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Objective To illustrate regional changes that occurred in screening for Down's syndrome (trisomy 21) in England and Wales from 1989 to 2008. Methods The National Down Syndrome Cytogenetic Register has collected data on all ante- and postnatal diagnoses of Down's syndrome in England and Wales since 1989 (n = 27,954). The percentages of (i) diagnoses made antenatally, (ii) antenatal diagnoses that had nuchal translucency (NT) measured, and (iii) antenatal diagnoses in mothers aged 37 and over with advanced maternal age as the sole recorded indication for diagnosis are presented according to where the mother lived Government Office Region), year of diagnosis (1989-1994, 1995-2000, 2001-2006, 2007-2008), and maternal age (<37 years, ≥37 years). Results The percentage of cases diagnosed antenatally has increased in younger women but varies between regions. It remained relatively constant at approximately 70% in older women. The use of NT measurement in antenatal screening has expanded rapidly but varies regionally, being most common in London and the South East where, in 2007-2008, over 75% of antenatal diagnoses in older women had NT measured. The sole indication of advanced maternal age has substantially reduced, and was less than 10% in older mothers in all regions in 2007-2008. Conclusions There are regional and maternal age variations in Down's syndrome screening and diagnosis. Some regions used NT measurements, and eliminated advanced maternal age as sole reason for antenatal diagnostic testing more quickly than others. The reasons for variations need to be identified and addressed to ensure that when new screening techniques become available, regional differences are minimized. [ABSTRACT FROM AUTHOR]

Objectives Antenatal screening for Down's syndrome relies on the use of multiple markers in combination. Markers that are highly correlated can cause statistical instability. We used the maximum variance inflation factor (VIFmax) to determine whether a screening test using multiple markers was robust to imprecision in the estimation of the marker distribution parameters. Methods The VIFmax for a specified screening test was calculated from the correlations between markers in Down's syndrome pregnancies for six tests: integrated and serum integrated tests without repeat measurements, both tests with repeat measurements across trimesters analysed in the standard way, and both tests with repeat measurements analysed as cross-trimester (CT) marker ratios. The screening performance of each test using published parameter values, in terms of the false-negative rates for a 3% false-positive rate (FN3), were calculated for simulated populations with medians 0.2 standard deviations (SD) higher or lower than the published values (to reflect imprecision in parameter estimation) for pregnancy-associated plasma protein A and unconjugated oestriol in affected pregnancies. For each test, the VIFmax value was compared with the coefficient of variation of the FN3 (FN3 CV). An independent set of 27 Down's syndrome pregnancies was used to determine how many had meaningless low risks (,1 in 10,000) with each test. Results Tests with VIFmax values greater than 5 had FN3CV values over 50%, but those with VIFmax values less than 5 had FN3 CV values less than 21%. The numbers of Down's syndrome pregnancies with meaningless low risk estimates in the independent set were 18 (64%) in tests with VIFmax values ≥5 and none for those with values >5. Conclusion VIFmax values of 5 or more suggest instability. The tests using CT marker ratios were stable (VIFmax < 3), but the tests using repeat measurements in the standard manner were not (VIFmax > 5). [ABSTRACT FROM AUTHOR]

