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Background\ud \ud Few potentially modifiable risk factors of male infertility have been identified, and while different diets and food groups have been associated with male infertility, evidence linking dietary factors including phytoestrogens and semen quality is limited and contradictory.\ud \ud \ud \ud Objectives\ud \ud To study the associations between phytoestrogen intake and other dietary factors and semen quality.\ud \ud \ud \ud Materials and Methods\ud \ud A case‐referent study was undertaken of the male partners, of couples attempting conception with unprotected intercourse for 12 months or more without success, recruited from 14 UK assisted reproduction clinics. A total of 1907 participants completed occupational, lifestyle and dietary questionnaires before semen quality (concentration, motility and morphology) were assessed. Food intake was estimated by a 65‐item food frequency questionnaire (FFQ) covering the 12 months prior to recruitment. Analyses of dietary risk factors for low motile sperm concentration (MSC: 3 times/wk.\ud \ud \ud \ud Discussion\ud \ud In this case‐referent study of men attending an infertility clinic for fertility diagnosis, we have identified that low MSC is inversely associated with daidzein intake. In contrast, daidzein intake was not associated with PM but eating red milk and drinking whole milk were protective.\ud \ud \ud \ud Conclusions\ud \ud Dietary factors associated with semen quality were identified, suggesting that male fertility might be improved by dietary changes.

It is often assumed that randomisation will prevent bias in estimation of treatment effects from clinical trials, but this is not true of the semiparametric Proportional Hazards model for survival data when there is underlying risk heterogeneity. Here, a new formula is proposed for estimation of this bias, improving on a previous formula through ease of use and clarity regarding the role of the mid-study cumulative hazard rate, shown to be an important factor for the bias magnitude. Informative censoring (IC) is recognised as a source of bias. Here, work on selection effects among survivors due to risk heterogeneity is extended to include IC. A new formula shows that bias in causal effect estimation under IC has two sources: one consequent on heterogeneity and one from the additional impact of IC. The formula provides new insights not previously shown: there may less bias under IC than when there is no IC and even, in principle, zero bias. When tested against simulated data, the new formulae are shown to be very accurate for prediction of bias in Proportional Hazards and accelerated failure time analyses which ignore heterogeneity. These data are also used to investigate the performance of accelerated failure time models which explicitly model risk heterogeneity ('frailty models') and G estimation. These methods remove bias when there is simple censoring but not with informative censoring when they may lead to overestimation of treatment effects. The new formulae may be used to help researchers judge the possible extent of bias in past studies. Copyright © 2017 John Wiley & Sons, Ltd.

Objective: Accurate estimation of the true incidence of ill-health is a goal of many surveillance systems. In surveillance schemes including zero reporting to remove ambiguity with nonresponse, reporter fatigue might increase the likelihood of a false zero case report in turn underestimating the true incidence rate and creating a biased downward trend over time.Study design and setting: Multilevel zero-inflated negative binomial models were fitted to incidence case reports of three surveillance schemes running between 1996 and 2012 in the United Kingdom. Estimates of the true annual incidence rates were produced by weighting the reported number of cases by the predicted excess zero rate in addition to the within-scheme standard adjustment for response rate and the participation rate.Results: Time since joining the scheme was associated with the odds of excess zero case reports for most schemes, resulting in weaker calendar trends. Estimated incidence rates (95% confidence interval) per 100,000 person years, were approximately doubled to 30 (21-39), 137 (116-157), 33 (27-39), when excess zero-rate adjustment was applied.Conclusion: If we accept that excess zeros are in reality nonresponse by busy reporters, then usual estimates of incidence are likely to be significantly underestimated and previously thought strong downward trends overestimated.

Mortality from circulatory disease (CD), ischemic heart disease (IHD) and cerebrovascular disease (CeVD) was investigated in relationship to cumulative doses of external gamma radiation and internal alpha radiation to the liver from deposited plutonium over long follow-up periods in two large cohorts of nuclear workers: the Russian Mayak Worker Cohort (MWC) and the UK Sellafield Worker Cohort (SWC). The MWC comprised 22,374 workers (74.6% males) with 5,123 CD deaths registered during 842,538 person-years of follow-up, while the SWC comprised 23,443 workers (87.8% males) with 2,322 CD deaths registered during 602,311 person-years of follow-up. Dose estimates for external gamma radiation and internal alpha radiation to the liver were calculated via a common methodology, in accordance with an agreed protocol. The mean cumulative external Hp(10) dose was 0.52 Sv for the MWC and 0.07 Sv for the SWC, while the mean cumulative internal dose was 0.19 Gy for the MWC and 0.01 Gy for the SWC. Categorical relative ri...

OBJECTIVE We investigated the effects of gestational age, birth weight, small for gestational age (SGA), and large for gestational age (LGA) on risk of childhood type 1 diabetes. RESEARCH DESIGN AND METHODS We conducted a population-based cohort study of all singleton live births in Sweden between 1973 and 2009 and a sibling control study. Perinatal data were extracted from the Swedish Medical Birth Register. Children with type 1 diabetes diagnosis were identified from the Swedish National Patient Register. Log-linear Poisson regression and conditional logistic regression were used for data analysis. RESULTS The study cohort consisted of 3,624,675 singleton live births (42,411,054 person-years). There were 13,944 type 1 diabetes cases during the study period. The sibling control study consisted of 11,403 children with type 1 diabetes and 17,920 siblings. Gestational age between 33 and 36 weeks (relative risk [RR] 1.18 [95% CI 1.09, 1.28) and 37 and 38 weeks (RR 1.12 [95% CI 1.07, 1.17]) was associated with type 1 diabetes in the cohort study and remained significant in the sibling control study. SGA (RR 0.83 [95% CI 0.75, 0.93]) and LGA (RR 1.14 [95% CI 1.04, 1.24]) were associated with type 1 diabetes in the cohort study. The SGA association remained unchanged in the sibling study, while the LGA association disappeared. Very low birth weight was associated with a reduced risk of type 1 diabetes. CONCLUSIONS The findings suggest a small association between gestational age and type 1 diabetes that is not likely due to familial confounding factors. Gestational age and type 1 diabetes may be related to insulin resistance due to early life growth restriction or altered gut microbiota in preterm babies.

Background: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments. Methods: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death. Results: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model. Conclusions: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals.

Introduction The calculation of incidence rates of work-related ill-health (WRIH) is essential when assessing employment sectors at risk. The Health and Occupational Reporting network in General Practice (THOR-GP) collects information on WRIH from approximately 250 GPs. To calculate rates, GP numerator data has to be divided by a compatible denominator. Aims To formulate the best methods of determining incidence rates from THOR-GP data Methods The THOR-GP denominator is the registered population of all participating GPs’ practices. Census data linked to practice postcodes were used to establish how the population was employed; practice list data were used to estimate the size of the population and adjusted for GP participation. Numerator data (incidence cases of WRIH) from 2006–2015 were adjusted for response rates and time sampling frequency. Numerator data were then divided by the denominator and rates calculated per 1 00 000 persons employed per annum Results The incidence rate of WRIH (from 6491 numerator cases) was 1350 per 1 00 000 persons employed per annum. Musculoskeletal disorders had the highest rates (640) followed by mental ill-health (516). Rates for musculoskeletal disorders were highest in agriculture (2232) and construction (1048) and for mental ill-health, in financial services (1113) and public administration/defense (1124). Conclusion All employed persons have access to a GP therefore calculating incidence rates from GP data allow identification of industries/occupations at higher risk of WRIH Using postcode-based census data to characterise the denominator (therefore specifically related to the numerator) enables rates to be calculated with greater accuracy compared with using national employment data.

