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Nicholas J Wald

Publications and source records attributed to Nicholas J Wald.

At least 19 recordsLinked to original sources
PubMed2006

Cross-trimester marker ratios in prenatal screening for Down syndrome.

OBJECTIVE: To examine the performance of Integrated Down syndrome screening (first- and second-trimester measurements integrated into a single screening test) when ratios of the levels of the same serum markers measured in both these trimesters (cross-trimester ratios) are added as new screening markers. METHODS: Using data from Serum Urine and Ultrasound Screening Study (SURUSS), second-trimester concentrations (in multiples of the median, or MoM) of pregnancy associated plasma protein A (PAPP-A), alphafetoprotein (AFP), unconjugated oestriol (uE(3)), human chorionic gonadotrophin (hCG) (free beta and total), and inhibin-A were divided by the first-trimester concentration to obtain a cross-trimester (CT) ratio for each analyte in 74 Down syndrome and 492 unaffected pregnancies. We identified CT ratios that improved screening performance and then, using Monte Carlo simulations, estimated the efficacy and cost effectiveness of adding them to the Integrated and serum Integrated tests. RESULTS: All the median CT ratios differed significantly between Down syndrome and unaffected pregnancies. Setting the Integrated test to achieve a 90% detection rate, the false-positive rate (FPR) was 0.7% with CT ratios for PAPP-A, uE(3), inhibin-A, and total hCG compared with 2.2% without CT ratios, a reduction of about two-thirds. Using the serum Integrated test to achieve the same 90% detection rate and the first-trimester measurements made at 11 completed weeks of pregnancy, the corresponding FPRs were 2.4 and 8.1%, a similar proportional reduction. The AFP CT ratio had little effect on screening performance. Using CT ratios did not increase the cost per Down syndrome pregnancy detected. CONCLUSION: The addition of CT ratios to an Integrated test substantially improves the efficacy and safety of prenatal screening for Down syndrome. It is cost effective and could be usefully introduced into screening programmes.

Biomarkers↗
PubMed2006

Effect on Down syndrome screening performance of adjusting for marker levels in a previous pregnancy.

OBJECTIVES: In prenatal screening for Down syndrome, serum marker values can be adjusted using values from a previous pregnancy to avoid the problem of women having a high chance of recurrent false-positive results. We investigate the effect of such adjustment on overall screening performance. METHODS: Monte Carlo simulation was used to investigate the effect of this adjustment on five widely used screening tests for Down syndrome (Triple, Quadruple, Combined, serum Integrated, Integrated tests). RESULTS: Adjustment for screening marker values (expressed in multiples of the median, (MoM)) in a previous pregnancy improved screening performance. The detection rate for a 1% false-positive rate (FPR) increased from 54 to 59% with the Triple test, from 63 to 68% with the Quadruple test, from 70 [corrected] to 75% for the Combined test, from 70 [corrected] to 76% for the serum Integrated test, and from 85 to 88% for the Integrated test. The FPR for an 85% detection rate decreased from 10 to 7.9%, 7.1 to 4.9%, 4.9 to 3.7%, 4.7 to 2.9% and 1.1 to 0.7% respectively for the five tests. Among women who have had a false-positive result in a previous pregnancy, adjustment substantially lowers the false-positive rate, for example, from 18 [corrected] to 7.3% with the Combined test using a 1 in 250 risk cut-off. CONCLUSION: MoM adjustment for values in a previous pregnancy improves overall screening performance and substantially reduces the high recurrent false-positive rate. This adjustment can be routinely applied in screening programmes through the screening software used to interpret a woman's screening results.

Adolescent↗
PubMed2006

Screening in early pregnancy for pre-eclampsia using Down syndrome quadruple test markers.

