The Effects of Gestation Dating on the Calculation of Patient-Specific Risks in Down's Syndrome Screening: Multivariate Case

When screening for Down's syndrome using biochemical markers, the measurements are adjusted for the gestational age of the fetus because the concentrations of the markers are known to change with gestational age. This adjustment is performed by referring each marker measurement to the population median for that marker for the appropriate estimated gestational age group. The measurement of gestational age is subject to error, whichever method is used, and so the population median used is usually the median of a mixture of distributions for different true gestational ages. Most screening programmes aim for a specific number of weeks and this produces a concentrated distribution of true gestational ages. This fact, combined with dating errors, leads to an asymmetric mixture for each gestational age group and hence to bias in the estimates of the medians. In a previous communication we have shown how the proportions in this mixture distribution can be estimated and how the true medians corresponding to a true gestational age can be estimated. The calculations presented were performed using a single marker, and the details of our method were restricted to this situation. This paper extends the method to the multimarker situation and, as expected, leads to a gain in the detection rate for a specified false positive rate. The true patient-specific risk estimates are again markedly different from the quoted nominal value obtained by ignoring the dating errors. The data set on which the method is illustrated uses two markers, although the technique generalises in an obvious way to more than two.

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The Effects of Gestation Dating on the Calculation of Patient Specific Risks in Down's Syndrome Screening

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456329503200506 ◽

1995 ◽

Vol 32 (5) ◽

pp. 464-477 ◽

Cited By ~ 4

Author(s):

Janine Bishop ◽

Frank D J Dunstan ◽

Barry J Nix ◽

Timothy M Reynolds

Keyword(s):

Gestational Age ◽

Detection Rate ◽

Down's Syndrome ◽

Estimation Method ◽

Down’S Syndrome ◽

Maternal Serum ◽

Patient Specific ◽

Detection Rates ◽

Age Dependent ◽

Single Marker

In Down's syndrome screening using biochemical markers, the marker concentrations are adjusted for the gestational age of the fetus, since they are known to change with gestational age. This adjustment is performed by referring to the population median of each marker for the appropriate gestational age group. The measurement of gestational age is subject to error, whatever method is used, and the population median used is actually the median of a mixture of distributions for different true gestational ages. We show how the proportions in this mixture can be estimated and how the true median corresponding to a given true gestational age can be estimated. For simplicity, we consider the case of using a single marker, namely maternal serum α-fetoprotein, and show that the usual estimation method has considerable bias. The effect of this mixture on the calculation of patient-specific risks is discussed and we show that detection rates can be improved by allowing for this error in the dating process. The overall detection rate is increased by about 1%. The increase in detection rate is age-dependent and for some maternal ages the increase is of the order of 5%. The comparative effects of different methods for dating are discussed.

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Screening for Down's Syndrome: The First Two Years Experience in Bristol

Journal of Medical Screening ◽

10.1177/096914139500200407 ◽

1995 ◽

Vol 2 (4) ◽

pp. 207-210 ◽

Cited By ~ 8

Author(s):

D J Goldie ◽

J P Astley ◽

J M Beaman ◽

D A Bickley ◽

A Gunneberg ◽

...

Keyword(s):

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

District General Hospital ◽

Serum Marker ◽

Serum Markers ◽

Maternal Serum ◽

Age Related ◽

Related Risk ◽

Positive Rate

Objectives – To evaluate the effectiveness of a programme for antenatal screening for Down's syndrome using a fetoprotein and total human chorionic gonadotrophin as maternal serum markers. Setting –A district general hospital providing a screening service to a local purchasing authority and (under contract) to another purchasing authority in the same region. Methods – Patients were counselled and screened between 15 and 20 weeks gestation and Down's risk estimates calculated using the maternal serum marker results as modifiers of the age related risk. Outcome was determined in collaboration with the Regional Cytogenetics Unit. Outcome Measures – Detection rate for Down's syndrome, false positive rate, uptake of screening, and uptake of amniocentesis. Results– In two years 22 816 women were screened (approximately 84% of population); 32 Down's pregnancies were identified, 19 (59.4%) had a reported risk of ≥1:250 and 20 (62.5%) a reported risk of ≥1:300. Of those screened before 17 weeks, 16/20 (80%) had a reported risk of ≥1: 300 compared with 4/12 (33%) of those screened later (P = 0.008); 4.64% of patients screened had reported risks ≥1: 250 and 5.87% reported risks of ≥ 1:300. Amniocentesis uptake was 70% in patients with reported risks of ≥ 1:300. Conclusions –Overall the screening programme was effective but screening before 17 weeks was very much more effective than screening later.

