Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk.

STUDY QUESTION: Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? SUMMARY ANSWER: Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. WHAT IS KNOWN ALREADY: Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. STUDY DESIGN, SIZE, DURATION: This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P < 0.001) and higher testosterone (AD 0.57 nmol/l, P < 0.001) and high molecular weight adiponectin than controls (AD 3.01 µg/ml, P = 0.02), but no significant differences in aPWV (AD -0.13 m/s, P = 0.33), ccIMT (AD -0.01 mm, P = 0.13), or e':a' (AD -0.01, P = 0.86) were observed. After adjustment for age, height and central pulse pressure, e':a' and aPWV were associated with logVF and IAUC. ccIMT was not related to logVF. The relationships between e':a' or aPWV and insulin resistance were only partly attenuated by adjusting for logVF. There was no significant relationship between aPWV or e':a' and either testosterone or adiponectin. LIMITATIONS, REASONS FOR CAUTION: The study recruited young women meeting the Rotterdam criteria for PCOS diagnosis; hence our findings may not be generalizable to older patients or those meeting other definitions of the syndrome. Biochemical hyperandrogenism was based solely on measurement of total testosterone. Cases and controls were not matched in advance for age and BMI, although the influence of these variables on the cardiovascular outcome measures was adjusted for. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that central arterial stiffness and diastolic dysfunction are not increased in young women with PCOS, whereas they are associated with both insulin resistance and central obesity. Obesity thus represents the greatest modifiable risk factor for cardiovascular disease in young women with PCOS and lifestyle measures which target weight reduction are critical. STUDY FUNDING/COMPETING INTERESTS: This study received no specific grant support from any funding body. The authors have no conflicts of interest to declare.

Effect of neighbourhood deprivation and social cohesion on mental health inequality: a multilevel population-based longitudinal study.

BACKGROUND: The common mental disorders (CMDs) of anxiety and depression are the most common form of poor mental health in the general population. Evidence from the small number of previous cohort studies on the role of neighbourhood factors in mental health is inconclusive. We tested the hypothesis that high levels of neighbourhood social cohesion modify an adverse association between change in individual mental health and neighbourhood deprivation. METHOD: We carried out a longitudinal multilevel analysis using data from the Caerphilly Health and Social Needs Cohort Study with a 7-year follow-up (n = 4426; age range 18-74 years at baseline). Neighbourhood deprivation and neighbourhood social cohesion were assessed at baseline and change in mental health between follow-up and baseline was assessed using the five-item Mental Health Inventory (MHI-5). RESULTS: Residence in the most deprived neighbourhoods was negatively associated with change in mental health, after adjusting for baseline individual socio-economic risk factors and transitions in life events. This negative effect was significantly reduced in high social cohesion neighbourhoods. The predicted change in mental health score was calculated for the 10th and 90th centiles of the household low-income distribution. The difference between them was -2.8 in the low social cohesion group and 1.1 in the high cohesion group. The difference between the groups was 3.9 [95% confidence interval (CI) 0.2-7.6]. CONCLUSIONS: The public health burden of poor mental health and mental health inequality could potentially be reduced by strengthening social cohesion in deprived neighbourhoods. This offers a mechanism to address the adverse effect of neighbourhood deprivation on population mental health.

The natural history of eczema from birth to adult life: a cohort study.

BACKGROUND: Eczema is common in infancy; however, there is little evidence about its natural history to adulthood. OBJECTIVES: To study the natural history of eczema from birth to young adult life with particular reference to its relation to atopy. METHODS: A birth cohort of children with atopic family histories was followed for 23 years. Clinical examinations were conducted until the age of 7 years, skin-prick tests and serum total IgE were recorded in infancy and at ages 7 and 23 years, and questionnaires about eczema symptoms were completed at 15 and 23 years. RESULTS: Information was obtained on 497 subjects at birth, 482 at 1 year, 440 at 7 years, 363 at 15 years and 304 at 23 years. Eczema usually remitted from age 1 to 7 years but became more persistent from the age of 15 years, especially in those who were atopic. The prevalence of eczema rose in women from age 15 to 23 years but declined in men. Adults with eczema had higher IgE than those without at 3 months (geometric mean 3·0 vs. 1·7 kU L(-1); P=0·01), 7 years (107·9 vs. 45·2 kU L(-1); P=0·01) and 23 years (123·4 vs. 42·3 kU L(-1); P=0·01), and were more likely to have had positive skin-prick tests at 1 year of age. Current eczema was associated with raised IgE in infancy and adulthood but not in childhood. CONCLUSIONS: Predisposed infants and children with eczema usually grow out of the disease, but in adolescence it is more likely to persist. Adult eczema is related to atopy from the age of 3 months.

