Mortality from aortic stenosis: prospective study of serum calcium and phosphate.

PURPOSE: To investigate the associations between levels of serum calcium and phosphate and subsequent death from aortic stenosis, and the implications for prevention. METHODS: A prospective (nested case-control) analysis of serum calcium and phosphate levels was performed in stored samples from the British United Provident Association prospective study of 21 520 men aged 35-64, followed for up to 32 years. There were 49 men without baseline valvular heart disease who subsequently died of aortic stenosis. Each was matched, for age, duration of sample storage and number of freeze-thaw cycles, with four unaffected control subjects. Odds ratios for death from aortic stenosis were estimated by logistic regression. RESULTS: Mean serum calcium concentration was higher in men who died of aortic stenosis than in those who did not (2.44 vs. 2.39 mmol L-1 ; P = 0.01). The risk of death from aortic stenosis in the highest calcium tertile was 2.87-fold higher than in the lowest tertile (95% confidence interval 1.22-6.76). There was a continuous dose-response relationship; risk of death from aortic stenosis increased by 51% (11-105%) per 0.1 mmol L-1 increase in serum calcium, equivalent to a 34% (10-52%) lower risk per 0.1 mmol L-1 decrease. Serum phosphate was not significantly higher in men who died of aortic stenosis than in those who did not (1.0 vs. 0.99 mmol L-1 ; P = 0.76). CONCLUSIONS: The association between serum calcium and subsequent mortality from aortic stenosis is of potential preventive significance. If confirmed quantitatively in other similar cohort studies, the results suggest that a very small reduction in serum calcium (about 5%) could translate into a large (about one-third) reduction in aortic stenosis.

Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening.

OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening.

Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

Prevalence of Down's Syndrome in England, 1998-2013: Comparison of linked surveillance data and electronic health records.

INTRODUCTION: Disease registers and electronic health records are valuable resources for disease surveillance and research but can be limited by variation in data quality over time. Quality may be limited in terms of the accuracy of clinical information, of the internal linkage that supports person-based analysis of most administrative datasets, or by errors in linkage between multiple datasets. OBJECTIVES: By linking the National Down Syndrome Cytogenetic Register (NDSCR) to Hospital Episode Statistics for England (HES), we aimed to assess the quality of each and establish a consistent approach for analysis of trends in prevalence of Down's syndrome among live births in England. METHODS: Probabilistic record linkage of NDSCR to HES for the period 1998-2013 was supported by linkage of babies to mothers within HES. Comparison of prevalence estimates in England were made using NDSCR only, HES data only, and linked data. Capture-recapture analysis and quantitative bias analysis were used to account for potential errors, including false positive diagnostic codes, unrecorded diagnoses, and linkage error. RESULTS: Analyses of single-source data indicated increasing live birth prevalence of Down's Syndrome, particularly in the analysis of HES. Linked data indicated a contrastingly stable prevalence of 12.3 (plausible range: 11.6-12.7) cases per 10 000 live births. CONCLUSION: Case ascertainment in NDSCR improved slightly over time, creating a picture of slowly increasing prevalence. The emerging epidemic suggested by HES primarily reflects improving linkage within HES (assignment of unique patient identifiers to hospital episodes). Administrative data are valuable but trends should be interpreted with caution, and with assessment of data quality over time. Data linkage with quantitative bias analysis can provide more robust estimation and, in this case, stronger evidence that prevalence is not increasing. Routine linkage of administrative and register data can enhance the value of each.

Maternal age-specific risk of non-chromosomal anomalies.

OBJECTIVES: To determine the excess risk of non-chromosomal congenital anomaly (NCA) among teenage mothers and older mothers. DESIGN AND SETTING: Population-based prevalence study using data from EUROCAT congenital anomaly registers in 23 regions of Europe in 15 countries, covering a total of 1.75 million births from 2000 to 2004. PARTICIPANTS: A total of 38,958 cases of NCA that were live births, fetal deaths with gestational age > or = 20 weeks or terminations of pregnancy following prenatal diagnosis of a congenital anomaly. MAIN OUTCOME MEASURES: Prevalence of NCA according to maternal age, and relative risk (RR) of NCA and 84 standard NCA subgroups compared with mothers aged 25-29. RESULTS: The crude prevalence of all NCA was 26.5 per 1000 births in teenage mothers (<20 years), 23.8 for mothers 20-24 years, 22.5 for mothers 25-29 years, 21.5 for mothers 30-34 years, 21.4 for mothers 35-39 years and 22.6 for mothers 40-44 years. The RR adjusted for country for teenage mothers was 1.11 (95% CI 1.06-1.17); 0.99 (95% CI 0.96-1.02) for mothers 35-39; and 1.01 (95% CI 0.95-1.07) for mothers 40-44. The pattern of maternal age-related risk varied significantly between countries: France, Ireland and Portugal had higher RR for teenage mothers, Germany and Poland had higher RR for older mothers. The maternal age-specific RR varied for different NCAs. Teenage mothers were at a significantly greater risk (P < 0.01) of gastroschisis, maternal infection syndromes, tricuspid atresia, anencephalus, nervous system and digestive system anomalies while older mothers were at a significantly greater risk (P < 0.01) of fetal alcohol syndrome, encephalocele, oesophageal atresia and thanatophoric dwarfism. CONCLUSIONS: Clinical and public health interventions are needed to reduce environmental risk factors for NCA, giving special attention to young mothers among whom some risk factors are more prevalent. Reassurance can be given to older mothers that their age in itself does not confer extra risk for NCA.