OBJECTIVES: To estimate the screening performance of early second-trimester prenatal serum markers for Down syndrome, in screening for the development of pre-eclampsia, and analyse the uncertainty over its screening performance. METHODS: A nested case-control study was carried out on 96 women with pre-eclampsia and 5 controls for each case from among the women attending three hospitals in London for their prenatal care. Record linkage between computerized obstetric and screening databases identified women with pre-eclampsia and unaffected control women. The stored frozen serum samples collected from these pregnancies between 15 and 22 weeks' gestation were retrieved and assayed for alpha-fetoprotein (AFP), unconjugated estriol (uE(3)), total human chorionic gonadotrophin (hCG), free beta-hCG and inhibin-A. RESULTS: Pre-eclampsia was identified from the computerized obstetric records and confirmed by examination of the medical notes. In the pregnancies that went on to develop pre-eclampsia, early second trimester inhibin-A and hCG values were significantly raised and uE(3) values were significantly lowered, while AFP values were not significantly altered. Using the Quadruple test markers (AFP, uE(3), hCG (total or free beta) and inhibin-A), an estimated 34% of pregnancies that developed pre-eclampsia were detected at a 5% false-positive rate. If all the women who had pre-eclampsia in a previous pregnancy (assuming a pre-eclampsia prevalence of 4%) are considered as screen positive and the serum test is applied to the remaining women, then around 42% of pre-eclamptic pregnancies would be detected at a 6.5% false-positive rate. Pre-eclampsia screening performance using the Quadruple test markers was materially better than that using the Triple test markers. CONCLUSION: Adding screening for pre-eclampsia to an existing Down syndrome screening programme using the Quadruple test markers is simple and worthwhile. It will detect over 40% of pregnancies with pre-eclampsia at an acceptable false-positive rate (about 6%) and with minimal additional costs.

Biomarkers↗
PubMed2006

Sequential and contingent prenatal screening for Down syndrome.

OBJECTIVE: To compare the Integrated test in three policies for prenatal Down syndrome screening: Integrated screening for all women, sequential screening (first-trimester tests allowing early completion of screening for high-risk pregnancies), and Contingent screening (early completion of screening for high- and low-risk pregnancies). DESIGN AND METHODS: Estimation of detection rates (DRs) and false-positive rates (FPRs) using Monte Carlo simulation and cost effectiveness for each method. SETTING AND POPULATION: Down syndrome affected and unaffected pregnancies studied in the Serum Urine and Ultrasound Screening Study (SURUSS). RESULTS AND MAIN OUTCOMES: Integrated screening has the best screening performance. The performance of the other two policies approached that of Integrated screening as the first-trimester test FPR decreased. If the first-trimester FPR is set to 0.5% (risk >or= 1 in 30) with an overall DR of 90%, sequential and contingent screening yield overall FPRs of 2.25% and 2.42%, respectively, and 66% of the affected pregnancies are detected by the first-trimester test. The Integrated test on all women yields an FPR of 2.15%. With sequential screening, 99.5% of women would proceed to an Integrated test, or 30% with contingent screening if those with first-trimester test risks of <or=1 in 2000 are classified screen-negative and receive no further testing. About 20% of affected pregnancies identified in the first trimester using sequential or contingent screening would have unnecessary terminations (they would miscarry before the early second trimester). Contingent screening is the most cost-effective if there is no alphafetoprotein screening for neural tube defects, otherwise Integrated screening is more cost-effective. CONCLUSIONS: Integrated screening for all women is the simplest, most effective, and the safest policy. Contingent screening is the most complex with the lowest screening performance. Making an earlier diagnosis with sequential and contingent screening has adverse consequences that are sufficient to discourage their use.

Cost-Benefit Analysis↗
PubMed2005

First-trimester or second-trimester screening, or both, for Down's syndrome.

BACKGROUND: It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters. METHODS: Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency). RESULTS: First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening. CONCLUSIONS: First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates.

Adult↗
PubMed2005

Prenatal screening for Down syndrome and neural tube defects in twin pregnancies.

Prenatal screening and diagnosis in a twin pregnancy is not straightforward. Once a twin pregnancy has been identified, women and their partners need time to consider the implications and decide whether they wish the pregnancy to be screened for Down syndrome or neural tube defects. We discuss here how multiple marker screening for Down syndrome and alpha-fetoprotein screening for neural tube defects can be carried out, given that this is the parents' chosen option and that the health professionals involved are capable of performing a diagnosis and selective feticide, should this arise.

Chorionic Gonadotropin, beta Subunit, Human↗
PubMed2005

The efficacy of combining several risk factors as a screening test.