Prevalence and pattern of cognitive impairment in a community cohort of men in South Wales: methodology and findings from the Caerphilly Prospective Study.

BACKGROUND/AIMS: The prevalence of dementia and cognitive impairment not dementia was investigated in the Caerphilly Prospective Study cohort (men currently aged 65-84 years). METHODS: Of 1,633 men eligible for cognitive screening, 1,225 (75%) were seen, with those failing the screening criteria (CAMCOG <83 or decline in CAMCOG >9) being neurologically examined. RESULTS: For dementia, diagnosed by DSM-IV criteria, the population prevalence was 5.2% rising to 6.1% in the screened population. For cognitive impairment not dementia, the prevalence in the screened population was 15.6% giving an overall prevalence of cognitive impairment of 21.8%. Prevalence rose fivefold between ages of 65 and 84 years to reach over 50%. CONCLUSION: These figures are likely to underestimate actual prevalence in this population, and developing effective interventions should be a public health priority.

Selecting specialist registrars by station interview.

Appointments to the specialist registrar (SpR) grade depend almost entirely on performance at interview, yet standard panel interviews do not directly assess the competences required of a medical trainee. In this study, station interviews were used to select neurology SpRs. Eighteen candidates were assessed in three interviews, each involving three stations: a curriculum vitae (CV)-based interview, an interview with a simulated patient, and a discussion of scenarios based upon teaching, audit and research. Two or three assessors at each station ranked candidates independently before discussing the pooled rankings and reading written references. The CV-based interview rankings (resembling a traditional panel interview) correlated less well with the overall rankings (r=0.54) than did research (r=0.83), information giving (r=0.75), audit (r=0.70) or teaching presentation (r=0.59). Station interviews appear fairer (providing more time, more independent examiners, fresh starts at each station), although they require more planning and expense. Competency-based assessments should be more widely used in selecting medical trainees.

A randomised controlled trial of clinical outreach education to rationalise antibiotic prescribing for acute dental pain in the primary care setting.

OBJECTIVE: To assess the effect of educational outreach visits on antibiotic prescribing for acute dental pain in primary care. STUDY DESIGN: RCT. SETTING: General dental practices in four health authority areas in Wales. SUBJECTS AND METHODS: General dental practitioners were recruited to the study and randomly allocated to one of the three study groups (control group, guideline group or intervention group). Following the intervention, practitioners completed a standardised questionnaire for each patient that presented with acute dental pain. INTERVENTIONS: The control group received no intervention. The guideline group received educational material by post. The intervention group received educational material by post and an academic detailing visit by a trained pharmacist. The educational material included evidence-based guidelines on prescribing for acute dental pain and patient information leaflets. MAIN OUTCOME MEASURES: The number of antibiotic prescriptions issued to patients presenting with dental pain and the number of 'inappropriate' antibiotic prescriptions. Antibiotics were considered to be inappropriate if the patient did not have symptoms indicative of spreading infection. RESULTS: A total of 1,497 completed questionnaires were received from 23, 20 and 27 general dental practitioners in the control, guideline and intervention group respectively. Patients in the intervention group received significantly fewer antibiotic prescriptions than patients in the control group (OR (95% CI) 0.63 (0.41, 0.95)) and significantly fewer inappropriate antibiotic prescriptions (OR (95% CI) 0.33 (0.21, 0.54)). However, antibiotic and inappropriate antibiotic prescribing were not significantly different in the guideline group compared to the control group (OR (95% CI) 0.83 (0.55, 1.21) and OR (95% CI) 0.82 (0.53, 1.29) respectively). CONCLUSIONS: Strategies based upon educational outreach visits may be successfully employed to rationalise antibiotic prescribing by dental practitioners.

Day-to-day variability of fasting plasma glucose in newly diagnosed type 2 diabetic subjects.