Correction to: EUROCAT: an update on its functions and activities.

The published online version contains the following errors: On the cover page "JRC Management Committee" - should be corrected to JRC-EUROCAT Management Committee. In the authors list under the title, same as above, "JRC Management Committee" should be corrected to JRC-EUROCAT Management Committee.

Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development.

ErbB2 receptor tyrosine kinase plays a role in neuregulin signaling and is expressed in the developing nervous system. We genetically rescued the cardiac defect of erbB2 null mutant embryos, which otherwise died at E11. These rescued erbB2 mutant mice die at birth and display a severe loss of both motor and sensory neurons. Motor and sensory axons are severely defasciculated and aberrantly projected within their final target tissues. Schwann cells are completely absent in the peripheral nerves. Schwann cell precursors are present within the DRG and proliferate normally, but their ability to migrate is decreased. Acetylcholine receptors cluster within the central band of the mutant diaphragm muscle. However, these clusters are dispersed and morphologically different from those in control muscle. Our results reveal an important role for erbB2 during normal peripheral nervous system development.

Multiple-marker screening for Down's syndrome: a method of assessing the statistical robustness of proposed tests.

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 (VIF(max)) to determine whether a screening test using multiple markers was robust to imprecision in the estimation of the marker distribution parameters. METHODS: The VIF(max) 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 (FN(3)), 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 VIF(max) value was compared with the coefficient of variation of the FN(3) (FN(3) 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 VIF(max) values greater than 5 had FN(3)CV values over 50%, but those with VIF(max) values less than 5 had FN(3) 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 VIF(max) values > or =5 and none for those with values <5. CONCLUSION: VIF(max) values of 5 or more suggest instability. The tests using CT marker ratios were stable (VIF(max) < 3), but the tests using repeat measurements in the standard manner were not (VIF(max) > 5).

EUROCAT: an update on its functions and activities.

This paper provides an outline of the development and growth of EUROCAT, the European network of congenital anomaly registers. In recent years the network has been through a period of transition and change. The Central Register of data has transferred from the Ulster University to the EU Joint-Research-Centre, Ispra, Italy.The benefits of combining data from across Europe, from different populations and countries are described by the uses to which these data can be put. These uses include:. surveillance of anomalies at a local, regional or pan-European level. pharmacovigilance. registration of rare diseasesNew studies and projects are underway, including EUROlinkCAT (a Horizon 2020 funded data-linkage project), promising a fruitful future in further research of congenital anomalies.

Estimating the birth prevalence and pregnancy outcomes of congenital malformations worldwide.

Congenital anomaly registries have two main surveillance aims: firstly to define baseline epidemiology of important congenital anomalies to facilitate programme, policy and resource planning, and secondly to identify clusters of cases and any other epidemiological changes that could give early warning of environmental or infectious hazards. However, setting up a sustainable registry and surveillance system is resource-intensive requiring national infrastructure for recording all cases and diagnostic facilities to identify those malformations that that are not externally visible. Consequently, not all countries have yet established robust surveillance systems. For these countries, methods are needed to generate estimates of prevalence of these disorders which can act as a starting point for assessing disease burden and service implications. Here, we describe how registry data from high-income settings can be used for generating reference rates that can be used as provisional estimates for countries with little or no observational data on non-syndromic congenital malformations.

Prevalence of neural tube defect pregnancies in England and Wales from 1964 to 2004.

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.

The effect of correlations between screening markers on screening performance.

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.

Estimating the risk of Down's syndrome in antenatal screening and the gestation at which this risk applies.

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.

The association between Ehlers-Danlos syndrome-hypermobility type and gastrointestinal symptoms in university students: a cross-sectional study.