BACKGROUND: Epidemiological evidence linking low dose pesticide exposure and chronic ill-health in UK sheep farmers is limited. Our aim was to examine whether neuropsychiatric disorders were associated with low dose chronic and/or more acute pesticide exposure in sheep farmers. METHODS: A cohort of British farmers working in the 1970s was sent a screening questionnaire which asked about their health and work history. The prevalence of screen-positive depression, dementia, Parkinsonism and neuropathy was determined using a priori algorithms. Self-reported pesticide exposure was assessed by whether the participant had ever handled the pesticide concentrate (for low dose chronic exposure) or sought advice for pesticide poisoning (acute exposure) and participants categorised into those with only acute or chronic exposure, those with both acute and chronic exposure and those with neither acute nor chronic exposure. Associations between acute and chronic pesticide exposure, and screen-positive ill-health were determined after adjustment for demographic, lifestyle, occupation and somatic severity scores and other variables. RESULTS: In those participants, who had never sought advice for pesticide poisoning, handling the pesticide concentrate for treating sheep was associated with elevated ORs for screen-positive neuropathy (ORadi 1.57 95%CI 0.97-2.54) and Parkinsonism (ORadj 1.56 95%CI 0.95-2.56) but not depression or dementia. In those participants who had handled the pesticide concentrate, seeking advice for pesticide poisoning was associated with screen-positive depression (Odds ratio, ORadj=9.97 95%CI 4.76-20.8 ), dementia (OR=6.94 95%CI 3.44-14.0), Parkinsonism (ORadj=4.77 95% 2.39-9.52), and neuropathy (ORadj=4.77 95%CI 2.39-9.52). Adjustment for somatic severity score modified little the associations with pesticide handling in those not acutely exposed but reduced the ORs for seeking advice for pesticide poisoning in those exposed chronically. Furthermore, stratification of results based upon somatic severity score indicated that the highest ORs for handling the pesticide concentrate associated with neuropathy and Parkinsonism were found in those participants whose somatic score was minimal. CONCLUSIONS: Results are consistent with low-dose exposure to pesticides being associated with screen-positive neuropathy and Parkinsonism but the stronger associations between seeking advice for pesticide poisoning and screen-positive ill-health suggest that acute pesticide exposure remains an important determinant of ill-health. Further work is required to better delineate to what extent low dose exposures may contribute to ill-health in populations without acute exposures. Somatising tendency does not appear to play an important role in this population.

Objective We examined occupational exposures and sperm morphology to establish whether exposures implicated differed from those affecting motile sperm concentration. Methods Computer aided sperm morphometric assessment was undertaken on morphology slides obtained as part of a multi-centre study in 1999–2002 of occupational factors in male infertility. Men attending 14 fertility clinics across the UK were recruited and gave a semen sample. Before results of the semen analysis were known, the men completed detailed questionnaires about their employment and lifestyle. Occupational exposures were assessed by occupational hygienists. Data were analysed using an unmatched case-referent design, allowing for clustering and for confounders. Three case definitions were used: poor morphology (normal morphology 6 ) and either condition. Results Morphology results were available for 1861/2011 men employed at the time of recruitment. Of these 1861, 296 (15.9%) had poor morphology; of the 2011with sperm count, 453 (22.5%) had low MSC; 654/1981 (33.0%) had either condition. Poor morphology, adjusted for confounding, was related to self-reported lifetime exposure to lead (OR=1.33; 95% CI 1.00 to 1.75). Low MSC was also related to self-reported lead and to hygienist-assessed glycol ether exposure. Self-reported use of paint stripper (OR=1.47; 95% CI 1.07 to 2.03) and lead, but not glycol ether, were significantly related to the combined case definition. Conclusions While this study did not identify any occupational exposure uniquely related to sperm morphology, the capacity of the study to detect risk was increased by including morphology with sperm concentration and motility.

Background Treatment of hypertension reduces incidence of stroke, myocardial infarction and heart failure perhaps partly by controlling different metabolic parameters. There is limited information regarding the changes in potassium, sodium, weight, cholesterol and glucose levels in patients using anti-hypertensives. This study aimed to determine changes in potassium, sodium, glucose, cholesterol, weight, urea and urate levels in patients using anti-hypertensives. Furthermore, to describe these changes and differences between the atenolol, hydrochlorothiazide plus amiloride and placebo arms of the Medical Research Council (MRC) elderly randomised controlled trial. Methods Patients were randomly allocated to one of the three treatment arms. Measurements were taken at baseline, end of year one and end of year two in 4396 subjects. Linear Mixed Models (LMM) were used to determine the longitudinal profiles of sodium, potassium, weight, cholesterol, glucose, urea and urate. Estimates of changes within groups and difference between groups were obtained. Results Patients randomised to receive hydrochlorothiazide + amiloride experienced a significantly greater mean reduction in potassium, sodium and weight compared to placebo at end of year one - mean differences in change −0.18 mmol/L, (95 % CI: −0.21, −0.15); −1.45 mmol/L, (95 % CI: −1.62, −1.29) and −0.46 kgs (95 % CI: −0.73, −0.20) respectively, and greater increases in cholesterol, urea and urate - mean differences in change 0.16 mmol/L, (95 % CI: 0.10,0.22); 0.77 mmol/L, (95 % CI: 0.68, 0.87) and 53.10 μmol/L, (95 % CI: 49.35, 56.85) respectively. Changes were in the same direction but smaller in the atenololarm except for potassium and weight (increases). No group differences in glucose were found. Conclusion Results were in line with expectation except for lack of change in glucose in the hydrochlorothiazide + amiloride arms. Electronic supplementary material The online version of this article (doi:10.1186/s12872-016-0368-2) contains supplementary material, which is available to authorized users.

It is often assumed that randomisation will prevent bias in estimation of treatment effects from clinical trials, but this is not true of the semiparametric Proportional Hazards model for survival data when there is underlying risk heterogeneity. Here, a new formula is proposed for estimation of this bias, improving on a previous formula through ease of use and clarity regarding the role of the mid-study cumulative hazard rate, shown to be an important factor for the bias magnitude. Informative censoring (IC) is recognised as a source of bias. Here, work on selection effects among survivors due to risk heterogeneity is extended to include IC. A new formula shows that bias in causal effect estimation under IC has two sources: one consequent on heterogeneity and one from the additional impact of IC. The formula provides new insights not previously shown: there may less bias under IC than when there is no IC and even, in principle, zero bias. When tested against simulated data, the new formulae are shown to be very accurate for prediction of bias in Proportional Hazards and accelerated failure time analyses which ignore heterogeneity. These data are also used to investigate the performance of accelerated failure time models which explicitly model risk heterogeneity ('frailty models') and G estimation. These methods remove bias when there is simple censoring but not with informative censoring when they may lead to overestimation of treatment effects. The new formulae may be used to help researchers judge the possible extent of bias in past studies. Copyright © 2017 John WileySons, Ltd.

