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1.  Long working hours, socioeconomic status, and the risk of incident type 2 diabetes: a meta-analysis of published and unpublished data from 222 120 individuals 
Summary
Background
Working long hours might have adverse health effects, but whether this is true for all socioeconomic status groups is unclear. In this meta-analysis stratified by socioeconomic status, we investigated the role of long working hours as a risk factor for type 2 diabetes.
Methods
We identified four published studies through a systematic literature search of PubMed and Embase up to April 30, 2014. Study inclusion criteria were English-language publication; prospective design (cohort study); investigation of the effect of working hours or overtime work; incident diabetes as an outcome; and relative risks, odds ratios, or hazard ratios (HRs) with 95% CIs, or sufficient information to calculate these estimates. Additionally, we used unpublished individual-level data from 19 cohort studies from the Individual-Participant-Data Meta-analysis in Working-Populations Consortium and international open-access data archives. Effect estimates from published and unpublished data from 222 120 men and women from the USA, Europe, Japan, and Australia were pooled with random-effects meta-analysis.
Findings
During 1·7 million person-years at risk, 4963 individuals developed diabetes (incidence 29 per 10 000 person-years). The minimally adjusted summary risk ratio for long (≥55 h per week) compared with standard working hours (35–40 h) was 1·07 (95% CI 0·89–1·27, difference in incidence three cases per 10 000 person-years) with significant heterogeneity in study-specific estimates (I2=53%, p=0·0016). In an analysis stratified by socioeconomic status, the association between long working hours and diabetes was evident in the low socioeconomic status group (risk ratio 1·29, 95% CI 1·06–1·57, difference in incidence 13 per 10 000 person-years, I2=0%, p=0·4662), but was null in the high socioeconomic status group (1·00, 95% CI 0·80–1·25, incidence difference zero per 10 000 person-years, I2=15%, p=0·2464). The association in the low socioeconomic status group was robust to adjustment for age, sex, obesity, and physical activity, and remained after exclusion of shift workers.
Interpretation
In this meta-analysis, the link between longer working hours and type 2 diabetes was apparent only in individuals in the low socioeconomic status groups.
Funding
Medical Research Council, European Union New and Emerging Risks in Occupational Safety and Health research programme, Finnish Work Environment Fund, Swedish Research Council for Working Life and Social Research, German Social Accident Insurance, Danish National Research Centre for the Working Environment, Academy of Finland, Ministry of Social Affairs and Employment (Netherlands), Economic and Social Research Council, US National Institutes of Health, and British Heart Foundation.
doi:10.1016/S2213-8587(14)70178-0
PMCID: PMC4286814  PMID: 25262544
2.  Genome-wide association study of alcohol dependence 
Archives of general psychiatry  2009;66(7):773-784.
Context
Identification of genes contributing to alcohol dependence will improve our understanding of the mechanisms underlying this disorder.
Objective
To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and follow-up study in a population of German male inpatients with an early age at onset.
Design
The GWAS included 487 male inpatients with DSM-IV alcohol dependence with an age at onset below 28 years and 1,358 population based control individuals. The follow-up study included 1,024 male inpatients and 996 age-matched male controls. All subjects were of German descent. The GWAS tested 524,396 single nucleotide polymorphisms (SNPs). All SNPs with p<10-4 were subjected to the follow-up study. In addition, nominally significant SNPs from those genes that had also shown expression changes in rat brains after chronic alcohol consumption were selected for the follow-up step.
Results
The GWAS produced 121 SNPs with nominal p<10-4. These, together with 19 additional SNPs from homologs of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, two closely linked intergenic SNPs met genome-wide significance (rs7590720 p=9.72×10-9; rs1344694 p=1.69×10-8). They are located on chromosome 2q35, a region which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including CDH13 and ADH1C genes which have been reported to be associated with alcohol dependence.
Conclusion
This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.
doi:10.1001/archgenpsychiatry.2009.83
PMCID: PMC4229246  PMID: 19581569
3.  Associations between Aspirin and other non-steroidal anti-inflammatory drugs and aortic valve or coronary artery calcification: The Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study 
Atherosclerosis  2013;229(2):310-316.
Background
The association between non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence of valvular and arterial calcification is not well established despite known associations between these drugs and cardiovascular events.
Objective
To compare the association between the baseline use of aspirin with other NSAID class medications with the incidence and prevalence of aortic valve calcification (AVC) and coronary artery calcium (CAC).
Methods
The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6,814 participants within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling. Results were adjusted for age, sex, ethnicity, study site, anti-hypertensive medication use, education, income, health insurance status, diabetes, smoking, exercise, body mass index, blood pressure, serum lipids, inflammatory markers, fasting glucose, statin medication use, and a simple diet score. Medication use was assessed by medication inventory at baseline which includes the use of non-prescription NSAIDs. MESA collects information on both incident and prevalent calcification. The 4,814 participants of the Heinz Nixdorf Recall (HNR) Study, a German prospective cohort study with similar measures of calcification, were included in this analysis to enable replication.