OBJECTIVE: To determine the day-to-day intraindividual variability of fasting plasma glucose (FPG) in newly diagnosed Caucasian type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: A total of 193 newly diagnosed, previously untreated, Caucasian type 2 diabetic subjects (135 men, 58 women) had FPG measured on two consecutive days (FPG1, FPG2). Ethical approval and subjects' full informed consent were obtained. Subjects fasted for 12 h before each study day and rested for at least 30 min before blood was taken. Plasma glucose was analyzed by a glucose oxidase method with intra- and interassay coefficients of variation (CVs) < 2%. Variability of FPG was assessed by comparison of percentage differences (PDs): PD = 100 (FPG2 - FPG1)/FPG1, with averaged FPG (FPGaver = [FPG1 + FPG2]/2). Biological and analytical variability were determined by use of SD2total = SD2biological + SD2analytical, where SD2analytical approximately equal to 2 x (CVglucose measurement)2. Given normally distributed data with zero mean, 95% of daily percentage differences will be expected to fall within a range of +/- 2 SDtotal. RESULTS: Subjects were age 54 +/- 10 years (mean +/- SD) and had BMI of 29.3 +/- 5.3 kg/m2. FPG values for both days were 12.2 +/- 3.4 mmol/l (FPG1) and 12.1 +/- 3.3 mmol/l (FPG2), with a mean paired difference (95% CI) of 0.1 (0.0 to 0.3) mmol/l. The variance of these differences increased with increasing FPGaver. The PDs did not exhibit this effect and were normally distributed (mean -0.6% [-1.7 to 0.4]; SD 7.4% [6.8 to 8.3]), giving a 95% variability (2 SD) of 14.8%. Biological variability (2 SDbiological) was 13.7%. No significant difference in PD was found between men and women (mean difference 1.3% [-1.0 to 3.6]; SDmale 7.4%, SDfemale 7.3%; P = 0.62). CONCLUSIONS: A total of 95% of the FPG values for this group of newly diagnosed type 2 diabetic subjects varied within approximately +/- 15% on a daily basis, with approximately 14% caused by biological variability. As these results are expressed in percentage terms, subjects in the group with higher FPG values are likely to experience larger changes in FPG values measured from day to day. This variability should be considered when using FPG for the diagnosis and/or monitoring of response to treatment in patients with type 2 diabetes.

Determining true glomerular filtration status in newly presenting type 2 diabetic subjects using age and sex adjustment.

OBJECTIVE: To determine age- and sex-adjusted reference ranges (ASARRs) for glomerular filtration status using data from nondiabetic subjects and to apply these to newly presenting type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: Glomerular filtration rate corrected for body surface area (cGFR) was determined using a radionuclide (51Cr-EDTA) method in 75 non-diabetic subjects (37 men, 38 women) and 219 type 2 diabetic subjects (157 men, 62 women). The 95% constant reference ranges (CRRs) were calculated as mean nondiabetic cGFR+/-1.96 SD. The 95% ASARRs were calculated by Altman's method from the nondiabetic cGFR versus age regression residuals for both male and female subjects. RESULTS: Using Altman's method, the intercepts, but not the gradients, of the cGFR versus age regressions were significantly different between male and female subjects (intercept difference [95% CI] 8.2 [1.3-15.1], gradient difference -0.4 [-1.1 to 0.3]). Fitting a common gradient, 95% ASARRs for normofiltration were found to be from 123.9 - (0.89 X age) to 181.7 - (0.89 x age) for male subjects, and from 116.0 - (0.89 X age) to 173.2 - (0.89 X age) for female subjects. The 95% CRR for normofiltration was 70.2-138.1 ml x min(-1) x (1.73 m)(-2). When applied to the diabetic cGFRs, the CRRs and ASARRs gave, respectively, 17% (37/219) versus 21% (46/219) hyperfiltrators and 83% (181/219) versus 79% (172/219) normofiltrators. Using the ASARRs, 14 normofiltrators (6 men, 8 women) were reclassified as hyperfiltrators (change [n/total n] [95% CI] 8% [14/181] [4-12]), and 5 hyperfiltrators (5 men, 0 women) were reclassified as normofiltrators (change 14% [5/37] [5-30]). CONCLUSIONS: We conclude that age and sex adjustment are essential to assess glomerular filtration status.

Syndrome X and endothelial dysfunction.

OBJECTIVE: Syndrome X (angina, normal coronary arteriogram and positive exercise test) remains an enigma with unexplained features and apparent conflicts of evidence. The present study addressed whether (i) the Syndrome is characterised by generalised flow-related endothelial dysfunction, (ii) myocardial thallium201 defects reflect myocardial or microvascular dysfunction, (iii) endothelial dysfunction and its consequences can be improved by oral L-arginine. METHODS: Flow-mediated brachial artery dilatation was measured by ultrasonic 'wall-tracking' in 7 Syndrome X patients, further characterised as having thallium201 defects and no known cause of endothelial dysfunction, and a normal control group. Syndrome X patients entered a 4-week randomised double-blind placebo-controlled cross-over trial of oral L-arginine (7 g twice daily), with brachial artery studies, exercise tests and technetium99 tetrafosmin scans. RESULTS: Flow-mediated dilatation was absent in Syndrome X vs. normal. Stress technetium99 tetrafosmin and thallium201 scans showed similar defects. Flow-mediated dilatation, symptom-limited exercise duration and peak oxygen consumption (VO2max) were increased but rate-pressure-product (RPP) and radionuclide defects were unchanged after L-arginine vs. placebo. CONCLUSIONS: The study supports coronary microvascular rather than myocardial dysfunction and shows loss of flow-mediated dilatation in systemic arteries. Oral L-arginine improved flow-mediated dilatation, exercise capacity and VO2max (by ca. 17%) despite unchanged RPP. The findings support generalised endothelial dysfunction. The arginine effects imply NO-mediated improvement of skeletal muscle perfusion suggesting improved homogeneity of microvascular distribution.