Objectives: It is widely thought that correlations between screening markers will tend to degrade screening performance. We performed a computer simulation study to investigate the quantitative effect of correlations between two markers on screening performance, using prenatal screening for Down's syndrome as an example, although the results apply generally. Methods: Monte Carlo simulation was used to generate values of two hypothetical markers, A and B, in 1000 affected and 1000 unaffected pregnancies. The means, standard deviations and correlations of A and B were varied in five different examples. Results: If markers A and B are, on average, higher in affected than unaffected pregnancies and each marker, individually, has the same detection rate for a given false-positive rate (i.e. the same screening performance), then the screening performance of A and B together tends to decrease as A and B become more positively correlated with each other (within affected or unaffected categories) and tends to increase as A and B become more negatively correlated. If A is, on average, higher in affected pregnancies and B is, on average, lower in affected pregnancies (but again each marker has the same screening performance), the opposite pattern is observed; screening performance increases as A and B become more positively correlated and screening performance decreases as they become more negatively correlated. If A and B have unequal screening performances, modest correlations between A and B have little effect on the screening performance of A and B together, but when the correlations are strong whether positive or negative (with r values greater than about 0.45 or less than -0.45) screening performance progressively increases. Conclusion: Correlations between screening markers considered separately in affected and unaffected pregnancies can either decrease or increase screening performance. In practice, these effects are usually modest, because most screening markers are not highly correlated with each other and the effects become important only with strong correlations, whether positive or negative. [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence of pregnancies with a neural tube defect (NTD) in England and Wales between 1964 and 2004 and to estimate the relative impact of antenatal screening and a change in the incidence of these defects on the prevalence of births with NTDs. Settings: Use of data published by the Office for National Statistics (ONS) on terminations of pregnancies with an NTD and births with an NTD from 1964 to 2004. Methods: Estimates were made of the total number of terminations of pregnancies and births with an NTD by taking account of the under-reporting of these terminations and births using a previously described method. In 1995 ONS started to report the number of terminations with an NTD rather than the total numbers of terminations with a central nervous system (CNS) malformation that had previously been used to estimate the number of NTD terminations. Adjustment was made for this and new estimates of the total number of NTD pregnancies were produced to 2004. Results: There were an estimated 969 pregnancies with NTDs (168 (17%) births and 801(83%) terminations) in England and Wales in 2004. An estimated 44% of NTD terminations and 32% of births were not reported as such. The birth prevalence per 1000 decreased fallen 93% from 3.6 in 1964 to 0.3 in 2004, 59% due to an underlying decrease in the prevalence of NTDs and 34% due to screening diagnosis and subsequent termination of affected pregnancies. Conclusion: The prevalence of NTD pregnancies decreased by around two per 1000 from 1964 to 1990 and thereafter remained fairly constant. The prevalence of NTD pregnancies is substantially underestimated if it is based only on reported NTD births (by 88%) and also if it is based on reported NTD births and terminations (by 52%), because most NTD pregnancies in England and Wales are terminated following antenatal screening and most of these terminations are not reported. [ABSTRACT FROM AUTHOR]

Objective: To validate empirically the accuracy of antenatal Down's syndrome screening using the Integrated test, to compare this with other screening tests (including the Integrated test with the addition of cross trimester [CT] marker ratios) and to suggest how such validation analyses should be presented and interpreted. Methods: Using data from 7809 unaffected and 27 Down's syndrome pregnancies that had had an Integrated test, risk estimates for various screening tests (maternal age, Double, Triple, Quadruple, Combined, Integrated and serum Integrated tests) that use Integrated test markers were categorized according to quintile categories of risk estimates of the 27 affected pregnancies. For each screening test, the median risk estimate for each category was plotted against the observed prevalence within each category. Such validation plots were also produced for the Integrated test with CT marker ratios by measuring the level of the serum markers in the trimester of pregnancy not already measured in stored samples of all affected and a one-in-five sample of unaffected pregnancies. The robustness of the method was assessed by repeating the analysis for the Integrated test after re-classifying affected pregnancies with low risk estimates as unaffected, simulating the underascertainment of cases. Results: The validation plots (i) confirmed the accuracy of risk estimation for the different tests (by how close the points lay to the line of identity between predicted risk and observed prevalence), (ii) demonstrated the differences in screening performance of the different tests (by the range of risk spanned by the points and, in particular, the separation between the points representing the lowest risk and the next point), and (iii) are robust to underascertainment of affected pregnancies (by having little influence on the closeness of the points to the line of identity). Conclusion: The validation plot is a useful, simple and robust way to assess the validity of new screening methods, to assess the accuracy of risk estimation and to audit the performance of screening programmes. [ABSTRACT FROM AUTHOR]

Objective: The screening performance of tests involving multiple markers is usually presented visually as two Gaussian relative frequency distributions of risk, one curve relating to affected and the other to unaffected individuals. If the distribution of the underlying screening markers is approximately Gaussian, risk estimates based on the same markers will usually also be approximately Gaussian. However, this approximation sometimes fails. Here we examine the circumstances when this occurs. Setting: A theoretical statistical analysis. Methods: Hypothetical log Gaussian relative distributions of affected and unaffected individuals were generated for three antenatal screening markers for Down's syndrome. Log likelihood ratios were calculated for each marker value and plots of the relative frequency distributions were compared with plots of Gaussian distributions based on the means and standard deviations of these log likelihood ratios. Results: When the standard deviations of the distributions of a perfectly Gaussian screening marker are similar in affected and unaffected individuals, the distributions of risk estimates are also approximately Gaussian. If the standard deviations differ materially, incorrectly assuming that the distributions of the risk estimates are Gaussian creates a graphical anomaly in which the distributions of risk in affected and unaffected individuals plotted on a continuous risk scale intersect in two places. This is theoretically impossible. Plotting the risk distributions empirically reveals that all individuals have an estimated risk above a specified value. For individuals with more extreme marker values, the risk estimates reverse and increase instead of continuing to decrease. Conclusion: It is useful to check whether a Gaussian approximation for the distribution of risk estimates based on a screening marker is valid. If the value of the marker level at which risk reversal occurs lies within the set truncation limits, these may need to be reset, and a Gaussian model may be inappropriate to illustrate the risk distributions. [ABSTRACT FROM AUTHOR]