Results
Mean age of the MESA participants was 62 years (51% female). After adjustment for possible confounding factors, a possible association between aspirin use and incident AVC (Relative Risk(RR): 1.60; 95%Confidence Interval (CI): 1.19–2.15) did not replicate in the HNR cohort (RR: 1.06; 95%CI: 0.87–1.28). There was no significant association between aspirin use and incident CAC in the MESA cohort (RR 1.08; 95%CI: 0.91–1.29) or in the HNR cohort (RR 1.24; 95%CI: 0.87–1.77). Non-aspirin NSAID use was not associated with either AVC or CAC in either cohort. There were no associations between regular cardiac dose aspirin and incident calcification in either cohort.
Conclusion
Baseline NSAID use, as assessed by medication inventory, appears to have no protective effect regarding the onset of calcification in either coronary arteries or aortic valves.
doi:10.1016/j.atherosclerosis.2013.05.002
PMCID: PMC3724227  PMID: 23880181
Non-steroidal anti-inflammatory drugs; aspirin; aortic valve calcification; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis; Heinz Nixdorf Recall Study
4.  Progression of coronary artery calcification seems to be inevitable, but predictable - results of the Heinz Nixdorf Recall (HNR) study† 
European Heart Journal  2014;35(42):2960-2971.
Aim
Coronary artery calcification (CAC), as a sign of atherosclerosis, can be detected and progression quantified using computed tomography (CT). We develop a tool for predicting CAC progression.
Methods and results
In 3481 participants (45–74 years, 53.1% women) CAC percentiles at baseline (CACb) and after five years (CAC5y) were evaluated, demonstrating progression along gender-specific percentiles, which showed exponentially shaped age-dependence. Using quantile regression on the log-scale (log(CACb+1)) we developed a tool to individually predict CAC5y, and compared to observed CAC5y. The difference between observed and predicted CAC5y (log-scale, mean±SD) was 0.08±1.11 and 0.06±1.29 in men and women. Agreement reached a kappa-value of 0.746 (95% confidence interval: 0.732–0.760) and concordance correlation (log-scale) of 0.886 (0.879–0.893). Explained variance of observed by predicted log(CAC5y+1) was 80.1% and 72.0% in men and women, and 81.0 and 73.6% including baseline risk factors. Evaluating the tool in 1940 individuals with CACb>0 and CACb<400 at baseline, of whom 242 (12.5%) developed CAC5y>400, yielded a sensitivity of 59.5%, specificity 96.1%, (+) and (−) predictive values of 68.3% and 94.3%. A pre-defined acceptance range around predicted CAC5y contained 68.1% of observed CAC5y; only 20% were expected by chance. Age, blood pressure, lipid-lowering medication, diabetes, and smoking contributed to progression above the acceptance range in men and, excepting age, in women.
Conclusion
CAC nearly inevitably progresses with limited influence of cardiovascular risk factors. This allowed the development of a mathematical tool for prediction of individual CAC progression, enabling anticipation of the age when CAC thresholds of high risk are reached.
doi:10.1093/eurheartj/ehu288
PMCID: PMC4223611  PMID: 25062951
Coronary artery calcification; Progression of atherosclerosis; CT; Imaging; Heinz Nixdorf Recall study; Epidemiology
5.  Exploring genetic variants predisposing to diabetes mellitus and their association with indicators of socioeconomic status 
BMC Public Health  2014;14:609.
Background
The relevance of disease-related genetic variants for the explanation of social inequalities in complex diseases is unclear and empirical analyses are largely missing. The aim of our study was to examine whether genetic variants predisposing to diabetes mellitus are associated with socioeconomic status in a population-based cohort.
Methods
We genotyped 11 selected diabetes-related single nucleotide polymorphisms in 4655 participants (age 45-75 years) of the Heinz Nixdorf Recall study. Diabetes status was self-reported or defined by blood glucose levels. Education, income and paternal occupation were assessed as indicators of socioeconomic status. Multiple regression analyses were used to examine the association of socioeconomic status and diabetes by estimating sex-specific and age-adjusted prevalence ratios and their corresponding 95%-confidence intervals. To explore the relationship between individual single nucleotide polymorphisms and socioeconomic status sex- and age-adjusted odds ratios were computed. We adjusted the alpha-level for multiple testing of 11 single nucleotide polymorphisms using Bonferroni’s method ( α BF ~ 0.005). In addition, we explored the association of a genetic risk score with socioeconomic status.
Results
Social inequalities in diabetes were observed for all indicators of socioeconomic status. However, there were no significant associations between individual diabetes-related risk alleles and socioeconomic status with odds ratios ranging from 0.87 to 1.23. Similarly, the genetic risk score analysis revealed no evidence for an association.
Conclusions
Our data provide no evidence for an association between 11 diabetes-related risk alleles and different indicators of socioeconomic status in a population-based cohort, suggesting that the explored genetic variants do not contribute to health inequalities in diabetes.
doi:10.1186/1471-2458-14-609
PMCID: PMC4071333  PMID: 24935819
Health inequalities; Diabetes mellitus; Genetics of complex diseases
6.  Comparison of Factors Associated with Carotid Intima-Media Thickness in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
Background
The measurement of carotid intima-media thickness (CIMT) is a valid method to quantify levels of atherosclerosis. The present study was conducted to compare the strengths of associations between CIMT and cardiovascular risk factors in two different populations.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) are two population-based prospective cohort studies of subclinical cardiovascular disease. All Caucasian subjects aged 45 to 75 years from these cohorts who were free of baseline cardiovascular disease (n = 2,820 in HNR, n = 2,270 in MESA) were combined. CIMT images were obtained using B-mode sonography at the right and left common carotid artery and measured 1 cm starting from the bulb.
