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2.  The obesity paradox in acute coronary syndrome: a meta-analysis 
European Journal of Epidemiology  2014;29(11):801-812.
In the general population, the lowest mortality risk is considered to be for the body mass index (BMI) range of 20–24.9 kg/m2. In chronic diseases (chronic kidney disease, chronic heart failure or chronic obstructive pulmonary disease) the best survival is observed in overweight or obese patients. Recently above-mentioned phenomenon, called obesity paradox, has been described in patients with coronary artery disease. Our aim was to analyze the relationship between BMI and total mortality in patients after acute coronary syndrome (ACS) in the context of obesity paradox. We searched scientific databases for studies describing relation in body mass index with mortality in patients with ACS. The study selection process was performed according to PRISMA statement. Crude mortality rates, odds ratio or risk ratio for all-cause mortality were extracted from articles and included into meta-analysis. 26 studies and 218,532 patients with ACS were included into meta-analysis. The highest risk of mortality was found in Low BMI patients—RR 1.47 (95 % CI 1.24–1.74). Overweight, obese and severely obese patients had lower mortality compared with those with normal BMI–RR 0.70 (95 % CI 0.64–0.76), RR 0.60, (95 % CI 0.53–0.68) and RR 0.70 (95 % CI 0.58–0.86), respectively. The obesity paradox in patients with ACS has been confirmed. Although it seems to be clear and quite obvious, outcomes should be interpreted with caution. It is remarkable that obese patients had more often diabetes mellitus and/or hypertension, but they were younger and had less bleeding complications, which could have influence on their survival.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-014-9961-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-014-9961-9
PMCID: PMC4220102  PMID: 25354991
Acute coronary syndrome; Obesity; Obesity paradox; Body mass index
3.  Quantifying the contributions of behavioral and biological risk factors to socioeconomic disparities in coronary heart disease incidence: The MORGEN study 
European journal of epidemiology  2013;28(10):10.1007/s10654-013-9847-2.
Quantifying the impact of different modifiable behavioral and biological risk factors on socioeconomic disparities in coronary heart disease (CHD) may help inform targeted, population-specific strategies to reduce the unequal distribution of the disease. Previous studies have used analytic approaches that limit our ability to disentangle the relative contributions of these risk factors to CHD disparities. The goal of this study was to assess mediation of the effect of low education on incident CHD by multiple risk factors simultaneously. Analyses are based on 15,067 participants of the Dutch Monitoring Project on Risk Factors for Chronic Diseases aged 20–65 years examined 1994–1997 and followed for events until January 1, 2008. Path analysis was used to quantify and test mediation of the low education-CHD association by behavioral (current cigarette smoking, heavy alcohol use, poor diet, and physical inactivity) and biological (obesity, hypertension, diabetes, and hypercholesterolemia) risk factors. Behavioral and biological risk factors accounted for 56.6% (95% CI: 42.6%–70.8%) of the low education-incident CHD association. Smoking was the strongest mediator, accounting for 27.3% (95% CI: 17.7%–37.4%) of the association, followed by obesity (10.2%; 95% CI: 4.5%–16.1%), physical inactivity (6.3%; 95% CI: 2.7%–10.0%), and hypertension (5.3%; 95% CI: 2.8%–8.0%). In summary, in a Dutch cohort, the majority of the relationship between low education and incident CHD was mediated by traditional behavioral and biological risk factors. Addressing barriers to smoking cessation, blood pressure and weight management, and physical activity may be the most effective approaches to eliminating socioeconomic inequalities in CHD.
doi:10.1007/s10654-013-9847-2
PMCID: PMC3844527  PMID: 24037117
socioeconomic status; coronary heart disease; health behaviors; risk factors
4.  Reconsidering the denominator of the attributable proportion for interaction 
European journal of epidemiology  2013;28(10):10.1007/s10654-013-9843-6.
doi:10.1007/s10654-013-9843-6
PMCID: PMC3882023  PMID: 24037116
5.  A genetic instrument for Mendelian randomization of fibrinogen 
European journal of epidemiology  2012;27(4):267-279.
Mendelian randomization studies on fibrinogen commonly use a single genetic variant as an instrument, but this may explain only a small proportion of the total phenotypic variance. We examined the contribution of multiple common single nucleotide polymorphisms (SNPs) and haplotypes in the entire fibrinogen gene cluster to plasma fibrinogen levels in two prospective cohorts, for use as instruments in future Mendelian randomization studies. Genotypes for 20 SNPs were determined in 2,778 middle-age (49–64 years) men from the Second-Northwick-Park-Heart Study (NPHS-II). These were replicated in 3,705 men from the Whitehall-II study (WH-II). Plasma fibrinogen levels were determined six times in NPHS-II and three times in WH-II. The minor alleles of four SNPs from the FGB gene, two from the FGA gene, and one from the FGG gene were associated with higher plasma fibrinogen levels. SNP rs1800790 (−455G >A) commonly used in Mendelian randomization studies was associated with R2 = 1.22% of the covariate adjusted residual variance in fibrinogen level. A variable selection procedure identified one additional SNP: rs2070011 (FGA) altogether explaining R2 = 1.45% of the residual variance in fibrinogen level. Using these SNPs no evidence for causality between the fibrinogen levels and coronary heart diseases was found in instrumental variables analysis. In the replication cohort, WH-II, the effects of the two SNPs on fibrinogen levels were consistent with the NPHS-II results. There is statistical evidence for several functional sites in the fibrinogen gene cluster that determine an individual’s plasma fibrinogen levels. Thus, a combination of several SNPs will provide a stronger instrument for fibrinogen Mendelian randomization studies.