Objective Concerns over occupational exposures to blood-borne viruses resulted in increased protective glove use; consequentially latex allergy became a hazard for some occupational groups. Interventions aimed at managing this problem included substitution measures (eg, non-powdered/non-latex gloves), but such changes may not occur simultaneously across occupational sectors. This study evaluated whether the incidence of occupational dermatoses fell after interventions aiming to reduce exposure to ‘latex and rubber glove allergens’ (‘latex’) were introduced, and whether these interventions were more effective for healthcare workers (HCWs), compared with non-HCWs. Methods Incidence rate ratios (IRRs) comparing cases reported to EPIDERM (a UK-wide surveillance scheme) during post versus pre-intervention periods were calculated, both where ‘latex’ was cited and for cases associated with other exposures (‘controls’). Results Among HCWs, cases of contact urticaria and allergic contact dermatitis (ACD) where ‘latex’ was cited showed significant downward trends post-intervention, with IRRs of 0.72, 95% CI; 0.52 to 1.00 and 0.47, 95% CI; 0.35 to 0.64 respectively. For HCWs, this fall in ‘latex’ associated ACD was significantly greater (p=0.02) than for other exposures (‘controls’) IRR=0.85, 95% CI; 0.57 to 1.28, and greater than that among non-HCWs (IRR 0.75, 95% CI; 0.61 to 0.93). Increases over time were seen for irritant contact dermatitis (ICD) reporting for HCWs, both for cases associated with ‘latex’ (IRR 1.47, 95% CI: 1.02 to 2.13) and for other exposures (‘controls’) IRR 1.36, 95% CI 1.06 to 1.76, but not for non-HCWs. Conclusions A reduction in overall ACD, particularly in HCWs, coincided with interventions aimed at managing workplace contact dermatoses associated with ‘latex’ exposure. A coincidental rise in ICD reporting is also important, both for hand care and for infection control strategies.

Noncompliance to treatment allocation is a key source of complication for causal inference. Efficacy estimation is likely to be compounded by the presence of noncompliance in both treatment arms of clinical trials where the intention-to-treat estimate provides a biased estimator for the true causal estimate even under homogeneous treatment effects assumption. Principal stratification method has been developed to address such posttreatment complications. The present work extends a principal stratification method that adjusts for noncompliance in two-treatment arms trials by developing model selection for covariates predicting compliance to treatment in each arm. We apply the method to analyse data from the Esprit study, which was conducted to ascertain whether unopposed oestrogen (hormone replacement therapy) reduced the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction. We adjust for noncompliance in both treatment arms under a Bayesian framework to produce causal risk ratio estimates for each principal stratum. For mild values of a sensitivity parameter and using separate predictors of compliance in each arm, principal stratification results suggested that compliance with hormone replacement therapy only would reduce the risk for death and myocardial reinfarction by about 47% and 25%, respectively, whereas compliance with either treatment would reduce the risk for death by 13% and reinfarction by 60% among the most compliant. However, the results were sensitive to the user-defined sensitivity parameter.

OBJECTIVES:To assess the impact of the blood pressure (BP) profile on cardiovascular risk in the Medical Research Council (UK) elderly trial; investigate whether the effects of hypertensive drugs in reducing event rates are solely a product of systolic pressure reduction.METHODS:Using longitudinal BP data from 4396 hypertensive patients, the general trend over time was estimated using a first-stage multilevel model. We then investigated how BP acted alongside other BP-related covariates in a second-stage 'time-to-event' statistical model, assessing risk for stroke events and coronary heart disease (CHD). Differences in outcome prediction between diuretic, ?-blocker and placebo treatment arms were investigated.RESULTS:The ?-blocker arm experienced comparatively poor control of current SBP, episodic peaks and variability in BP levels. After adjusting for the mean level, variability in SBP over time was significant: risk ratio was 1.15 [95% confidence interval (CI): 1.01-1.31] across all patients for stroke events. The risk ratio for current SBP was 1.36 (95% CI: 1.16-1.58). Current DBP and variability in DBP also predicted stroke independently: risk ratios was 1.43 and 1.18, respectively. The risk factors exhibited weaker associations with CHD risk; only the highest measured value and variability in SBP showed a statistically significant association: risk ratios were 1.26 and 1.16, respectively.CONCLUSION:Individual risk characterization could be augmented with additional prognostic information, besides current SBP, including current diastolic pressure, temporal variability over and above general trends and historical measurements.

Background & Aims Irritable bowel syndrome (IBS) is the most commonly diagnosed gastrointestinal condition and is most prevalent in women of reproductive age. We investigated the effects of IBS on risk for adverse outcomes from pregnancy. Methods We conducted a cohort study by using the United Kingdom General Practice Research Database. The study cohort consisted of 100,000 women selected by stratified random sampling from all women with a diagnosis of pregnancy from January 1, 1990, to December 31, 2008. Those with a recorded diagnosis of IBS before pregnancy were identified (n = 26,543). Outcome measures were spontaneous miscarriage, ectopic pregnancy, preeclampsia, and stillbirth. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between IBS and pregnancy outcomes were estimated by using logistic regression adjusted for several potential confounders. Results Of women diagnosed with IBS before pregnancy, 6578 (7%) had a spontaneous miscarriage, 741 (0.74%) had an ectopic pregnancy, 425 (0.43%) developed preeclampsia, and 217 (0.22%) had a stillbirth. Maternal IBS was associated with a moderately increased risk of miscarriage (OR, 1.21; 95% CI, 1.13–1.30) and ectopic pregnancy (OR, 1.28%; 95% CI, 1.06–1.55). There did not appear to be an association between IBS and preeclampsia (OR, 1.09; 95% CI, 0.85–1.39) or stillbirth (OR, 1.00; 95% CI, 0.69–1.44). Conclusions IBS, a common disorder in women of reproductive age, appears to increase the risk of miscarriage and ectopic pregnancy. These findings indicate the importance of prenatal care for women with IBS.

It is known that measurement error leads to bias in assessing exposure effects, which can however, be corrected if independent replicates are available. For expensive replicates, two-stage (2S) studies that produce data ‘missing by design’, may be preferred over a single-stage (1S) study, because in the second stage, measurement of replicates is restricted to a sample of first-stage subjects. Motivated by an occupational study on the acute effect of carbon black exposure on respiratory morbidity, we compare the performance of several bias-correction methods for both designs in a simulation study: an instrumental variable method (EVROS IV) based on grouping strategies, which had been recommended especially when measurement error is large, the regression calibration and the simulation extrapolation methods. For the 2S design, either the problem of ‘missing’ data was ignored or the ‘missing’ data were imputed using multiple imputations. Both in 1S and 2S designs, in the case of small or moderate measurement error, regression calibration was shown to be the preferred approach in terms of root mean square error. For 2S designs, regression calibration as implemented by Stata software is not recommended in contrast to our implementation of this method; the ‘problematic’ implementation of regression calibration although substantially improved with use of multiple imputations. The EVROS IV method, under a good/fairly good grouping, outperforms the regression calibration approach in both design scenarios when exposure mismeasurement is severe. Both in 1S and 2S designs with moderate or large measurement error, simulation extrapolation severely failed to correct for bias. Copyright © 2012 John Wiley & Sons, Ltd.