Results
In both studies, age, male sex, and systolic blood pressure showed the strongest association (P < .0001 for each) for a higher CIMT. The mean of mean far wall CIMT was slightly higher in MESA participants (0.71 vs 0.67 mm). Almost all significant variables were consistent between the two cohorts in both magnitude of association with CIMT and statistical significance, including age, sex, smoking, diabetes, cholesterol levels, and blood pressure. For example, the association with systolic blood pressure was (ΔSD = 0.011; 95% confidence interval, 0.0009 to 0.014) per mm Hg in MESA and (ΔSD = 0.010; 95% confidence interval, 0.005 to 0.021) per mm Hg in HNR. This consistency persisted throughout the traditional (Framingham) risk factors.
Conclusions
A comparison of the associations between traditional cardiovascular risk factors and CIMT across two culturally diverse populations showed remarkable consistency.
doi:10.1016/j.echo.2013.03.011
PMCID: PMC3694173  PMID: 23611058
Carotid intima-media thickness; Subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis; MESA; Heinz Nixdorf Recall Study; HNR
7.  Study protocol for examining job strain as a risk factor for severe unipolar depression in an individual participant meta-analysis of 14 European cohorts 
F1000Research  2014;2:233.
Background: Previous studies have shown that gainfully employed individuals with high work demands and low control at work (denoted “job strain”) are at increased risk of common mental disorders, including depression. Most existing studies have, however, measured depression using self-rated symptom scales that do not necessarily correspond to clinically diagnosed depression. In addition, a meta-analysis from 2008 indicated publication bias in the field.
 
Methods: This study protocol describes the planned design and analyses of an individual participant data meta-analysis, to examine whether job strain is associated with an increased risk of clinically diagnosed unipolar depression based on hospital treatment registers.  The study will be based on data from approximately 120,000 individuals who participated in 14 studies on work environment and health in 4 European countries. The self-reported working conditions data will be merged with national registers on psychiatric hospital treatment, primarily hospital admissions. Study-specific risk estimates for the association between job strain and depression will be calculated using Cox regressions. The study-specific risk estimates will be pooled using random effects meta-analysis.
 
Discussion: The planned analyses will help clarify whether job strain is associated with an increased risk of clinically diagnosed unipolar depression. As the analysis is based on pre-planned study protocols and an individual participant data meta-analysis, the pooled risk estimates will not be influenced by selective reporting and publication bias. However, the results of the planned study may only pertain to severe cases of unipolar depression, because of the outcome measure applied.
doi:10.12688/f1000research.2-233.v2
PMCID: PMC3938244  PMID: 24627793
8.  Job Strain and the Risk of Inflammatory Bowel Diseases: Individual-Participant Meta-Analysis of 95 000 Men and Women 
PLoS ONE  2014;9(2):e88711.
Background and Aims
Many clinicians, patients and patient advocacy groups believe stress to have a causal role in inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. However, this is not corroborated by clear epidemiological research evidence. We investigated the association between work-related stress and incident Crohn's disease and ulcerative colitis using individual-level data from 95 000 European adults.
Methods
We conducted individual-participant data meta-analyses in a set of pooled data from 11 prospective European studies. All studies are a part of the IPD-Work Consortium. Work-related psychosocial stress was operationalised as job strain (a combination of high demands and low control at work) and was self-reported at baseline. Crohn's disease and ulcerative colitis were ascertained from national hospitalisation and drug reimbursement registers. The associations between job strain and inflammatory bowel disease outcomes were modelled using Cox proportional hazards regression. The study-specific results were combined in random effects meta-analyses.
Results
Of the 95 379 participants who were free of inflammatory bowel disease at baseline, 111 men and women developed Crohn's disease and 414 developed ulcerative colitis during follow-up. Job strain at baseline was not associated with incident Crohn's disease (multivariable-adjusted random effects hazard ratio: 0.83, 95% confidence interval: 0.48, 1.43) or ulcerative colitis (hazard ratio: 1.06, 95% CI: 0.76, 1.48). There was negligible heterogeneity among the study-specific associations.
Conclusions
Our findings suggest that job strain, an indicator of work-related stress, is not a major risk factor for Crohn's disease or ulcerative colitis.
doi:10.1371/journal.pone.0088711
PMCID: PMC3928274  PMID: 24558416
9.  Work stress and depressive symptoms in older employees: impact of national labour and social policies 
BMC Public Health  2013;13:1086.
Background
Maintaining health and work ability among older employees is a primary target of national labour and social policies (NLSP) in Europe. Depression makes a significant contribution to early retirement, and chronic work-related stress is associated with elevated risks of depression. We test this latter association among older employees and explore to what extent indicators of distinct NLSP modify the association between work stress and depressive symptoms. We choose six indicators, classified in three categories: (1) investment in active labour market policies, (2) employment protection, (3) level of distributive justice.
Methods
We use data from three longitudinal ageing studies (SHARE, HRS, ELSA) including 5650 men and women in 13 countries. Information on work stress (effort-reward imbalance, low work control) and depressive symptoms (CES-D, EURO-D) was obtained. Six NLSP indicators were selected from OECD databases. Associations of work stress (2004) with depressive symptoms (2006) and their modification by policy indicators were analysed using logistic multilevel models.