Risk of post-traumatic stress disorder following traumatic events in a community sample.

AIMS: Post-traumatic stress disorder (PTSD) is typically associated with high-risk population groups, but the risk of PTSD that is associated with trauma experienced in the community, and effect of changes in diagnostic criteria in DSM-5 on prevalence in the general population, is unknown. METHODS: Cross-sectional analysis of population-based data from 4558 adults aged 25-83 years resident in Caerphilly county borough, Wales, UK. Exposure to different traumatic events was assessed using categorisation of free-text descriptions of trauma. PTSD caseness was determined using items assessing Diagnostic and Statistical Manual IV (DSM-IV) and DSM-5 A criteria and the Traumatic Screening Questionnaire. RESULTS: Of the 4558 participants, 1971 (47.0%) reported a traumatic event. The most common DSM-IV A1 qualifying trauma was life-threatening illnesses and injuries (13.6%). The highest risk of PTSD was associated with assaultive violence [34.1%]. The prevalence of PTSD using DSM-IV A criteria was 14.3% (95% confidence interval [CI] = 12.8, 15.9%). Using DSM-5 A criteria reduced the prevalence to 8.0 (95% CI = 6.9, 9.4%), primarily due to exclusion of DSM-IV A1 qualifying events, such as life-threatening illnesses. CONCLUSIONS: Nearly one-half of a general community sample had experienced a traumatic event and of these around one in seven was a DSM-IV case of PTSD. Although the majority of research has concentrated on combat, rape and assaultive violence, life threatening illness is a more common cause of PTSD in the community. Removal of this traumatic event in DSM-5 could reduce the number of cases of PTSD by around 6.0%.

The assessment of different methods of data reduction for qualitative assays.

An increasing number of biochemical tests for the detection of ailments such as hepatitis, AIDS, listeria poisoning etc are becoming qualitative in nature since the concern is over whether contamination is present or not rather than to what degree it is present. Many tests have an underlying quantitative scale that is dichotomised by the calculation of a detection limit, whereby a result is deemed negative, say, if its assay response is less than the detection limit and positive otherwise. A number of methods have been proposed for determining the detection limit and a few authors have tried to compare some of these methods. To date, as far as we are aware, these comparisons have been neither exhaustive nor conclusive. We propose a comparison criterion based on the false positive and false negative rates and use this criterion to assess five different methods via a simulation study. For the simulation model used, under the conditions imposed, we conclude that a detection limit based on control samples is probably the most efficient. Each method of calculating the detection limit has a coefficient associated with it for determining the exact position of the detection limit. The criteria, to date, for selecting the value of this coefficient seem arbitrary since whole numbers are often quoted, presumably reflecting convenience. Our simulation approach provides a possible method for determining the value of the coefficient which gives rise to a specified false positive or false negative rate.

Age-specific detection and false-positive rates: an aid to counseling in Down syndrome risk screening.

OBJECTIVE: To determine whether the serum screening test for Down syndrome provides equal detection efficacy for women of all ages, to improve the data available for patient counseling both before testing and afterward in the event of a positive result. METHODS: We examined the effect of age on Down screening by generating a set of "normal" and "Down syndrome" likelihood ratios by computer simulation. The expected false-positive and detection rates were derived for different age groups by counting the proportion of cases in which the likelihood ratio could modify the age-specific risk to be greater than the cutoff risk of one in 300 (equivalent to an incidence of 3.33 per 1000). The predictive value of a positive result was calculated using Baye's theorem. RESULTS: Detection rates, false-positive rates, and predictive values were shown to be age-dependent. CONCLUSIONS: Knowledge of the age dependency of Down syndrome screening results may be useful in explaining to patients that the Down screen can only detect a proportion of cases and that a negative result does not guarantee normality. This knowledge may also be helpful in minimizing psychological stress, as a positive result indicates only a small chance that the fetus will have Down syndrome.

Gastric acid suppression does not promote clostridial diarrhoea in the elderly.