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Adding ductus venosus blood flow as a categorical variable to the Combined and Integrated tests in Down's syndrome screening

Journal of Medical Screening ◽

10.1258/jms.2011.011084 ◽

2012 ◽

Vol 19 (1) ◽

pp. 49-50 ◽

Cited By ~ 4

Author(s):

Nicholas J Wald ◽

Jonathan P Bestwick ◽

Antoni Borrell

Keyword(s):

Blood Flow ◽

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

Screening Tests ◽

Ductus Venosus ◽

Published Data ◽

Antenatal Screening ◽

Categorical Variable ◽

Positive Rate

Ductus venosus blood flow, expressed as a pulsatility index (DVPI) has been shown to improve the performance of the Combined and Integrated antenatal screening tests for Down's syndrome using previously published data. The use of ductus venosus blood flow as a categorical marker (reversed or absent end diastolic blood flow indicating a positive result) is less discriminatory but simpler, so is sometimes preferred over DVPI. For example, with the Integrated test the false-positive rate for a 90% detection rate was 1.5% as a categorical marker compared with 1.1% expressed as DVPI. We here provide the necessary algorithm and parameters for using ductus venosus blood flow as a categorical marker with the Combined and Integrated tests.

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A prospective clinical trial to compare the performance of dried blood spots prenatal screening for Down’s syndrome with conventional non-invasive testing technology

Experimental Biology and Medicine ◽

10.1177/1535370216683837 ◽

2017 ◽

Vol 242 (5) ◽

pp. 547-553

Author(s):

Huiying Hu ◽

Yulin Jiang ◽

Minghui Zhang ◽

Shanying Liu ◽

Na Hao ◽

...

Keyword(s):

High Risk ◽

False Positive ◽

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

Dried Blood Spots ◽

High Risk Women ◽

Secondary Screening ◽

Serum Screening ◽

Positive Rate

To evaluate, side by side, the efficiency of dried blood spots (DBSs) against serum screening for Down’s syndrome, and then, to construct a two-tier strategy by topping up the fetal cell-free DNA (cfDNA) secondary screening over the high-risk women marked by the primary blood testing to build a practical screening tactic to identify fetal Down’s syndrome. One thousand eight hundred and thirty-seven low-risk Chinese women, with singleton pregnancy, were enrolled for the study. Alpha-fetoprotein and free beta human chorionic gonadotropin were measured for the serum as well as for the parallel DBS samples. Partial high-risk pregnant women identified by primary blood testing (n = 38) were also subject to the secondary cfDNA screening. Diagnostic amniocentesis was utilized to confirm the screening results. The true positive rate for Down’s syndrome detection was 100% for both blood screening methods; however, the false-positive rate was 3.0% for DBS and 4.0% for serum screening, respectively. DBS correlated well with serum screening on Down’s syndrome detection. Three out of 38 primary high-risk women displayed chromosomal abnormalities by cfDNA analysis, which were confirmed by amniocentesis. Either the true detection rate or the false-positive rate for Down’s syndrome between DBS and the serum test is comparable. In addition, blood primary screening aligned with secondary cfDNA analysis, a “before and after” two-tier screening strategy, can massively decrease the false-positive rate, which, then, dramatically reduces the demand for invasive diagnostic operation. Impact statement Children born with Down’s syndrome display a wide range of mental and physical disability. Currently, there is no effective treatment to ease the burden and anxiety of the Down’s syndrome family and the surrounding society. This study is to evaluate the efficiency of dried blood spots against serum screening for Down’s syndrome and to construct a two-tier strategy by topping up the fetal cell-free DNA (cfDNA) secondary screening over the high-risk women marked by the primary blood testing to build a practical screening tactic to identify fetal Down’s syndrome. Results demonstrate that fetal cfDNA can significantly reduce false-positive rate close to none while distinguishing all true positives. Thus, we recommend that fetal cfDNA analysis to be utilized as a secondary screening tool atop of the primary blood protein screening to further minimize the capacity of undesirable invasive diagnostic operations.

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Ductus Venosus Pulsatility Index as an Antenatal Screening Marker for Down'S Syndrome: Use with the Combined and Integrated Tests

Journal of Medical Screening ◽

10.1258/jms.2009.009043 ◽

2009 ◽

Vol 16 (3) ◽

pp. 112-118 ◽

Cited By ~ 13

Author(s):

A Borrell ◽

V Borobio ◽

J P Bestwick ◽

N J Wald

Keyword(s):

Cost Effectiveness ◽

False Positive ◽

Pulsatility Index ◽

Detection Rate ◽

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

Ductus Venosus ◽

Positive Rate ◽

Screening Marker

Objectives To assess the value of ductus venosus blood flow (expressed as pulsatility index, DVPI) in antenatal Down's syndrome screening when used with the Combined and Integrated tests. Methods DVPI measurements between 10 and 13 weeks’ gestation in 66 Down's syndrome and 7184 unaffected pregnancies were collected from women attending the Hospital Clinic, Barcelona, for antenatal care from 1999 to 2007 and combined with the Serum Urine and Ultrasound Screening Study (SURUSS) data to model screening performance, safety and cost-effectiveness of the screening tests with and without DVPI. Results The median DVPI multiple of the normal median in Down's syndrome pregnancies was 1.55 (95% CI 1.36–1.73). As a single screening marker without using maternal age, DVPI has a 62% detection rate for a 5% false-positive rate. At a 90% detection rate (first trimester measurements at 11 weeks’ gestation) the addition of DVPI reduced the false-positive rate of the Combined test from 8.5% to 4.6% and the Integrated test from 2.0% to 1.1%, with a corresponding reduction in fetal losses from diagnostic procedures. There was no material loss of cost-effectiveness. Conclusion Addition of DVPI measurements to the Combined and Integrated tests substantially improves the efficacy and safety of antenatal Down's syndrome screening.

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Combined First-Trimester Screening in Northern Finland: Experiences of the First Ten Years

Clinical Medicine Insights Reproductive Health ◽

10.4137/cmrh.s14958 ◽

2014 ◽

Vol 8 ◽

pp. CMRH.S14958

Author(s):

Merilainen Anna ◽

Peuhkurinen Sini ◽

Honkasalo Timppa ◽

Laitinen Paivi ◽

Kokkonen Hannaleena ◽

...

Keyword(s):

Detection Rate ◽

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

First Trimester ◽

First Trimester Screening ◽

Invasive Procedures ◽

Screening Performance ◽

Positive Rate ◽

Trimester Screening

Objective To evaluate the efficacy of first trimester combined screening for Down's syndrome in Northern Finland during the first 10 years of practice. Methods During 1 January 2002 to 31 December 2011, 47,896 women participated voluntarily in combined screening during first trimester. The risk cutoff was 1:250. The study period was divided into two time periods; 2002-2006 and 2007-2011. Results During the first half of the study period, the detection rate (DR) was 77.3% with a 4.9% false-positive rate (FPR). During the latter half, the DR was 77.1% with a 2.8% FPR. Conclusions An important issue is the number of invasive procedures needed to detect one case of Down's syndrome. The screening performance improved markedly in the latter five years period since the FPR lowered from 4.9% to 2.8% and the number of invasive procedures needed to detect one case of Down's syndrome lowered from 15 to 11.

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Antenatal reflex DNA screening for trisomy 18 and trisomy 13 in addition to Down’s syndrome

Journal of Medical Screening ◽

10.1177/0969141315617982 ◽

2016 ◽

Vol 23 (4) ◽

pp. 171-174 ◽

Cited By ~ 2

Author(s):

Jonathan P Bestwick ◽

Nicholas J Wald

Keyword(s):

Detection Rate ◽

Plasma Sample ◽

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

Trisomy 18 ◽

Trisomy 13 ◽

Dna Test ◽

Combined Test ◽

Positive Rate

Objective Antenatal reflex DNA screening for Down’s syndrome has a high screening performance. We aimed to determine the performance of trisomy 18 and trisomy 13 reflex DNA screening when added to Down’s syndrome screening. Methods In our modelled screening protocol, women provide two samples: a serum sample for a Combined test and a plasma sample for a possible DNA test. Women with Down’s syndrome, trisomy 18, or trisomy 13 Combined test risks above a single cut-off have a reflex DNA test using the plasma sample, without the need to recall them to collect another sample and provide counselling. Women with a failed DNA test (after a second attempt using a fresh plasma sample) have an Integrated test, and are classified as positive if any of the Down’s syndrome, trisomy 18, or trisomy 13 Integrated test risks are greater than 1 in 25. Results At 1 in 800 term risk cut-offs for Down’s syndrome, trisomy 18, and trisomy 13, an estimated 10% of women are reflexed to DNA screening, yielding a 91% Down’s syndrome detection rate, an 89% trisomy 18 detection rate, and a 79% trisomy 13 detection rate for a 0.05% false-positive rate. At a 1 in 1900 term risk cut-off for Down’s syndrome, trisomy 18, or trisomy 13, an estimated 20% of women are reflexed to DNA screening, and this yields a 94% Down’s syndrome detection rate, a 92% trisomy 18 detection rate, and an 84% trisomy 13 detection rate for a 0.10% false-positive rate. Conclusion Reflex DNA screening for trisomies 18 and 13 can be usefully added to reflex DNA screening for Down’s syndrome.

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Effect of screening algorithm, parameter values and median smoothing on patient-specific risk estimates for Down's syndrome screening

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1258/0004563001899168 ◽

2000 ◽

Vol 37 (2) ◽

pp. 165-173 ◽

Cited By ~ 6

Author(s):

Karen L Williams ◽

Barry A J Nix ◽

Frank D J Dunstan

Keyword(s):

False Positive ◽

False Positive Rate ◽

Down's Syndrome ◽

Down’S Syndrome ◽

Population Level ◽

Patient Specific ◽

External Quality Assessment Scheme ◽

Detection Rates ◽

Individual Patient Level ◽

Parameter Values

The efficiency of a screening programme for Down's syndrome is usually expressed in terms of the detection rate for a given false positive rate. Two programmes with approximately equal detection rates and false positive rates would then be regarded as being broadly equivalent. While this might be the case at a population level, we show in this paper that it may be far from true at the individual patient level. Different algorithms, or even different implementations of the same algorithm can lead to calculation of very different individual risks and can result in different decisions for individual patients. Even though two programmes might lead to the same number of referrals, they could be referring quite different women. We consider the effect of using different parameter values within an algorithm, different algorithms and alternative ways of estimating the gestational age-dependent medians of the marker values. We show that the combined effects of these factors could explain much of the range of risks reported in the UK National External Quality Assessment Scheme for Down's syndrome screening.

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