Results
Risk of depressive symptoms at follow-up is higher among those experiencing effort-reward imbalance (OR: 1.55 95% CI 1.27-1.89) and low control (OR: 1.46 95% CI 1.19-1.79) at work. Interaction terms indicate a modifying effect of a majority of protective NLSP indicators on the strength of associations of effort - reward imbalance with depressive symptoms.
Conclusions
Work stress is associated with elevated risk of prospective depressive symptoms among older employees from 13 European countries. Protective labour and social policies modify the strength of these associations. If further supported findings may have important policy implications.
doi:10.1186/1471-2458-13-1086
PMCID: PMC4222833  PMID: 24256638
Depressive symptoms; Labour and social policies; Work stress; Demand-control; Effort-reward imbalance; Cross-national study
10.  Study protocol for examining job strain as a risk factor for severe unipolar depression in an individual participant meta-analysis of 14 European cohorts 
F1000Research  2013;2:233.
Background: Previous studies have shown that gainfully employed individuals with high work demands and low control at work (denoted “job strain”) are at increased risk of common mental disorders, including depression. Most existing studies have, however, measured depression using self-rated symptom scales that do not necessarily correspond to clinically diagnosed depression. In addition, a meta-analysis from 2008 indicated publication bias in the field.
 
Methods: This study protocol describes the planned design and analyses of an individual participant data meta-analysis, to examine whether job strain is associated with an increased risk of clinically diagnosed unipolar depression based on hospital treatment registers.  The study will be based on data from approximately 120,000 individuals who participated in 14 studies on work environment and health in 4 European countries. The self-reported working conditions data will be merged with national registers on psychiatric hospital treatment, primarily hospital admissions. Study-specific risk estimates for the association between job strain and depression will be calculated using Cox regressions. The study-specific risk estimates will be pooled using random effects meta-analysis.
 
Discussion: The planned analyses will help clarify whether job strain is associated with an increased risk of clinically diagnosed unipolar depression. As the analysis is based on pre-planned study protocols and an individual participant data meta-analysis, the pooled risk estimates will not be influenced by selective reporting and publication bias. However, the results of the planned study may only pertain to severe cases of unipolar depression, because of the outcome measure applied.
doi:10.12688/f1000research.2-233.v1
PMCID: PMC3938244  PMID: 24627793
11.  Job Strain and Cardiovascular Disease Risk Factors: Meta-Analysis of Individual-Participant Data from 47,000 Men and Women 
PLoS ONE  2013;8(6):e67323.
Background
Job strain is associated with an increased coronary heart disease risk, but few large-scale studies have examined the relationship of this psychosocial characteristic with the biological risk factors that potentially mediate the job strain – heart disease association.
Methodology and Principal Findings
We pooled cross-sectional, individual-level data from eight studies comprising 47,045 participants to investigate the association between job strain and the following cardiovascular disease risk factors: diabetes, blood pressure, pulse pressure, lipid fractions, smoking, alcohol consumption, physical inactivity, obesity, and overall cardiovascular disease risk as indexed by the Framingham Risk Score. In age-, sex-, and socioeconomic status-adjusted analyses, compared to those without job strain, people with job strain were more likely to have diabetes (odds ratio 1.29; 95% CI: 1.11–1.51), to smoke (1.14; 1.08–1.20), to be physically inactive (1.34; 1.26–1.41), and to be obese (1.12; 1.04–1.20). The association between job strain and elevated Framingham risk score (1.13; 1.03–1.25) was attributable to the higher prevalence of diabetes, smoking and physical inactivity among those reporting job strain.
Conclusions
In this meta-analysis of work-related stress and cardiovascular disease risk factors, job strain was linked to adverse lifestyle and diabetes. No association was observed between job strain, clinic blood pressure or blood lipids.
doi:10.1371/journal.pone.0067323
PMCID: PMC3688665  PMID: 23840664
12.  Associations of job strain and lifestyle risk factors with risk of coronary artery disease: a meta-analysis of individual participant data 
Background:
It is unclear whether a healthy lifestyle mitigates the adverse effects of job strain on coronary artery disease. We examined the associations of job strain and lifestyle risk factors with the risk of coronary artery disease.
Methods:
We pooled individual-level data from 7 cohort studies comprising 102 128 men and women who were free of existing coronary artery disease at baseline (1985–2000). Questionnaires were used to measure job strain (yes v. no) and 4 lifestyle risk factors: current smoking, physical inactivity, heavy drinking and obesity. We grouped participants into 3 lifestyle categories: healthy (no lifestyle risk factors), moderately unhealthy (1 risk factor) and unhealthy (2–4 risk factors). The primary outcome was incident coronary artery disease (defined as first nonfatal myocardial infarction or cardiac-related death).
Results:
There were 1086 incident events in 743 948 person-years at risk during a mean follow-up of 7.3 years. The risk of coronary artery disease among people who had an unhealthy lifestyle compared with those who had a healthy lifestyle (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.18–2.98; population attributable risk 26.4%) was higher than the risk among participants who had job strain compared with those who had no job strain (HR 1.25, 95% CI 1.06–1.47; population attributable risk 3.8%). The 10-year incidence of coronary artery disease among participants with job strain and a healthy lifestyle (14.7 per 1000) was 53% lower than the incidence among those with job strain and an unhealthy lifestyle (31.2 per 1000).