Objective Knowledge on the time-course (trends) of work-related asthma (WRA) remains sparse. The aim of this study was to describe WRA trends in terms of industrial activities and the main causal agents in France over the period 2001–2009. Method Data were collected from the French national network of occupational health surveillance and prevention ( Reseau National de Vigilance et de Prevention des Pathologies Professionnelles (RNV3P)). Several statistical models (non-parametric test, zero-inflated negative binomial, logistic regression and time-series models) were used and compared with assess trends. Results Over the study period, 2914 WRA cases were included in the network. A significant decrease was observed overall and for some agents such as isocyanates (p=0.007), aldehydes (p=0.01) and latex (p=0.01). Conversely, a significant increase was observed for cases related to exposure to quaternary ammonium compounds (p=0.003). The health and social sector demonstrated both a growing number of cases related to the use of quaternary ammonium compounds and a decrease of cases related to aldehyde and latex exposure. Conclusions WRA declined in France over the study period. The only significant increase concerned WRA related to exposure to quaternary ammonium compounds. Zero-inflated negative binomial and logistic regression models appear to describe adequately these data.

BACKGROUND: Issues surrounding sickness absence are of interest due to growing awareness of the costs to employers and the UK economy, a greater understanding of the interaction between health and work, and increasing evidence that work is beneficial to physical and mental well-being. The Health & Occupation Reporting network in General Practice (THOR-GP) is a national source of information on work-related sickness absence. AIMS: To assess the factors influencing work-related sickness absence in the UK. METHODS: General practitioners (GPs) report cases of work-related ill-health via an online web form. Sickness absence information reported with each case was compared by demographic information, diagnosis/symptom and employment factors. RESULTS: Between 2006 and 2009, THOR-GP received 5683 case reports of work-related ill-health; 53% were musculoskeletal diagnoses and 31% were mental ill-health diagnoses. Over half (56%) of cases reported had associated sickness absence. Diagnosis had a highly significant influence on the occurrence of any associated sickness absence. Eighty-one per cent of mental ill-health cases were reported to result in sickness absence compared to 50% of musculoskeletal cases. Public sector employees incurred sickness absence more frequently than those from the private sector. Industries with the highest mental ill-health incidence rates had sickness absence episodes most frequently. Within employment groups, levels of sickness absence were inversely proportional to the level of self-employment. CONCLUSIONS: These data reported by GPs with vocational training in occupational medicine may help to inform policy decisions targeting work-related exposures and the management of sickness absence, thereby reducing the UK burden of work-related sickness absence.

Noncompliance often complicates estimation of treatment efficacy from randomized trials. Under random noncompliance, per protocol analyses or even simple regression adjustments for noncompliance, could be adequate for causal inference, but special methods are needed when noncompliance is related to risk. For survival data, Robins and Tsiatis introduced the semi-parametric structural Causal Accelerated Life Model (CALM) which allows time-dependent departures from randomized treatment in either arm and relates each observed event time to a potential event time that would have been observed if the control treatment had been given throughout the trial. Alternatively, Loeys and Goetghebeur developed a structural Proportional Hazards (C-Prophet) model for when there is all-or-nothing noncompliance in the treatment arm only. Whitebiet al. proposed a 'complier average causal effect' method for Proportional Hazards estimation which allows time-dependent departures from randomized treatment in the active arm. A time-invariant version of this estimator (CHARM) consists of a simple adjustment to the Intention-to-Treat hazard ratio estimate. We used simulation studies mimicking a randomized controlled trial of active treatment versus control with censored time-to-event data, and under both random and non-random time-dependent noncompliance, to evaluate performance of these methods in terms of 95 per cent confidence interval coverage, bias and root mean square errors (RMSE). All methods performed well in terms of bias, even the C-Prophet used after treating time-varying compliance as all-or-nothing. Coverage of the latter method, as implemented in Stata, was too low. The CALM method performed best in terms of bias and coverage but had the largest RMSE.

There is conflicting evidence regarding the effect of coeliac disease (CD) in the father on birthweight and preterm birth. We investigated the association between paternal CD and birthweight and preterm birth. Medical records of all singleton live-born children in Denmark between 1 January 1979 and 31 December 2004 were linked to information about parents' diseases. Fathers who were diagnosed with CD were then identified. Fathers with CD were considered treated if they were diagnosed before pregnancy and untreated if they were diagnosed after the date of conception. The outcome measures were: birthweight, small-for-gestational age (birthweight

This is the final paper in a four-part series which addresses the methodology of research studies under ethical review. The focus is on study conduct, governance and peer review. The nature and adequacy of peer review as a mechanism for assessing the study design and analysis are discussed. The paper argues that a properly constituted and functioning research team is crucial to the ethical conduct of a study and that an ethical review of methodology should extend beyond study design and analysis to a concern with data collection, storage and availability, and publication. While ethical review committees cannot monitor study conduct, they can ensure that the protocol pays sufficient attention to appropriate monitoring structures and personnel.

Objectives To assess diagnostic agreement for occupational asthma, and to identify case and rater characteristics associated with this diagnosis. Methods Summaries of possible occupational asthma cases were sent to 104 occupational and respiratory physicians. Raters assigned likelihood scores (0–100%) of occupational asthma based on case histories (phase 1), and on histories plus investigative procedures (phase 2). Interclass correlation coefficients were calculated as statistical measures of reliability for occupational asthma scores. Comparisons between mean scores were assessed for statistical significance using tests based on multilevel models. RRs were calculated to summarise effects of raters9 demographics, and of supplying investigative procedures information. Results Occupational asthma scores showed limited agreement within each group of (occupational or respiratory) physicians, but scores were not systematically different. The difference between mean overall scores was 2.1% (52.1% occupational physicians; 50.0% respiratory physicians) in phase 1 (95% CI −2.6 to 6.8, p=0.37). In phase 2, mean overall scores were 46.1% (occupational physicians) and 41.5% (respiratory physicians); the difference in mean overall scores was 4.6% (95% CI −3.5 to 12.5, p=0.27). Raters with General Medical Council registration ≥1986 were more likely to give a positive occupational asthma diagnosis. In phase 2, male raters were more likely to label cases as occupational asthma than female raters (RR 4.5, 95% CI 3.3 to 6.0). Conclusions The RR of a positive occupational asthma diagnosis was unaffected by clinical speciality. Further work on why physicians consider cases to be occupational asthma will assist better diagnosis and prevention of this disease.

OBJECTIVES: To investigate whether deprivation index modifies the acute effect of black smoke on cardiorespiratory mortality. METHODS: Generalised linear Poisson regression models were used to investigate whether deprivation index (as measured by the Carstairs deprivation index) modified the acute effect of black smoke on mortality in two largest Scottish cities (Glasgow and Edinburgh) between January 1981 and December 2001. Lag periods of up to 1 month were assumed for the effects of black smoke. RESULTS: Deprivation index significantly modified the effect of black smoke on mortality, with black smoke effects generally increasing as level of deprivation increased. The interaction coefficient from a parametric model assuming a linear interaction between black smoke (microg/m(-3)) and deprivation in their effect on mortality--equivalent to a test of 'linear trend' across Carstairs categories--was significant for all mortality outcomes. In a model where black smoke effects were estimated independently for each deprivation category, the estimated increase in respiratory mortality over the ensuing 1-month period associated with a 10 microg/m(3) increase in the mean black smoke concentration was 8.0% (95% CI 5.1 to 10.9) for subjects residing in the 'most' deprived category (Carstairs category 7) compared to 3.7% (95% CI -0.7 to 8.4) for subjects residing in the 'least' deprived category (Carstairs category 1). CONCLUSIONS: The results suggest a stronger effect of black smoke on mortality among people living in more deprived areas. The effect was greatest for respiratory mortality, although significant trends were also seen for other groups. If corroborated, these findings could have important public health implications.