doi:10.1007/s10654-012-9666-x
PMCID: PMC4181528  PMID: 22388766
Fibrinogen gene; Tagging SNPs; Haplotypes; Mendelian randomization
6.  Bidirectional association between physical activity and symptoms of anxiety and depression: the Whitehall II study 
European journal of epidemiology  2012;27(7):537-546.
Although it has been hypothesized that the association of physical activity with depressive and anxiety symptoms is bidirectional, few studies have examined this issue in a prospective setting. We studied this bidirectional association using data on physical activity and symptoms of anxiety and depression at three points in time over 8 years. A total of 9,309 participants of the British Whitehall II prospective cohort study provided data on physical activity, anxiety and depression symptoms and 10 covariates at baseline in 1985. We analysed the associations of physical activity with anxiety and/or depression symptoms using multinomial logistic regression (with anxiety and depression symptoms as dependent variables) and binary logistic regression (with physical activity as the dependent variable). There was a cross-sectional inverse association between physical activity and anxiety and/or depressive symptoms at baseline (ORs between 0.63 and 0.72). In cumulative analyses, regular physical activity across all three data waves, but not irregular physical activity, was associated with reduced likelihood of depressive symptoms at follow-up (OR = 0.71, 95 % CI 0.54, 0.99). In a converse analysis, participants with anxiety and depression symptoms at baseline had higher odds of not meeting the recommended levels of physical activity at follow-up (OR = 1.79, 95 % CI 1.17, 2.74). This was also the case in individuals with anxiety and/or depression symptoms at both baseline and follow-up (OR = 1.70, 95 % CI 1.10, 2.63). The association between physical activity and symptoms of anxiety and/or depression appears to be bidirectional.
doi:10.1007/s10654-012-9692-8
PMCID: PMC4180054  PMID: 22623145
Common mental disorders; Physical activity; Bidirectional association; Longitudinal studies
7.  BiomarCaRE: rationale and design of the European BiomarCaRE project including 300,000 participants from 13 European countries 
European Journal of Epidemiology  2014;29(10):777-790.
Biomarkers are considered as tools to enhance cardiovascular risk estimation. However, the value of biomarkers on risk estimation beyond European risk scores, their comparative impact among different European regions and their role towards personalised medicine remains uncertain. Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) is an European collaborative research project with the primary objective to assess the value of established and emerging biomarkers for cardiovascular risk prediction. BiomarCaRE integrates clinical and epidemiological biomarker research and commercial enterprises throughout Europe to combine innovation in biomarker discovery for cardiovascular disease prediction with consecutive validation of biomarker effectiveness in large, well-defined primary and secondary prevention cohorts including over 300,000 participants from 13 European countries. Results from this study will contribute to improved cardiovascular risk prediction across different European populations. The present publication describes the rationale and design of the BiomarCaRE project.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-014-9952-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-014-9952-x
PMCID: PMC4197377  PMID: 25238720
BiomarCaRE; Biomarker; Cardiovascular Risk Assessment; MORGAM; EU
8.  Models of population-based analyses for data collected from large extended families 
European journal of epidemiology  2010;25(12):855-865.
Large studies of extended families usually collect valuable phenotypic data that may have scientific value for purposes other than testing genetic hypotheses if the families were not selected in a biased manner. These purposes include assessing population-based associations of diseases with risk factors/covariates and estimating population characteristics such as disease prevalence and incidence. Relatedness among participants however, violates the traditional assumption of independent observations in these classic analyses. The commonly used adjustment method for relatedness in population-based analyses is to use marginal models, in which clusters (families) are assumed to be independent (unrelated) with a simple and identical covariance (family) structure such as those called independent, exchangeable and unstructured covariance structures. However, using these simple covariance structures may not be optimally appropriate for outcomes collected from large extended families, and may under- or over-estimate the variances of estimators and thus lead to uncertainty in inferences. Moreover, the assumption that families are unrelated with an identical family structure in a marginal model may not be satisfied for family studies with large extended families. The aim of this paper is to propose models incorporating marginal models approaches with a covariance structure for assessing population-based associations of diseases with their risk factors/covariates and estimating population characteristics for epidemiological studies while adjusting for the complicated relatedness among outcomes (continuous/categorical, normally/non-normally distributed) collected from large extended families. We also discuss theoretical issues of the proposed models and show that the proposed models and covariance structure are appropriate for and capable of achieving the aim.
doi:10.1007/s10654-010-9512-y
PMCID: PMC4167007  PMID: 20882324
Correlated outcomes; Marginal models; Family study; Large and inter-related extended families
9.  Early Life Exposures and the Risk of Adult Glioma 
European journal of epidemiology  2013;28(9):753-758.