Interpretation:
The risk of coronary artery disease was highest among participants who reported job strain and an unhealthy lifestyle; those with job strain and a healthy lifestyle had half the rate of disease. A healthy lifestyle may substantially reduce disease risk among people with job strain.
doi:10.1503/cmaj.121735
PMCID: PMC3680555  PMID: 23670152
13.  Job Strain as a Risk Factor for Leisure-Time Physical Inactivity: An Individual-Participant Meta-Analysis of Up to 170,000 Men and Women 
American Journal of Epidemiology  2012;176(12):1078-1089.
Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 1985–1988 to 2006–2008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50% women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 2–9 years. In cross-sectional analyses, the odds for physical inactivity were 26% higher (odds ratio = 1.26, 95% confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21% higher (odds ratio = 1.21, 95% confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21% and 20% higher for those with high-strain (odds ratio = 1.21, 95% confidence interval: 1.11, 1.32) and passive (odds ratio = 1.20, 95% confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.
doi:10.1093/aje/kws336
PMCID: PMC3521479  PMID: 23144364
cohort studies; exercise; physical activity; psychosocial factors; working population
14.  Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data 
Lancet  2012;380(9852):1491-1497.
Summary
Background
Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies.
Methods
We used individual records from 13 European cohort studies (1985–2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death.
Findings
30 214 (15%) of 197 473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years [SD 1·7]), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10–1·37). This effect estimate was higher in published (1·43, 1·15–1·77) than unpublished (1·16, 1·02–1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15–1·48) and 5 years (1·30, 1·13–1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%.
Interpretation
Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking.
Funding
Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.
doi:10.1016/S0140-6736(12)60994-5
PMCID: PMC3486012  PMID: 22981903
15.  Insomnia and urban neighbourhood contexts – are associations modified by individual social characteristics and change of residence? Results from a population-based study using residential histories 
BMC Public Health  2012;12:810.
Background
Until now, insomnia has not been much of interest in epidemiological neighbourhood studies, although literature provides evidence enough for insomnia-related mechanisms being potentially dependent on neighbourhood contexts. Besides, studies have shown differences in sleep along individual social characteristics that might render residents more vulnerable to neighbourhood contextual exposures. Given the role of exposure duration and changes in the relationship between neighbourhoods and health, we studied associations of neighbourhood unemployment and months under residential turnover with insomnia by covering ten years of residential history of nearly 3,000 urban residents in the Ruhr Area, Germany.
Methods
Individual data were retrieved from the Heinz Nixdorf Recall Study, a population-based study of randomly chosen participants from adjacent cities, which contains self-rated insomnia symptoms and individual social characteristics. Participants’ residential addresses were retrospectively assessed using public registries. We built individually derived exposure measures informing about mean neighbourhood unemployment rates and months under high residential turnover. These measures were major predictors in multivariate logistic regressions modelling the association between social neighbourhood characteristics and insomnia in the whole sample and subgroups defined by low income, low education, social isolation, and change of residence. Traffic-related noise, age, gender, economic activity, and education were considered as covariates.
Results
Nearly 12 per cent of the participants complained about insomnia. Associations of neighbourhood unemployment with insomnia were more consistent than those of residential turnover in the whole sample (adjusted OR 1.42, 95% CI 1.00-2.03 for neighbourhood unemployment and OR 1.33, 95% CI 0.78-2.25 for residential turnover in the highest exposure categories). In low-income and socially isolated participants, neighbourhood unemployment odds of reporting insomnia were particularly elevated (adjusted OR 2.90, 95% CI 1.39-6.02 and OR 3.32, 95% CI 1.11-9.96, respectively). Less educated participants displayed relatively high odds of reporting insomnia throughout all upper neighbourhood unemployment exposure categories. Change of residence weakened associations, whereas undisrupted exposure sharpened them by trend.
Conclusions
Our findings hint at multiple stressors being effective in both the neighbourhood context and individual resident, possibly reflecting precarious life situations undermining residents’ sleep and health chances. Moreover, our results suggest a temporal dependency in the association between neighbourhood and insomnia.
doi:10.1186/1471-2458-12-810
PMCID: PMC3503830  PMID: 22994885
Insomnia; Neighbourhood unemployment; Residential turnover; Income; Education; Social isolation; Change of residence.
16.  Depressive symptoms and psychosocial stress at work among older employees in three continents 
Background
To assess whether an association of psychosocial stress at work with depressive symptoms among older employees is evident in a set of comparable empirical studies from Europe, North America and Asia.
Methods
Cross-sectional and longitudinal multivariate regression analyses of data from 4 cohort studies with elder workers (2004 and 2006) testing associations of psychosocial stress at work (‘effort-reward imbalance’; ‘low control’) with depressive symptoms.
Results
Cross-sectional analyses from 17 countries with 14.236 participants reveal elevated odds ratios of depressive symptoms among people experiencing high work stress compared to those with low or no work stress. Adjusted odds ratios vary from 1.64 (95% CI 1.02-2.63) in Japan to 1.97 (95% CI 1.75-2.23) in Europe and 2.28 (95% CI 1.59-3.28) in the USA. Odds ratios from additional longitudinal analyses (in 13 countries) controlling for baseline depression are smaller, but remain in part significant.