This is the third of four papers to be published in Research Ethics Review in 2009, that address methodological issues of relevance to research ethics committees. It focuses on three issues: the representativeness of study participants, the size of the study and data analysis. Differences between best practices in qualitative and quantitative research are highlighted. The paper argues that, while lack of representativeness may not be unethical, the ethical implications of unnecessary restrictions on eligibility should be considered by committees. Studies that are either too small or too big can pose problems. Research teams need to have the necessary competence to enable an appropriate analysis focused on the main objectives and interpreted in the context of the limitations of the study design.

BACKGROUND: There is concern about the frequency of work-related mental ill-health and 'stress' within the UK. AIMS: To provide a measure of the incidence of work-related mental ill-health reported by specialist psychiatrists and occupational physicians to UK voluntary reporting schemes during the period 2002-05. Additionally, an investigation of determinants, notably factors identified by reporters as precipitants in cases of work-related mental ill-health was undertaken. METHODS: The study used data collected by The Health and Occupation Reporting Network (THOR) from 2002 to 2005. Cases were analysed by age, gender, industry and precipitating event. RESULTS: Estimated annual average incidence rates and 95% confidence intervals of work-related mental ill-health diagnoses reported to THOR between 2002 and 2005 by psychiatrists were 89 (78, 101) per million and by occupational physicians were 1589 (1443, 1735) per million. For both groups of reporters, anxiety and depression continued to make up the largest proportion of diagnoses. The majority of cases were attributed to factors such as workload and difficulties with other workers. There was some suggestion that the type of factors associated with the mental ill-health case reports varied between industrial sectors. CONCLUSIONS: Work-related anxiety and depression and stress continue to constitute a significant proportion of all work-related mental ill-health diagnoses in the UK, with workload and interpersonal relationships reported as significant risk factors. Further investigations may determine whether guidance for employers and employees on work-related mental ill-health would benefit from being more industry specific.

We consider the behaviour of three approaches to efficacy estimation--using so-called 'as treated' (AT), 'per protocol' (PP) and 'instrumental variable' (IV) analyses--and of the Intention to Treat estimator, in a two-arm randomized treatment trial with a Normally distributed outcome when there is treatment effect heterogeneity and non-random compliance with assigned treatment. Formulae are derived for the bias of estimators when used either to estimate average treatment effect (ACE) or to estimate complier average treatment effect (CACE) under several models for the relationship between compliance and potential outcomes. These enable the expected values of AT, PP and IV estimators to be ranked in relation to ACE, and show that AT and PP estimators are generally biased for both ACE and CACE even under homogeneity. However, we show that the difference between any pair of (AT, PP, IV) estimates can be used to estimate the correlation between the latent variable determining compliance behaviour and one potential outcome. In the absence of measures that predict compliance, bounds for ACE can only be set given strong assumptions. Regarding the Intention to Treat estimator, while this is 'biased towards the null' if viewed as a measure of CACE, we show that it is not always so in relation to ACE. Finally we discuss the behaviour of the estimators under weak and strong null hypotheses.

This is the second of four papers to be published in Research Ethics Review in 2009 that address methodological issues of relevance to research ethics committees. It focuses on three issues: the appropriateness of the research question, the different types of study design available, including both qualitative and quantitative, and the need for, and choice of, a control group. The paper argues that these issues are key to ethical consideration since inappropriate design may not be salvageable and can lead to unusable data, in which case the risks and burdens to participants would be unjustified.

Objectives: The ability to measure temporal trends in disease incidence is important, but valid methods are needed. This study investigates UK trends during 1996–2005 in work-related skin and respiratory diseases including non-malignant pleural disease, asthma, mesothelioma and pneumoconiosis and the potential for bias when using surveillance systems for this purpose. Methods: The volunteer reporters in three surveillance schemes were specialist physicians for skin diseases, specialist physicians for respiratory diseases and occupational physicians, respectively, who provided monthly reports of new cases of disease which they considered work related. Poisson regression models were used to investigate variation by calendar year (trend), season and reporter characteristics. Separately, temporal patterns in the probabilities of non-response and zero reports were investigated. Annual changes in disease incidences were compared between reporter groups. Results: There was little evidence of change in incidences of non-malignant pleural disease, mesothelioma, skin neoplasia and urticaria, but falls were seen for contact dermatitis and pneumoconiosis. Although the directions of change were similar across reporter groups, the magnitude of annual change in incidence was often inconsistent: for occupational asthma, it was −1.9% (95% CI −5.2 to 1.4) and −12.1% (95% CI−19.5 to −4.1) using respiratory and occupational physician reports, respectively. Response rates were high (∼85%), but non-response increased slightly with membership time, as did the probability of a zero return in some groups. Adjustment of results for presumed reporting fatigue led to an upward correction in some calendar trends. Conclusions: As some estimated changes in incidence based on volunteer reporting may be biased by reporting fatigue, apparent downward trends need to be interpreted cautiously. Differences in the population bases of the surveillance schemes and UK health service capacity constraints may also explain the differences in trends found here.

Objective: To investigate the relation between shift work and death from ischaemic heart disease (IHD) and evidence for confounding by social class and healthy shift worker effects. Methods: A case-referent study nested within an industrial cohort was used. Cases (n = 635) were cohort members who died of ischaemic heart disease (ICD 410–414) during 1950–98 aged 75 or under. Referents were matched on age and year of starting work at the site and were alive at time of case’s death. Shift work status was determined from historical personnel records and pre-employment weight, height, blood pressure and smoking from medical records. Social class at first employment was inferred from job titles. To overcome potential bias due to a healthy shift worker hire effect, odds ratios were calculated from survivors 10 years after hire. To control for any healthy shift worker survivor effect, they were adjusted for duration of employment and time since termination of employment. Conditional logistic regression analysis was used to estimate ORs. Results: 55% of subjects had worked as shift workers. Shift workers were more likely than day workers to belong to social class IV or V. The OR for shift workers compared with day workers, after adjustment for pre-employment risk factors, duration of employment and restricted to those who survived 10 years after hire was 1.11 (90% CI 0.90 to 1.37). This reduced to 1.04 (90% CI 0.83 to 1.30) after inclusion of social class. No dose-response relation was found. Conclusion: No excess risk of death from IHD for shift workers was found. The potential for confounding by social class in this relatively homogeneous cohort underlines the need to consider such confounding in more heterogeneous populations.

Objectives: To determine whether the effect of black smoke on cardiorespiratory mortality is modified by cold temperatures. Methods: Poisson regression models were used to investigate the relationship between lagged black smoke concentration and daily mortality, and whether the effect of black smoke on mortality was modified by cold temperature, for the three largest Scottish cities (Glasgow, Edinburgh and Aberdeen) over the period January 1981 to December 2001. Main results: For all cause, respiratory and non-cardiorespiratory mortality, there was evidence of a significant association between mortality and lagged black smoke concentration (up to approximately 2 to 4 weeks). Generally the maximum black smoke effect occurred at lag 0, although these estimates were not statistically significant. A significant association between cardiovascular mortality and black smoke was not observed. A 10 µgm-3 increase in the daily mean black smoke concentration on any given day was associated with a 1.68 percent (95% CI: 0.72, 2.65) increase in all cause mortality and a 0.43 percent (95% CI: -0.97, 1.86), 5.36 percent (95% CI: 2.93, 7.84) and 2.13 percent (95% CI: 0.82, 3.47) increase in cardiovascular, respiratory and non-cardiorespiratory mortality, respectively, over the ensuing 30-day period. There was no evidence that the effect of black smoke on mortality varied significantly between seasons (cool and warm periods). There was a suggestion of a modest interaction between black smoke and temperature in their effect on respiratory mortality, with the results indicating that this interaction is confined to the lowest temperature range. For all cause, cardiovascular and non-cardiorespiratory mortality the inclusion of interaction terms did not improve the models, although for all cause, and non-cardiorespiratory mortality there was a suggestion for interaction between temperature and recent black smoke exposure. Conclusions: The results of this study have suggested modest evidence of a greater effect of black smoke on mortality at low temperatures. Since extremes of cold and particulate pollution may coexist, for example during temperature inversion episodes, the results of this study may have important public health implications.

To investigate the relation between male infertility and occupational exposures, particularly glycol ethers.A case-referent study was designed in which men attending 14 fertility clinics in 11 centres across the UK in 1999-2002 were recruited following 12 months of unprotected intercourse and without a previous semen analysis. Cases were those with low motile sperm concentration (MSC) relative to the time since their last ejaculation (MSC12 x 10(6) for 3 days of abstinence). Referents were other men attending these clinics and meeting the inclusion criteria. A single semen sample was collected at the clinic and analysed at the andrology laboratory serving each hospital. Concentration was determined manually with motility assessed centrally from video recordings. Exposures and confounding factors were assessed from self-completed and nurse-interviewer questionnaires, completed prior to the results of the semen analysis. The occupational histories were assessed for exposures relative to UK norms by a team of occupational hygienists blind to case status.Of 2118 men in employment at the time of the interview, 874 (41.3%) were cases. Work with organic solvents, particularly glycol ethers, in the 3 months before the first clinic visit was associated with the likelihood of low motile sperm count. Unadjusted odds ratios (OR) for moderate and high glycol ether exposure (compared with none) were 1.70 (95% CI: 1.11 to 2.61) and 2.54 (95% CI: 1.24 to 5.21). Adjustment for potential confounders (surgery to the testes, previous conception, wearing boxer shorts, drinking alcohol, employed in manual work) reduced the risk associated with glycol ether exposure: moderate OR = 1.46 (95% CI: 0.93 to 2.28), high OR = 2.25 (95% CI: 1.08 to 4.69). No other occupational risk factor was identified.Glycol ether exposure was related to low motile sperm count in men attending fertility clinics. This suggests that, at the time of the study, glycol ethers continued to be a hazard for male fertility.

BACKGROUND: Estimated incidence rates for occupational skin disease in the U.K. are provided by voluntary surveillance schemes involving dermatologists and occupational physicians. These rates allow monitoring of occupational dermatoses, and intervention planning aimed at reducing workplace risks. OBJECTIVES: To summarize occupational skin disease reported to The Health and Occupation Reporting (THOR) network (2002-2005), and to provide baseline information for comparison with future studies of occupational skin disease in the U.K. and beyond. METHODS: Incidence rates for occupational dermatoses were calculated using THOR data as numerators, and Labour Force Survey data or information from the most recent U.K. survey on provision of occupational physician services as denominators. RESULTS: In the U.K. (2002-2005) the average annual incidence rate of work-related skin disease reported to THOR by dermatologists was 91.3 [95% confidence interval (CI) 81.8-101.1] per million, and by occupational physicians was 316.6 (95% CI 251.8-381.3) per million. Most reports were of contact dermatitis: dermatologists 68.0 (95% CI 59.8-76.2) per million, occupational physicians 259.7 (95% CI 200.8-318.6) per million. CONCLUSIONS: Information produced by THOR is an important source for calculating incidence rates of occupational skin disease. A range of reporting groups should also be used when building an overall picture of occupational skin disease incidence in the U.K.

Aims: To investigate the validity of measures of noise exposure derived retrospectively for a cohort of nuclear energy workers for the period 1950–98, by investigating their ability to predict hearing loss. Methods: Subjects were men aged 45–65 chosen from a larger group of employees—assembled for a nested case-control study of noise and death from ischaemic heart disease—who had had at least one audiogram after at least five years’ work. Average hearing loss, across both ears and the frequencies 0.5, 1, 2, and 4 kHz, was calculated from the last audiogram for each man. Previous noise exposure at work was assessed retrospectively by three hygienists using work histories, noise survey records from 1965–98, and judgement about use of hearing protection devices. Smoking and age at the time of the audiogram were extracted from records. Differences in hearing loss between men categorised by cumulative noise exposure were assessed after controlling for age, smoking, year of test, and previous test experience. Results: There were 186 and 150 eligible subjects at sites A and B of the company respectively who were employed for an average of 20 years. Compared to men with less than one year’s exposure to levels of 85dB(A) or greater, hearing loss was greater by 3.7 dB (90% CI −2.6 to 10.1), 3.8 dB (90% CI −2.6 to 10.3), 7.0 dB (90% CI 1.1 to 12.9) and 10.1 dB (90% CI 4.2 to 16.0) in the lowest to highest categories of cumulative noise exposure at site B. In contrast, at site A, the corresponding figures were −2.2 dB, −2.4 dB, −1.8 dB, and −4.4 dB, with no confidence interval excluding zero. Conclusions: Noise estimation at one site was shown to have predictive validity in terms of hearing loss, but not at the other site. Reasons for the differences between sites are discussed.

Although incidence data for work-related ill-health in the UK are available, more detailed information for smaller geographical areas has hitherto been unpublished.To estimate the incidence of work-related ill-health reported by clinical specialists in Scotland, 2002-2003.THOR (The Health and Occupation Reporting network) is a UK wide reporting scheme for work-related ill-health. In 2002-2003, 241 out of 2162 physicians in THOR were based in Scotland. We have summarized the reported cases and calculated incidence rates for categories of ill-health by age, gender and industry. The UK Labour Force Survey (2002) was used to provide denominator data, with comparisons made between rates for Scotland and the rest of the UK.In 2002-2003, 4043 estimated cases were reported from Scotland. Mental ill-health was most frequently reported (41%); followed by musculoskeletal disorders (31%), skin disorders (16%), respiratory disease (10%), hearing disorders (2%) and infection (1%). The reported average annual incidence rate per 100,000 employees for all work-related ill-health in Scotland was 86.0. The highest reported rate for mental ill-health was found for employees in public administration and defence (76.7 per 100,000), and health and social work (72.3 per 100,000). The construction industry had the highest reported rate of musculoskeletal disorders (41.6 per 100,000), while hairdressers appeared at most risk of developing occupational contact dermatitis (rate=86.4 per 100,000).Despite its limitations, THOR has indicated types of work-related ill-health and related industries for targeted disease prevention in Scotland.

BACKGROUND: Older women have been observed to have more serious injury particularly fractures after slips, trips or falls at the workplace. It is unclear whether this excess reflects a greater likelihood of falling or a greater proportion presenting with fractures once the fall has occurred. METHODS: Two studies were carried out: Study A, of 130 women who fell at work and matched referents, and Study B, of 120 women who fell at work and sustained a major fracture and 314 matched referents who fell but for whom no fracture was recorded. In Study A, the workplace of the case and referent was observed, questionnaires completed and objective health measures carried out. Study B relied on information obtained from the subject by postal questionnaire. RESULTS: Women who fell were older than referents matched on workplace and occupation, but age did not continue to be a significant factor after allowing for bodyweight and use of spectacles. Fractures were more common in older women who fell, particularly post-menopausal women with low body mass. The risk of fracture increased steadily with age without an obvious discontinuity around the likely age of menopause. CONCLUSIONS: The observed excess of fractures in older women falling at work appeared to be explained by the greater risk of fracture among those who fell.