Exposure to common infections in early life may stimulate immune development and reduce the risk for developing cancer. Birth order and family size are proxies for the timing of exposure to childhood infections with several studies showing a reduced risk of glioma associated with a higher order of birth (and presumed younger age at infection). The aim of this study was to examine whether birth order, family size, and other early life exposures are associated with the risk of glioma in adults using data collected in a large clinic-based US case-control study including 889 glioma cases and 903 community controls. A structured interviewer-administered questionnaire was used to collect information on family structure, childhood exposures and other potential risk factors. Logistic regression was used to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for the association between early life factors and glioma risk. Persons having any siblings were at significantly lower risk for glioma when compared to those reporting no siblings (OR = 0.64; 95% CI: 0.44-0.93; p = 0.020). Compared to first-borns, individuals with older siblings had a significantly lower risk (OR = 0.75; 95% CI: 0.61-0.91; p = 0.004). Birth weight, having been breast fed in infancy, and season of birth were not associated with glioma risk. The current findings lend further support to a growing body of evidence that early exposure to childhood infections reduces the risk of glioma onset in children and adults.
doi:10.1007/s10654-013-9811-1
PMCID: PMC3791322  PMID: 23681776
glioma; birth order; siblings; birth weight; breast feeding
10.  Adult height and head and neck cancer: a pooled analysis within the INHANCE Consortium 
Background
Several epidemiological studies have shown a positive association between adult height and cancer incidence. The only study conducted among women on mouth and pharynx cancer risk, however, reported an inverse association. This study aims to investigate the association between height and the risk of head and neck cancer (HNC) within a large international consortium of HNC.
Methods
We analyzed pooled individual-level data from 24 case-control studies participating in the International Head and Neck Cancer Epidemiology Consortium. Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were estimated separately for men and women for associations between height and HNC risk. Educational level, tobacco smoking, and alcohol consumption were included in all regression models. Stratified analyses by HNC subsites were performed.
Results
This project included 17,666 cases and 28,198 controls. We found an inverse association between height and HNC (adjusted OR per 10 cm height =0.91, 95% CI 0.86–0.95 for men; adjusted OR=0.86, 95% CI 0.79–0.93 for women). In men, the estimated OR did vary by educational level, smoking status, geographic area, and control source. No differences by subsites were detected.
Conclusions
Adult height is inversely associated with HNC risk. As height can be considered a marker of childhood illness and low energy intake, the inverse association is consistent with prior studies showing that HNC occur more frequently among deprived individuals. Further studies designed to elucidate the mechanism of such association would be warranted.
doi:10.1007/s10654-013-9863-2
PMCID: PMC4122122  PMID: 24271556
11.  Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls 
European journal of epidemiology  2013;28(8):621-647.
BACKGROUND
Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden,FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies.
METHODS
We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR).
RESULTS
We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95% confidence intervals [CI]: 0.98–1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR=4.22; 95% CI: 3.35–5.32; and OR=2.79;95% CI: 2.25–3.46, respectively), in double hterozygotes (OR=3.42; 95%CI 1.64-7.13), and in homozygous FVL or PT20210A (OR=11.45; 95%CI: 6.79-19.29; and OR: 2.79; 95%CI: 2.25 – 3.46, respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤45 years (p-value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045).
CONCLUSIONS
In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.
doi:10.1007/s10654-013-9825-8
PMCID: PMC3935237  PMID: 23900608
Venous thromboembolism; genetic susceptibility; Factor V Leiden; Prothrombin G202010A; Methylentetrahydrofolate reductase C677T
12.  A critical review of the epidemiology of Agent Orange/TCDD and prostate cancer 
European Journal of Epidemiology  2014;29(10):667-723.
To inform risk assessment and regulatory decision-making, the relationship between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and prostate cancer requires clarification. This article systematically and critically reviews the epidemiologic evidence on the association between exposure to TCDD or Agent Orange, a TCDD-contaminated herbicide used during the Vietnam War, and prostate cancer risk. Articles evaluated include 11 studies of three cohorts, four case–control or cross-sectional studies, and three case-only studies of military veterans with information on estimated Agent Orange or TCDD exposure; 13 studies of seven cohorts, one case–control study, and eight proportionate morbidity or mortality studies of Vietnam veterans without information on Agent Orange exposure; 11 cohort studies of workers with occupational exposure to TCDD; and two studies of one community cohort with environmental exposure to TCDD. The most informative studies, including those of Vietnam veterans involved in Agent Orange spraying or other handling, herbicide manufacturing or spraying workers with occupational TCDD exposure, and community members exposed to TCDD through an industrial accident, consistently reported no significant increase in prostate cancer incidence or mortality. Only some potentially confounded studies of Vietnam veterans compared with the general population, studies with unreliable estimates of Agent Orange exposure, and analyses of selected subgroups of Vietnam veterans reported positive associations. