics and Gynecology 05/2013; · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Aims: To determine first trimester maternal serum placental protein 13 (PP13) in singletons vs. twins with and without severe preeclampsia (PE). Methods: Serum samples were prospectively collected at 8-14 weeks of gestation. PP13 was determined by solid-phase immunoassay. Patients were recruited in community clinics throughout the country, and from the twin antenatal assessment clinic in Assaf Harofeh Medical Center, Zerifin, Israel. Demographics, medical, and pregnancy history were obtained at enrollment. Pregnancy outcome was collected after delivery. PP13 was compared by the Wilcoxon rank sum test. Results: In singletons, PP13 declined with maternal weight and was lower in in vitro fertilization. Levels were converted into multiples of the median (MoMs) accordingly. In twins, the median was 1.74 MoM (n=76) vs. 1.00 in singletons (n=676, P<0.0001). Among twins with severe PE (n=10), the median was 1.53 MoM vs. 1.74 in unaffected twins (P=0.10), and 2.26 (n=6) for mild PE (P=0.30). Among singletons with severe PE, the median was 0.44 MoM (n=26, P<0.0001), and for mild PE 0.62 (n=17, P<0.001). Conclusion: PP13 is higher in twins than singletons, corresponding to the larger placental mass. Among singletons with severe PE, levels were significantly reduced, however, among twins, only a non-significant tendency for a reduction was recorded, and warrants further investigation in a larger series.
Journal of Perinatal Medicine 05/2013; · 1.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To determine the principal factors contributing to the cost of avoiding a birth with Down syndrome, using cell free (cf)DNA to replace conventional screening. METHODS: A range of unit costs were assigned to each item in the screening process. Detection rates were estimated by meta-analysis and modeling. The marginal cost associated with the detection of additional cases using cfDNA was estimated from the difference in average costs divided by the difference in detection. RESULTS: The main factor was the unit cost of cfDNA testing. For example, replacing a Combined test costing $150 with 3% false-positive rate and invasive testing at $1000, by cfDNA tests at $2000, $1500, $1000 and $500, the marginal cost is $8.0, $5.8, $3.6 and $1.4 million, respectively. Costs were lower when replacing a Quadruple test and higher for a 5% false-positive rate, but the relative importance of cfDNA unit cost was unchanged. A contingent policy whereby 10-20% women were selected for cfDNA testing by conventional screening was considerably more cost-efficient. Costs were sensitive to cfDNA uptake. CONCLUSION: Universal cfDNA screening for Down syndrome will only become affordable by public health purchasers if costs falls substantially. Until this happens, the contingent use of cfDNA is recommended. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: To determine the feasibility of digital PCR analysis for noninvasive prenatal diagnosis of trisomy 21.
Through power equations, we modeled the number of wells necessary to determine the feasibility of digital PCR as a practical method for trisomy 21 risk assessment.
The number of wells needed is a direct correlate of the ability to isolate free fetal DNA. If a 20% fetal DNA enhancement can be achieved, then 2,609 counts would be sufficient to achieve a 99% detection rate for a 1% false-positive rate and potentially feasible with readily available plates. However, if only a 2% increase is seen, then 220,816 counts will be necessary, and over 110,000 would be needed just to achieve 95% for a 5% false-positive rate - both far beyond current commercially available technology.
There are several noninvasive prenatal diagnostic methods which may reach commercialization; all have differing potential advantages and disadvantages. Digital PCR is potentially a cheaper methodology for trisomy 21, but it is too early to determine the optimal method.
Fetal Diagnosis and Therapy 04/2012; 31(4):244-7. · 1.90 Impact Factor