SUMMARY This paper addresses optimal design and efficiency of two-phase (2P) case–control studies in which the first phase uses an error-prone exposure measure, Z , while the second phase measures true, dichotomous exposure, X , in a subset of subjects. Optimal design of a separate second phase, to be added to a preexisting study, is also investigated. Differential misclassification is assumed throughout. Results are also applicable to 2P cohort studies with error-prone and error-free measures of disease status but error-free exposure measures. While software based on the mean score method of Reilly and Pepe (1995, Biometrika 82, 299–314) can find optimal designs given pilot data, the lack of simple formulae makes it difficult to generalize about efficiency compared to one-phase (1P) studies based on X alone. Here, formulae for the optimal ratios of cases to controls and first- to second-phase sizes, and the optimal second-phase stratified sampling fractions, given a fixed budget, are given. The maximum efficiency of 2P designs compared to a 1P design is deduced and is shown to be bounded from above by a function of the sensitivities and specificities of Z . The efficiency of ‘balanced’ separate second-phase designs (Breslow and Cain, 1988, Biometrika 75, 11–20)—in which equal numbers of subjects are chosen from each first-phase strata— compared to optimal design is deduced, enabling situations where balanced designs are nearly optimal to be identified.

Two-phase designs for estimation of prevalence, where the first-phase classification is fallible and the second is accurate but relatively expensive, are not necessarily justified on efficiency grounds. However, they might be advantageous for dual-purpose studies, for example where prevalence estimation is followed by a clinical trial or case-control study, if they can identify cases of disease for the second study in a cost-effective way. Alternatively, they may be justified on ethical grounds if they can identify more, previously undetected but treatable cases of disease, than a simple random sample design. An approach to sampling is proposed, which formally combines the goals of efficient prevalence estimation and case detection by setting different notional study costs for investigating cases and noncases. Two variants of the method are compared with an "ethical" two-phase scheme proposed by Shrout and Newman (1989, Biometrics 45, 549-555), and with the most efficient scheme for prevalence estimation alone, in terms of the standard error of the prevalence estimate, the expected number of cases, and the fraction of cases among second-phase subjects, given a fixed budget. One variant yields the highest fraction and expected number of cases but also the largest standard errors. The other yields a higher fraction than Shrout and Newman's scheme and a similar number of cases but appears to do so more efficiently.

Background Unbiased estimation of the prevalence of diseases and other conditions is important but can be expensive, especially for conditions which do not necessarily lead to contact with health services. A two-phase population survey may seem an attractive option when there is a relatively cheap, although fallible, test for disease status available: the test is used in the first phase of the survey but in the second, only a subsample are classified by the relatively expensive, gold standard. Previously the cost efficiency of such studies compared with simple, one-phase random sample designs was investigated empirically and some questions remain unclear. Methods A simple formula for the maximum reduction in cost or standard error that can be achieved by two-phase sampling compared with simple random sampling is derived mathematically. A formula for the minimum reduction is also given and the influence of prevalence on efficiency explained. Results The main result shows that the sensitivity and specificity of the first stage test set an absolute limit on the efficiency of two-phase designs; in particular, two-phase sampling can never be justified on efficiency grounds alone if the test is not accurate enough.

Confounding should always be addressed in studies concerned with causality. When present, it results in a biased estimate of the effect of exposure on disease. The bias can be negative—resulting in underestimation of the exposure effect—or positive, and can even reverse the apparent direction of effect. It is a concern no matter what the design of the study or what statistic is used to measure the effect of exposure. The potential for confounding can be reduced by good study design, but in non-randomised studies this is unlikely to resolve the problem fully. Hence statistical adjustment methods, to reduce the bias caused by measured confounders, are also frequently considered. Such adjustment presupposes that one knows which factors are confounders. However, recent literature on methods for identifying confounders suggest that these are not always obvious. Indeed, in pursuit of guidelines, authors have had to reexamine the meanings of confounding and confounders with some ambiguity and conflict emerging. This literature is reviewed and a recent modification to the traditional definition of a confounder, which emphasises causal rather than statistical relationships, is described and illustrated. Some well known problems in occupational epidemiology, arising from health related selection, are considered in the light of recent ideas. Control of confounding through study design is not addressed, nor is the article concerned with details of statistical methods for adjustment. An overview of design and analysis in relation to confounding by age may be useful additional reading.1 It is assumed that the reader has at least a basic knowledge of epidemiological methods. Unless otherwise stated, definitions and comments apply to all causal study designs including case–control studies. ### Example Consider a study of the relationship between exposure to silica dust and lung cancer where the rate of lung cancer in exposed workers is twice that in unexposed subjects, giving …

BACKGROUND: Reducing healthcare-associated infections (HCAI) has been a priority in the UK over recent decades and this has been reflected in interventions focussing on improving hygiene procedures. OBJECTIVES: to evaluate whether these interventions coincided with an increased incidence of work-related irritant contact dermatitis (ICD) attributed to hand hygiene or/and other hygiene measures in healthcare workers (HCW). METHODS: A quasi-experimental (interrupted time series) design was used to compare trends in incidence of ICD in HCW attributed to hygiene before and after interventions to reduce HCAI with trends in the same periods in control groups (ICD in other workers). Cases of ICD reported to a UK surveillance scheme from 1996 to 2012 were analysed. The time periods compared were defined objectively based on the dates of the publication of National evidence-based guidelines, the UK health act 2006 and the Cleanyourhands campaign. RESULTS: The reported incidence of ICD in HCW attributed to hygiene has increased steadily from 1996 to 2012 (annual incidence rate ratio; 95% confidence interval: hand hygiene only 1.10; 1.07 to 1.12, all hygiene 1.05; 1.03 to 1.07) whereas the incidence in other workers is declining. An increase in incidence of ICD in HCW attributed to hand hygiene was observed at the beginning of the Cleanyourhands campaign. CONCLUSIONS: The increasing incidence of ICD in HCWs combined with the popularity of interventions to reduce HCAI warrants increased effort towards identifying products and implementing practices posing the least risk of ICD. This article is protected by copyright. All rights reserved.

Working Group 2; Cost Action IS1002—Monitoring trends in Occupational Diseases and tracing new and Emerging Risks in a NETwork (MODERNET); International audience; Objectives: The European Union (EU) strategy for health and safety at work underlines the need to reduce the incidence of occupational diseases (OD), but European statistics to evaluate this common goal are scarce. We aim to estimate and compare changes in incidence over time for occupational asthma, contact dermatitis, noise-induced hearing loss (NIHL), carpal tunnel syndrome (CTS) and upper limb musculoskeletal disorders across 10 European countries.Methods: OD surveillance systems that potentially reflected nationally representative trends in incidence within Belgium, the Czech Republic, Finland, France, Italy, the Netherlands, Norway, Spain, Switzerland and the UK provided data. Case counts were analysed using a negative binomial regression model with year as the main covariate. Many systems collected data from networks of 'centres', requiring the use of a multilevel negative binomial model. Some models made allowance for changes in compensation or reporting rules.Results: Reports of contact dermatitis and asthma, conditions with shorter time between exposure to causal substances and OD, were consistently declining with only a few exceptions. For OD with physical causal exposures there was more variation between countries. Reported NIHL was increasing in Belgium, Spain, Switzerland and the Netherlands and decreasing elsewhere. Trends in CTS and upper limb musculoskeletal disorders varied widely within and between countries.Conclusions: This is the first direct comparison of trends in OD within Europe and is consistent with a positive impact of European initiatives addressing exposures relevant to asthma and contact dermatitis. Taking a more flexible approach allowed comparisons of surveillance data between and within countries without harmonisation of data collection methods.