Gastric acid prevents bacterial colonization of the stomach and suppression of its secretion might predispose to Clostridium difficile (CD) diarrhoea. We retrospectively studied elderly patients admitted to medical wards of an acute hospital to determine whether the incidence of CD diarrhoea was greater among those previously treated with gastric acid suppressants. From records of stool CD toxin tests undertaken in 1995 and 1996, we found 126 cases with positive results, and selected 126 controls with negative results. Information about pre-morbid illness, predisposing factors for CD and medication received in the preceding 16 weeks was obtained from case-notes. A greater number of CD positive cases had received antibiotics such as Cefuroxime, ciprofloxacin or macrolides with or without metronidazole, were more severely disabled, required assistance for feeding, or had hypoalbuminaemia before the onset of diarrhoea. A greater number of controls had received lactulose, suggesting either that its laxative effect resembled CD infection prompting frequent stool tests, or that it offered protection against CD in this group. Both groups were similar for the use of proton-pump inhibitors or H2-receptor antagonists, suggesting that susceptible elderly patients are not more likely to develop CD diarrhoea after receiving gastric acid suppression therapy.

Changes in the risk of schizophrenia in Scotland: is there an environmental factor?

Various studies have suggested that there may be an environmental factor in schizophrenia acting before or at birth but with delayed effects. Evidence that the risk of developing schizophrenia varies randomly with the year of birth would help confirm the existence of such a factor. Data from the Scottish Health Service Information and Statistics Division, comprising all first admissions for ICD-9 schizophrenia in the years 1963-91, were used to estimate the lifetime risk of developing schizophrenia for each year of birth from 1900 to 1969. In the period after 1928 the lifetime risk steadily declined. The rate of decline was greater in females. The random fluctuations in the risks in females did not change systematically, but there was a significant decline in the variability of these fluctuations in males. These random fluctuations suggest a possible role for randomly varying environmental influences around the time of birth. Our findings suggest a possible diminution in the role of such environmental influences in schizophrenia among males in Scotland in the years 1929 to 1969.

Lack of benefit of dietary advice to men with angina: results of a controlled trial.

OBJECTIVE: To see whether mortality among men with angina can be reduced by dietary advice. DESIGN: A randomized controlled factorial trial. SETTING: Male patients of general practitioners in south Wales. SUBJECTS: A total of 3114 men under 70 y of age with angina. INTERVENTIONS: Subjects were randomly allocated to four groups: (1) advised to eat two portions of oily fish each week, or to take three fish oil capsules daily; (2) advised to eat more fruit, vegetables and oats; (3) given both the above types of advice; and (4) given no specific dietary advice. Mortality was ascertained after 3-9 y. RESULTS: Compliance was better with the fish advice than with the fruit advice. All-cause mortality was not reduced by either form of advice, and no other effects were attributable to fruit advice. Risk of cardiac death was higher among subjects advised to take oily fish than among those not so advised; the adjusted hazard ratio was 1.26 (95% confidence interval 1.00, 1.58; P=0.047), and even greater for sudden cardiac death (1.54; 95% CI 1.06, 2.23; P=0.025). The excess risk was largely located among the subgroup given fish oil capsules. There was no evidence that it was due to interactions with medication. CONCLUSIONS: Advice to eat more fruit was poorly complied with and had no detectable effect on mortality. Men advised to eat oily fish, and particularly those supplied with fish oil capsules, had a higher risk of cardiac death. This result is unexplained; it may arise from risk compensation or some other effect on patients' or doctors' behaviour.

Screening for Down's syndrome: the effect of test date on the detection rate.

Screening tests for Down's syndrome are carried out at different gestational ages. Because of fetal loss, crude estimates of their detection rates cannot be directly compared. We present methods for estimating the true detection rates along with their standard errors. This enables a proper statistical comparison of the true detection rates of tests carried out, for example, in different trimesters.

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

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.

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.

The effects of gestation dating on the calculation of patient specific risks in Down's syndrome screening.

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 alpha-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.

Correlation of marker values in Down's syndrome screening: the effect of dating error.

Central to any screening algorithm for Down's syndrome are the values used for the parameters in the multivariate Gaussian statistical model that is used to describe the joint distribution of the marker values. There has been much discussion about the values of the means and standard deviations which are appropriate but little interest has been shown in the values of the correlation coefficients between markers. There has been some speculation that the range of parameter values quoted in the literature arises from factors such as storage of samples, between-assay effects and differences in assay methodologies. We show that gestational dating error, among other factors, could be responsible for much of the variation that is present in quoted parameter values, though the factors mentioned above clearly have an effect.