Conclusion
Findings indicate that psychosocial stress at work might be a relevant risk factor for depressive symptoms among older employees across countries and continents. This observation may call for global policy efforts to improve quality of work in view of a rapidly aging workforce, in particular in times of economic globalization.
doi:10.1186/1744-8603-8-27
PMCID: PMC3503785  PMID: 22818354
Work stress; Depressive symptoms; Older employees; Globalization; Effort-reward imbalance; Job control; Surveys
17.  Job Strain and Tobacco Smoking: An Individual-Participant Data Meta-Analysis of 166 130 Adults in 15 European Studies 
PLoS ONE  2012;7(7):e35463.
Background
Tobacco smoking is a major contributor to the public health burden and healthcare costs worldwide, but the determinants of smoking behaviours are poorly understood. We conducted a large individual-participant meta-analysis to examine the extent to which work-related stress, operationalised as job strain, is associated with tobacco smoking in working adults.
Methodology and Principal Findings
We analysed cross-sectional data from 15 European studies comprising 166 130 participants. Longitudinal data from six studies were used. Job strain and smoking were self-reported. Smoking was harmonised into three categories never, ex- and current. We modelled the cross-sectional associations using logistic regression and the results pooled in random effects meta-analyses. Mixed effects logistic regression was used to examine longitudinal associations. Of the 166 130 participants, 17% reported job strain, 42% were never smokers, 33% ex-smokers and 25% current smokers. In the analyses of the cross-sectional data, current smokers had higher odds of job strain than never-smokers (age, sex and socioeconomic position-adjusted odds ratio: 1.11, 95% confidence interval: 1.03, 1.18). Current smokers with job strain smoked, on average, three cigarettes per week more than current smokers without job strain. In the analyses of longitudinal data (1 to 9 years of follow-up), there was no clear evidence for longitudinal associations between job strain and taking up or quitting smoking.
Conclusions
Our findings show that smokers are slightly more likely than non-smokers to report work-related stress. In addition, smokers who reported work stress smoked, on average, slightly more cigarettes than stress-free smokers.
doi:10.1371/journal.pone.0035463
PMCID: PMC3391192  PMID: 22792154
18.  Job Strain and Alcohol Intake: A Collaborative Meta-Analysis of Individual-Participant Data from 140 000 Men and Women 
PLoS ONE  2012;7(7):e40101.
Background
The relationship between work-related stress and alcohol intake is uncertain. In order to add to the thus far inconsistent evidence from relatively small studies, we conducted individual-participant meta-analyses of the association between work-related stress (operationalised as self-reported job strain) and alcohol intake.
Methodology and Principal Findings
We analysed cross-sectional data from 12 European studies (n = 142 140) and longitudinal data from four studies (n = 48 646). Job strain and alcohol intake were self-reported. Job strain was analysed as a binary variable (strain vs. no strain). Alcohol intake was harmonised into the following categories: none, moderate (women: 1–14, men: 1–21 drinks/week), intermediate (women: 15–20, men: 22–27 drinks/week) and heavy (women: >20, men: >27 drinks/week). Cross-sectional associations were modelled using logistic regression and the results pooled in random effects meta-analyses. Longitudinal associations were examined using mixed effects logistic and modified Poisson regression. Compared to moderate drinkers, non-drinkers and (random effects odds ratio (OR): 1.10, 95% CI: 1.05, 1.14) and heavy drinkers (OR: 1.12, 95% CI: 1.00, 1.26) had higher odds of job strain. Intermediate drinkers, on the other hand, had lower odds of job strain (OR: 0.92, 95% CI: 0.86, 0.99). We found no clear evidence for longitudinal associations between job strain and alcohol intake.
Conclusions
Our findings suggest that compared to moderate drinkers, non-drinkers and heavy drinkers are more likely and intermediate drinkers less likely to report work-related stress.
doi:10.1371/journal.pone.0040101
PMCID: PMC3391232  PMID: 22792218
19.  The mediating effect of social relationships on the association between socioeconomic status and subjective health – results from the Heinz Nixdorf Recall cohort study 
BMC Public Health  2012;12:285.
Background
Socioeconomic status (SES) is an important determinant of population health. Explanatory approaches on how SES determines health have so far included numerous factors, amongst them psychosocial factors such as social relationships. However, it is unclear whether social relationships can help explain socioeconomic differences in general subjective health. Do different aspects of social relationships contribute differently to the explanation? Based on a cohort study of middle and older aged residents (45 to 75 years) from the Ruhr Area in Germany our study tries to clarify the matter.
Methods
For the analyses data from the population-based prospective Heinz Nixdorf Recall (HNR) Study is used. As indicators of SES education, equivalent household income and occupational status were employed. Social relations were assessed by including structural as well as functional aspects. Structural aspects were estimated by the Social Integration Index (SII) and functional aspects were measured by availability of emotional and instrumental support. Data on general subjective health status was available for both baseline examination (2000–2003) and a 5-year follow-up (2006–2008). The sample consists of 4,146 men and women. Four logistic regression models were calculated: in the first model we controlled for age and subjective health at baseline, while in models 2 and 3, either functional or structural aspects of social relationships were introduced separately. Model 4 then included all variables. As former studies indicated different health effects of SES and social relations in men and women, analyses were conducted with the overall sample as well as for each gender alone.