Summary Background Results of observational studies suggest that hormone replacement therapy (HRT) could reduce the risk of coronary heart disease (CHD), but those of randomised trials do not indicate a lower risk in women who use oestrogen plus progestagen. The aim of this study was to ascertain whether or not unopposed oestrogen reduces the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction. Methods The study was a randomised, blinded, placebo controlled, secondary prevention trial of postmenopausal women, age 50–69 years (n=1017) who had survived a first myocardial infarction. Individuals were recruited from 35 hospitals in England and Wales. Women received either one tablet of oestradiol valerate (2 mg; n=513) or placebo (n=504), daily for 2 years. Primary outcomes were reinfarction or cardiac death, and all-cause mortality. Analyses were by intention-to-treat. Secondary outcomes were uterine bleeding, endometrial cancer, stroke or other embolic events, and fractures. Findings Frequency of reinfarction or cardiac death did not differ between treatment groups at 24 months (rate ratio 0·99, 95% CI 0·70–1·41, p=0·97). Similarly, the reduction in all-cause mortality between those who took oestrogen and those on placebo was not significant (0·79, 0·50–1·27, p=0·34). The relative risk of any death (0·56, 0·23–1·33) and cardiac death (0·33, 0·11–1·01) was lowest at 3 months post-recruitment. Interpretation Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a myocardial infarction.

Objective Hexavalent chromate (chromate) in cement is a well-recognised cause of allergic contact dermatitis (ACD). Consequently in January 2005, following European Union legislation (EU Directive 2003/53/EC), the use or supply of cement containing >2 ppm of chromate was prohibited in the UK (COSHH 2004). This analysis of work-related ill-health surveillance aims to evaluate the effectiveness of this legislation. Method Changes in the incidence of work-related ACD cases returned to The Health and Occupation Reporting network by dermatologists were analysed taking in to account attribution to chromate and occupation. Results There was a significant decline in the incidence of both ACD attributed to chromate (incidence rate ratio 0.48, 95% CI 0.36 to 0.64) and ACD not-attributed chromate (0.76, 95% CI 0.69 to 0.85) between the time period preceding the EU legislation (2002–2004) and the postlegislation period (2005–2009). However, the decline in ACD attributed to chromate was significantly greater (p=0.006). This decline was further increased in workers potentially exposed to cement (incidence rate ratio 0.37, p=0.001). The majority of the decline in incidence occurred during 2005. Conclusion The timing of this significant decline in the UK incidence of chromate attributed ACD, and the greater decline in workers potentially exposed to cement strongly suggests that the EU Directive2003/53/EC was successful in reducing exposure to chromate in cement in the UK.

Objective Self-reported work-related ill health (SWI) data show a high incidence of occupational ill health and a high burden of cancer attributable to occupational factors in the UK construction industry. However, there is little information on the incidence of medically reported work-related ill health (WRI) within this industry. This study aims to examine the incidence of WRI within the UK construction industry. Method Standardised incidence rate ratios (SRRs) were used to compare incidence rates of reports of medically certified work-related ill health returned to The Health and Occupation Reporting network (THOR) within the UK construction industry with all other UK industries combined. Results Male UK construction industry workers aged under 65 years had significantly raised SRRs for respiratory (3.8, 95% CI 3.5 to 4.2), skin (1.6, 1.4 to 1.8) and musculoskeletal disorders (MSD; 1.9, 1.6 to 2.2). These SRRs were further raised for those working within a construction trade. The increased SRRs for skin disease within male construction industry workers were due to contact dermatitis (1.4, 1.2 to 1.6) and neoplasia (4.2, 3.3 to 5.3). For respiratory disease, the increased SRRs were due to non-malignant pleural disease (7.1, 6.3 to 8.1), mesothelioma (7.1, 6.0 to 8.3), lung cancer (5.4, 3.2 to 8.9) and pneumoconiosis (5.5, 3.7 to 8.0), but the SRRs for asthma (0.09, 0.06 to 0.11) and mental ill health (0.3, 0.1 to 0.4) were significantly reduced. Conclusion The significantly raised SRRs for medically reported MSD and significantly reduced SRRs for mental ill health in construction workers confirm self-reported UK data. These SRRs provide a baseline of the incidence of WRI in the UK construction industry from which to monitor the effects of changes in policy or exposures.

BACKGROUND:: Accuracy of incidence estimates may be affected by biases that depend on frequency of approach to reporters and reporting window length. A time-sampling strategy enables infrequent approaches with short windows but has never been evaluated. METHODS:: A randomized crossover trial compared incidence estimates of work-related diseases using time-sampled versus continuous-time reporting. Physicians were randomly allocated either to report every month (12/12) in 2004 and for 1 randomly chosen month (1/12) in 2005, or to the reverse sequence. Numbers of new cases of work-related disease reported per reporter per month for 1/12 and 12/12 reporting periods were compared. RESULTS:: Response rates were high (87%). Withdrawal from the study was higher under 12/12 reporting. The rate ratio for 1/12 versus 12/12 reporting was 1.26 (95% confidence interval = 1.11-1.42). Rates declined gradually in the 12/12 groups over the year, consistent with reporting fatigue. CONCLUSIONS:: Increased frequency of data collection may reduce incidence estimates.

PURPOSE: To examine how hypertension interacts with other known risk factors in affecting the risk of stroke in a primary care based setting. METHODS: Cases were patients with first-ever stroke identified from the community-based stroke register in 1994–95 in northwest England. Two controls per case were randomly selected from the same primary care site and matched by age and sex. Information on predefined risk factors was extracted from medical records. RESULTS: 267 cases and 534 controls were included. Adjusted odds ratio (OR) for stroke from hypertension was 2.6 (95% confidence interval: 1.7–3.9). In hypertensives who were current smokers, risk of stroke was increased 6 fold OR = 6.1 2.7–13.7 as compared to non-smokers without hypertension. Hypertensives who had a preexisting history of myocardial infarction or obesity or diabetes had 3 fold higher risks of stroke. Subjects with hypertension and with a history of transient ischemic attack or atrial fibrillation had ⩾ 8 fold excess risk of stroke. Among them, the risk was greater in those with poorly controlled or untreated hypertension OR = 13.2 2.6–67.0 and in those with well or moderately controlled OR = 5.2 1.6–17.2 as compared to subjects without both risk factors. There appeared to be a steady increase in risk of stroke according to the number of risk factors present, particularly in hypertensive subjects. CONCLUSIONS: Stroke risks in hypertensives associated with combinations of other risk factors appeared to follow an additive model. Subjects with multiple risk factors should be targeted in order to reduce the overall risk for stroke.

This is the first of four papers to be published in Research Ethics Review in 2009 that address methodological issues of relevance to research ethics committees. These will be practical papers, intended to assist ethics committee members to determine whether a research method is both ethically justified and likely to lead to high quality research. This paper prepares the way for the series through a consideration of the relationship between research ethics and methodology.