BACKGROUND: Patients with Ehlers-Danlos syndrome-hypermobility type (EDS-HT) have increased prevalence of gastrointestinal (GI) symptoms, particularly reflux and dyspepsia. EDS-HT is associated with dysautonomia, psychopathology, and chronic pain which can be associated with GI symptoms. The association between GI symptoms and EDS-HT in a 'non-patient' population and the effect of the above-mentioned factors has never been studied. METHODS: In a cross sectional study, a hypermobility questionnaire was used to screen university students; further clinical examination established the diagnosis of EDS-HT. Validated questionnaires assessed for GI, somatic, pain and autonomic symptoms, psychopathology and quality of life (QOL). These were compared in students with and without EDS-HT; logistic regression analysis examined associations between EDS-HT, GI symptoms and other variables. KEY RESULTS: Of 1998 students screened, 162 were included: 74 EDS-HT (21.0 years, 53% female) vs 88 Non-EDS-HT (21.5 years, 65% female). Compared to non-EDS-HT students, EDS-HT students were more likely to have multiple GI symptoms (41.9% vs 27.3% P=.05), particularly postprandial fullness (34.4% vs 15.9%, P=.01) and early satiety (32% vs 17%, P=.03), greater autonomic (P<.001) and somatic symptoms (P=.04) but not psychopathology (P>.8). The association between EDS-HT and postprandial symptoms was dependent on autonomic factors but independent of pain and psychopathology. Pain-related QOL scores were reduced in the EDS-HT group (80 vs 90, P=.03). CONCLUSIONS AND INFERENCES: The previously described association between EDS-HT, dyspepsia, pain and autonomic symptoms in patients is also present in non-patient groups. Future studies are necessary to explore the etiological role of connective tissue in GI and extra intestinal symptoms.

The proportions of Down's syndrome pregnancies detected prenatally in England and Wales from 1989 to 2004.

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.

Validation plots in antenatal screening for Down's syndrome.

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.

Cardiorespiratory fitness and white matter integrity in Alzheimer's disease.

The objective of this study was to investigate the relationship between cardiorespiratory (CR) fitness and the brain's white matter tract integrity using diffusion tensor imaging (DTI) in the Alzheimer's disease (AD) population. We recruited older adults in the early stages of AD (n = 37; CDR = 0.5 and 1) and collected cross-sectional fitness and diffusion imaging data. We examined the association between CR fitness (peak oxygen consumption [VO2peak]) and fractional anisotropy (FA) in AD-related white matter tracts using two processing methodologies: a tract-of-interest approach and tract-based spatial statistic (TBSS). Subsequent diffusivity metrics (radial diffusivity [RD], mean diffusivity [MD], and axial diffusivity [A × D]) were also correlated with VO2peak. The tract-of-interest approach showed that higher VO2peak was associated with preserved white matter integrity as measured by increased FA in the right inferior fronto-occipital fasciculus (p = 0.035, r = 0.36). We did not find a significant correlation using TBSS, though there was a trend for a positive association between white matter integrity and higher VO2peak measures (p < 0.01 uncorrected). Our findings indicate that higher CR fitness levels in early AD participants may be related to preserved white matter integrity. However to draw stronger conclusions, further study on the relationship between fitness and white matter deterioration in AD is necessary.

Prevention of neural tube defects in the UK: a missed opportunity.

OBJECTIVE: In 1991, the Medical Research Council (MRC) Vitamin Study demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). We aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in the UK from 1998 as it had been in the USA. DESIGN: Estimates of NTD prevalence, the preventive effect of folic acid and the proportion of women taking folic acid supplements before pregnancy were used to predict the number of NTD pregnancies that would have been prevented if folic acid fortification had been implemented. SETTING: Eight congenital anomaly registers in England and Wales. MAIN OUTCOME MEASURES: The prevalence of pregnancies with an NTD in the UK and the number of these pregnancies that would have been prevented if folic acid fortification had been implemented. RESULTS: From 1991 to 2012, the prevalence of NTD pregnancies was 1.28 (95% CI 1.24 to 1.31) per 1000 total births (19% live births, 81% terminations and 0.5% stillbirths and fetal deaths ≥20 weeks' gestation). If the USA levels of folic acid fortification from 1998 onwards had been adopted in the UK, an estimated 2014 fewer NTD pregnancies would have occurred. CONCLUSIONS: Failure to implement folic acid fortification in the UK has caused, and continues to cause, avoidable terminations of pregnancy, stillbirths, neonatal deaths and permanent serious disability in surviving children.

Graphical presentation of distributions of risk in screening.

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.