Results
Prospective associations of SES and subjective health were reduced after introducing social relationships into the regression models. Percentage reductions between 2% and 30% were observed in the overall sample when all aspects of social relations were included. The percentage reductions were strongest in the lowest SES group. Gender specific analyses revealed mediating effects of social relationships in women and men. The magnitude of mediating effects varied depending on the indicators of SES and social relations.
Conclusions
Social relationships substantially contribute to the explanation of SES differences in subjective health. Interventions for improving social relations which especially focus on socially deprived groups are likely to help reducing socioeconomic disparities in health.
doi:10.1186/1471-2458-12-285
PMCID: PMC3408349  PMID: 22510464
20.  Long-Term Urban Particulate Air Pollution, Traffic Noise, and Arterial Blood Pressure 
Environmental Health Perspectives  2011;119(12):1706-1711.
Background: Recent studies have shown an association of short-term exposure to fine particulate matter (PM) with transient increases in blood pressure (BP), but it is unclear whether long-term exposure has an effect on arterial BP and hypertension.
Objectives: We investigated the cross-sectional association of residential long-term PM exposure with arterial BP and hypertension, taking short-term variations of PM and long-term road traffic noise exposure into account.
Methods: We used baseline data (2000–2003) on 4,291 participants, 45–75 years of age, from the Heinz Nixdorf Recall Study, a population-based prospective cohort in Germany. Urban background exposure to PM with aerodynamic diameter ≤ 2.5 μm (PM2.5) and ≤ 10 μm (PM10) was assessed with a dispersion and chemistry transport model. We used generalized additive models, adjusting for short-term PM, meteorology, traffic proximity, and individual risk factors.
Results: An interquartile increase in PM2.5 (2.4 μg/m3) was associated with estimated increases in mean systolic and diastolic BP of 1.4 mmHg [95% confidence interval (CI): 0.5, 2.3] and 0.9 mmHg (95% CI: 0.4, 1.4), respectively. The observed relationship was independent of long-term exposure to road traffic noise and robust to the inclusion of many potential confounders. Residential proximity to high traffic and traffic noise exposure showed a tendency toward higher BP and an elevated prevalence of hypertension.
Conclusions: We found an association of long-term exposure to PM with increased arterial BP in a population-based sample. This finding supports our hypothesis that long-term PM exposure may promote atherosclerosis, with air-pollution–induced increases in BP being one possible biological pathway.
doi:10.1289/ehp.1103564
PMCID: PMC3261981  PMID: 21827977
atherosclerosis; environmental epidemiology; hypertension; particulate matter; traffic emissions
21.  Secondhand Smoke Exposure and Coronary Artery Calcification among Nonsmoking Participants of a Population-Based Cohort 
Environmental Health Perspectives  2011;119(11):1556-1561.
Background: Secondhand smoke (SHS) consists of fine particulate matter, carcinogens, and various toxins that affect large parts of the population. SHS increases the risk for acute cardiovascular events and may contribute to the development of atherosclerosis.
Objectives: We investigated the association of SHS with coronary artery calcification (CAC).
Methods: In this cross-sectional analysis, we used baseline data (2000–2003) from 1,766 never-smokers without clinically manifested coronary heart disease, 45–75 years of age, from the Heinz Nixdorf Recall Study, an ongoing, prospective, population-based cohort study in Germany. Self-reported frequent SHS at home, at work, and in other places was assessed by questionnaire. CAC scores were derived based on electron-beam computed tomography. We conducted multiple linear regression analysis using exposure to SHS as the explanatory variable and ln(CAC+1) as the response variable. We conducted logistic regression to estimate the odds ratio (OR) for presence of any CAC.
Results: Frequent exposure to SHS was reported by 21.5% of participants. After adjustment for age, sex, and socioeconomic status, CAC + 1 was 21.1% [95% confidence interval (CI): –5.5%, 55.2%] higher in exposed than in unexposed participants. After adjusting for other cardiovascular risk factors, the association was attenuated (15.4%; 95% CI: –9.6%, 47.2%). SHS exposure was also associated with a CAC score > 0 (fully adjusted OR = 1.38; 95% CI: 1.03, 1.84).
Conclusions: Self-reported frequent exposure to SHS was associated with subclinical coronary atherosclerosis in our cross-sectional study population. Considering the widespread exposure and the clinical relevance of coronary atherosclerosis, this result, if confirmed, is of public health importance.
doi:10.1289/ehp.1003347
PMCID: PMC3226494  PMID: 21742575
cardiovascular atherosclerosis; comparative risk assessment; environmental epidemiology; population health; secondhand smoke
22.  Does socioeconomic status affect the association of social relationships and health? A moderator analysis 
Background
Social relations have repeatedly been found to be an important determinant of health. However, it is unclear whether the association between social relations and health is consistent throughout different status groups. It is likely that health effects of social relations vary in different status groups, as stated in the hypothesis of differential vulnerability. In this analysis we explore whether socioeconomic status (SES) moderates the association between social relations and health.