This paper summarises the main evidence and conclusions relating to using blood pressure measurement as a screening test to identify people who will develop ischaemic heart disease (IHD) or stroke, as recently published in a Health Technology Assessment report1. While blood pressure is recognised as an important cause of stroke and IHD, and lowering blood pressure can substantially lower the risk of these diseases, the measurement of blood pressure is a poor screening test. It is not good in distinguishing those who will and will not develop these diseases. The poor screening performance is illustrated by the findings that in the largest cohort study, persons in the top 10% of the distribution of systolic blood pressure experienced only 21% of all IHD events and 28% of all strokes at a given age. Using several cardiovascular risk factors in combination does not add materially to the poor screening performance of blood pressure alone. Among persons in a specified age group, the 5% at highest risk experience 17% of all heart disease deaths with risk computation based on blood pressure alone, 22% when based on blood pressure and apolipoprotein B (or LDL cholesterol) in combination, and only 28% using these two, smoking and three other cardiovascular risk factors all in combination. Identifying patients at the time of hospital discharge following myocardial infarction or stroke is the most effective screening test to identify those who will die of cardiovascular disease. In patients with a history of myocardial infarction or stroke the cardiovascular death rate in the absence of treatment is about 5% per year, a risk that persists for at least 15 years. In the absence of treatment, about half of all deaths from heart disease in a population occur after hospital discharge following the first infarct. Among persons with no history of cardiovascular disease, age is a better screening test than the reversible risk factors, and the best policy is to offer treatment to all persons above a specified age such as 55 years. [ABSTRACT FROM AUTHOR]

Objectives: To revise the estimates of maternal age specific live birth prevalence of Down's syndrome in the absence of antenatal screening and selective termination using newly available data. Setting and Design: Data were used from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all antenatally or postnatally diagnosed cases of Down's syndrome in which a karyotype was confirmed between 1989 and 1998 in England and Wales. It is the largest single series of data on the prevalence of Down's syndrome. Results and conclusion: The prevalence does not continue increasing at an increasing rate with age above age 45 as has been previously assumed. Above this age the rate of increase declines with increasing age. The overall age pattern is sigmoidal. A new logit logistic model is proposed which fits the data well. The risk of a Down's syndrome live birth is given by: risk=1/(1+exp(7.330-4.211/(1+exp(-0.282x(age-37.23))))). [ABSTRACT FROM AUTHOR]

Objective To investigate whether an appropriate combination of maternal serum inhibin A, free β-human chorionic gonadotropin (free β-hCG), unconjugated estriol (uE 3), and alpha-fetoprotein (AFP) may be an effective means of screening for pre-eclampsia in the second trimester of pregnancy. Setting Women who attended an antenatal clinic in Oxford, from whom serum samples were stored, 19 of whom subsequently developed pre-eclampsia. Methods Serum inhibin A, free β-hCG, uE 3, and AFP were measured in 32 serum samples collected from the 19 women who developed pre-eclampsia and, for each sample, in three control samples collected from women with unaffected pregnancies matched for gestational age and maternal age. Results In pregnancies that developed pre-eclampsia the median inhibin A value was raised (1.7 multiples of the median (MoM) for unaffected pregnancies (95% confidence interval (95% CI) 1.1 to 2.7 MoM), the median free β-hCG was raised (2.1, 1.4 to 3.3 MoM) and the median uE 3 was lowered (0.8, 0.6 to 0.98 MoM) after 19 completed weeks of gestation and at least 2 weeks before the onset of proteinuria. Values of AFP were similar in affected and unaffected pregnancies. Combining the values of inhibin A, free β-hCG, and uE 3 to form a screening test would detect an estimated 55% of affected pregnancies with a false positive rate of 5%. Conclusions Inhibin A, free β-hCG, and uE 3 in combination may be a useful screening test during the second trimester for pre-eclampsia. [ABSTRACT FROM AUTHOR]

In England and Wales there has been a large decline in the birth prevalence of neural tube defects (NTDs) from the early 1970s (reported rates of about 3.2 per 1000 births) to the present (0.1 per 1000 births in 1997). The reported number of terminations of NTD pregnancies increased from 0.02 per 1000 in 1970 to 0.66 per 1000 in 1997, much too small an increase to explain the decline in NTD births. Some underreporting of NTD terminations is recognised. We estimated its extent using 1976–80 data on reported central nervous system (CNS) defect terminations and NTD births in an analysis in which the true total number of NTD pregnancies during this short period was assumed to have either remained constant or else to have been changing by a constant amount per year. The estimate was that 56% of NTD terminations were not reported as such and this fitted the data well. In 1997 the estimated birth prevalence of NTDs was 0.14 per 1000 births, a fall of 96% since 1970. This 96% was apportioned as 40% due to antenatal screening and termination of pregnancy and 56% due to a decline in incidence. Over the period 1970–97 there was an increase in dietary folate, and this will have at least in part caused the decline in incidence of NTDs. [ABSTRACT FROM AUTHOR]