OBJECTIVE: To determine the quantitative effect on overall screening performance (detection rate for a given false-positive rate) of using several moderately strong, independent risk factors in combination as screening markers. SETTING: Theoretical statistical analysis. METHODS: For the purposes of this analysis, it was assumed that all risk factors were independent, had Gaussian distributions with the same standard deviation in affected and unaffected individuals and had the same screening performance. We determined the overall screening performance associated with using an increasing number of risk factors together, with each risk factor having a detection rate of 10%, 15% or 20% for a 5% false-positive rate. The overall screening performance was estimated as the detection rate for a 5% false-positive rate. RESULTS: Combining the risk factors increased the screening performance, but the gain in detection at a constant false-positive rate was relatively modest and diminished with the addition of each risk factor. Combining three risk factors, each with a 15% detection rate for a 5% false-positive rate, yields a 28% detection rate. Combining five risk factors increases the detection rate to 39%. If the individual risk factors have a detection rate of 10% for a 5% false-positive rate, it would require combining about 15 such risk factors to achieve a comparable overall detection rate (41%). CONCLUSION: It is intuitively thought that combining moderately strong risk factors can substantially improve screening performance. For example, most cardiovascular risk factors that may be used in screening for ischaemic heart disease events, such as serum cholesterol and blood pressure, have a relatively modest screening performance (about 15% detection rate for a 5% false-positive rate). It would require the combination of about 15 or 20 such risk factors to achieve detection rates of about 80% for a 5% false-positive rate. This is impractical, given the risk factors so far discovered, because there are too few risk factors and their associations with disease are too weak.

Biomarkers↗
PubMed2004

Prenatal screening for Down syndrome: the problem of recurrent false-positives.

OBJECTIVES: It has been reported that, in prenatal screening programmes for Down syndrome, women who have false-positive results in one pregnancy have an increased risk of a false-positive result in a subsequent pregnancy. We examined the effect of this in the screening programme conducted from the Wolfson Institute of Preventive Medicine with a view to determining the magnitude of the effect, and to describe a method of avoiding the problem. METHODS: Six thousand four hundred and forty-eight women were identified who had had two singleton pregnancies without Down syndrome in the screening programme based at the Wolfson Institute of Preventive Medicine, in which both pregnancies were screened using a Quadruple test (maternal age with alphafetoprotein (AFP), unconjugated oestriol (uE(3)), total or free beta-human chorionic gonadotrophin (hCG) and either free alpha-hCG or inhibin-A as the fourth serum marker). RESULTS: Among women who had a false-positive result in their initial pregnancy, the false-positive rate in the subsequent pregnancy was high: 20% (46/229), about three times higher than both the overall observed false-positive rate (6.6%), and the expected false-positive rate, in subsequent pregnancies that were false-positive in their initial pregnancy (7.5%) (p < 0.001). This arises because serum marker levels in one pregnancy are associated with the levels in a subsequent pregnancy. Using the slope (the regression coefficient b) of each marker level in a subsequent pregnancy regressed on the value in the first pregnancy, it is possible to adjust all marker values in a subsequent pregnancy to allow for the higher-than-expected false-positive rate. This can be done by dividing the observed MoM value for each marker by the 'expected' MoM, which is the MoM value in a previous pregnancy raised to the power b. CONCLUSIONS: If a woman has had a false-positive result in one pregnancy, she is much more likely to have a false-positive screening result in a subsequent pregnancy than women in general. The problem can be avoided by adjusting the serum markers in all women who have been screened in a previous pregnancy and who have not had a previous pregnancy with Down syndrome.

Down Syndrome↗
PubMed2004

Second-trimester prenatal screening markers for Down syndrome in women with insulin-dependent diabetes mellitus.

Published studies have shown that some serum markers used in screening for Down syndrome tend to be lower among women with insulin-dependent diabetes mellitus (IDDM). On this basis, many screening programmes adjust the marker levels to take account of this difference. Recent studies suggested that the marker levels were not different, and so adjustment may no longer be needed, possibly because of better diabetic control. Data from a prenatal screening programme for Down syndrome were examined to see whether the median values of second-trimester screening markers were still reduced in pregnant women with IDDM. A total of 366 women with IDDM singleton pregnancies without Down syndrome were identified from the screening programme at Barts from 1989 to 2002. After allowing for maternal weight, the median multiples of the median (MoM) for IDDM-unaffected singleton pregnancies were as follows: 0.88 (95% confidence interval 0.84-0.93) for alphafetoprotein (AFP), 0.95 (0.91-0.99) for unconjugated oestriol (uE3), 0.90 (0.80-1.01) for total human chorionic gonadotrophin (total hCG), 0.98 (0.88-1.08) for free beta-hCG, and 0.99 (0.89-1.10) for inhibin-A. The median levels for AFP and uE3 were statistically significantly lower in pregnant women with IDDM. The other markers were not significantly different in women with and without IDDM. There remains a case for adjusting AFP and uE3 levels in women with IDDM in prenatal screening programmes for Down syndrome.

Biomarkers↗