Methods
In the baseline examination of the Heinz Nixdorf Recall study, conducted in a dense populated Western German region (N = 4,814, response rate 56%), SES was measured by income and education. Social relations were classified by using both structural as well as functional measures. The Social Integration Index was used as a structural measure, whilst functional aspects were assessed by emotional and instrumental support. Health was indicated by self-rated health (1 item) and a short version of the CES-D scale measuring the frequency of depressive symptoms. Based on logistic regression models we calculated the relative excess risk due to interaction (RERI) which indicates existing moderator effects.
Results
Our findings show highest odds ratios (ORs) for both poor self-rated health and more frequent depressive symptoms when respondents have a low SES as well as inappropriate social relations. For example, respondents with low income and a low level of social integration have an OR for a high depression score of 2.85 (95% CI 2.32-4.49), compared to an OR of 1.44 (95% CI 1.12-1.86) amongst those with a low income but a high level of social integration and an OR of 1.72 (95% CI 1.45-2.03) amongst respondents with high income but a low level of social integration. As reference group those reporting high income and a high level of social integration were used.
Conclusions
The analyses indicate that the association of social relations and subjective health differs across SES groups as we find moderating effects of SES. However, results are inconsistent as nearly all RERI scores are positive but do not reach a significant level. Also moderating effects vary between women and men and depending on the indicators of SES and social relations used. Thus, the hypothesis of differential vulnerability can only partially be supported. In terms of practical implications, psychosocial and health interventions aiming towards the enhancement of social relations should especially consider the situation of the socially deprived.
doi:10.1186/1475-9276-10-43
PMCID: PMC3216239  PMID: 21995609
23.  Chronic Residential Exposure to Particulate Matter Air Pollution and Systemic Inflammatory Markers 
Environmental Health Perspectives  2009;117(8):1302-1308.
Background
Long-term exposure to urban air pollution may accelerate atherogenesis, but mechanisms are still unclear. The induction of a low-grade systemic inflammatory state is a plausible mechanistic pathway. Objectives: We analyzed the association of residential long-term exposure to particulate matter (PM) and high traffic with systemic inflammatory markers.
Methods
We used baseline data from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study of 4,814 participants that started in 2000. Fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposure based on a small-scale dispersion and chemistry transport model was assigned to each home address. We calculated distances between residences and major roads. Long-term exposure to air pollution (annual PM2.5 and distance to high traffic) and concentration of inflammatory markers [high-sensitivity C-reactive protein (hs-CRP) and fibrinogen] on the day of the baseline visit were analyzed with sex-stratified multiple linear regression, controlling for individual-level risk factors.
Results
In the adjusted analysis, a cross-sectional exposure difference of 3.91 μg/m3 in PM2.5 (interdecile range) was associated with increases in hs-CRP of 23.9% [95% confidence interval (CI), 4.1 to 47.4%] and fibrinogen of 3.9% (95% CI, 0.3 to 7.7%) in men, whereas we found no association in women. Chronic traffic exposure was not associated with inflammatory markers. Short-term exposures to air pollutants and temperature did not influence the results markedly.
Conclusions
Our study indicates that long-term residential exposure to high levels of PM2.5 is associated with systemic inflammatory markers in men. This might provide a link between air pollution and coronary atherosclerosis.
doi:10.1289/ehp.0800362
PMCID: PMC2721876  PMID: 19672412
air quality; cardiovascular disease; epidemiology; inflammation; roadway proximity
24.  Hip fractures and area level socioeconomic conditions: a population-based study 
BMC Public Health  2009;9:114.
Background
Only a limited number of studies have analyzed the association between hip fracture incidence and socioeconomic conditions. Most, but not all found an association, and results are in part conflicting. The aim of our study was to evaluate the association between hip fractures and socioeconomic conditions in Germany, from 1995 to 2004, on a census tract area level.
Methods
We used data from the national hospital discharge diagnosis register and data on socioeconomic and demographic characteristics of 131 census tracts from official statistics. Associations between the hip fracture incidence and socioeconomic conditions were analyzed by multiple Poisson regression models, taking overdispersion into account.
Results
The risk of hip fracture decreased by 4% with a 7% increase (about one interquartile range) of non-German nationals. It decreased by 10% with a 6% increased rate of unemployment, increased by 7% with a 2% increase of the proportion of welfare recipients, and also increased by 3% with an increase of the proportion of single parent families of 1.9%.
Conclusion
Our results showed weak associations between indicators of socioeconomic conditions at area level and hip fracture risk; the varied by type of indicator. We conclude that hip fracture incidence might be influenced by the socioeconomic context of a region, but further analysis using more specific markers for deprivation on a smaller scale and individual-level data are needed.
doi:10.1186/1471-2458-9-114
PMCID: PMC2685377  PMID: 19397798
25.  Signs of subclinical coronary atherosclerosis in relation to risk factor distribution in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
European Heart Journal  2008;29(22):2782-2791.
Aims
Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR).
Methods and results
The measured CAC in 2220 MESA participants were compared with those in 3126 HNR participants with the inclusion criteria such as age 45–75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72–0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19–1.63), since many HNR participants have small (near zero) CAC values.
Conclusions
The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort.
doi:10.1093/eurheartj/ehn439
PMCID: PMC2582985  PMID: 18845666
Epidemiology; Atherosclerosis; Coronary artery calcium; Risk factors; Screening

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