Objective To derive a rational method of selecting the age range over which screening tests for cancer should be offered (that is, over which they would be most effective in saving life). Main outcome measureThe number of person-years of life that are lost through deaths occurring at each year of age from each of six cancers. Results For each cancer the number of years of life lost to age 80, plotted against age at death, showed a rise followed by a fall. The peak indicates the age at which deaths from the cancer result in most years of life lost. Special screening tests, such as mammography for breast cancer, will be most effective in saving life shortly before that age. The peak (as a five year age span) occurs at age 55–59 for breast cancer (189 years of life lost per 10 000 women per year), 70–74 for prostate cancer (114), 65–69 for colorectal cancer (96), 55–59 for ovarian cancer (61), 50–54 for cervical cancer (47), and 45–50 for melanoma (8). The precise interval by which special screening tests should precede the peak age is not critical; five years would be appropriate. Given current evidence on the efficacy of cancer screening, if it were stipulated that screening could only be performed when at least 50 years of life were to be gained per 10 000 persons screened, only mammography for breast cancer would be conducted, between the ages of 50 and 59. If the stipulation was 25 or more years of life gained mammography would be offered to women aged 40–69 and cervical smears to women aged 35–59. With only 10 or more years of life gained (unlikely to be worthwhile) mammography would be extended to women aged 30–74, cervical smears to 25–69, and faecal occult blood testing for colorectal cancer offered to those aged 45–74. Extending cervical cancer screening to age 69 would save more years of life than the present policy of screening women aged 20–29. Extending breast cancer screening to the age of 74 would be more effective than cervical screening at any age. Conclusions Determining the number of years of life lost through deaths from a particular cancer at each age is useful in public health screening policy, both in selecting the age range over which special screening tests of proven efficacy should be offered and in quantitatively comparing the value of screening for different cancers. [ABSTRACT FROM AUTHOR]

Two equations are given to estimate the risk of a woman having a Down's syndrome pregnancy according to maternal age: one for use in estimating antenatal screening performance and the other for use in estimating an individual woman's risk of having an affected pregnancy. Because Down's syndrome pregnancies have an increased tendency to result in a spontaneous fetal loss, the estimation of a woman's risk of having an affected pregnancy will be dependent on gestational age. The best estimates of the prevalence of Down's syndrome are obtained from information relating to births and can reliably be adjusted to prevalence in early second trimester. The most reliable estimates of risk of a Down's syndrome pregnancy using all the currently used markers apply to early in the second trimester. These risks cannot accurately be adjusted to apply to term, because the first trimester markers have not in general been studied in pregnancies that continue to term. Therefore the early second trimester of pregnancy is the gestational age at which all screening performances should be given for the different antenatal screening programmes for Down's syndrome. [ABSTRACT FROM AUTHOR]

Objectives: The proportion of Down's syndrome pregnancies detected prenatally in England and Wales is lower in younger mothers than in older mothers. This paper examines the reasons for this apparent age inequality. Methods: We used data from the National Down Syndrome Cytogenetic Register (NDSCR) to examine the time trend of the proportion of Down's syndrome pregnancies diagnosed prenatally according to maternal age over the years 1989–2004 in England and Wales. Results: A lower proportion of younger mothers had their Down's syndrome pregnancy detected prenatally than older mothers; however, this gap has been closing over time. For example, for mothers under 25 years of age only 13% of Down's syndrome pregnancies were detected prenatally from 1989 to 1992, with this figure rising to 34% in 2001–2004, compared with proportions of 74% in both periods for mothers over 44 years of age. A lower uptake of screening among younger women could not explain these differences. The differences in detection rates of the screening methods according to maternal age, particularly of the older screening tests, could account for these differences. Conclusions: The closing gap between the proportions of younger and older women having their affected pregnancy prenatally diagnosed is a confirmation of the improvement of screening methods over time. [ABSTRACT FROM AUTHOR]

The article discusses the strategy of mass screening for neuroblastoma in children. Because of the ease of the screening test through catecholamine metabolite measurement and also due to the fact that early presenters of neuroblastoma have a better prognosis, there seemed to be logic to performing mass screening in children. The author concludes, however, based on studies in Quebec, Canada and in Germany, that screening is not only without value, but may even cause damage.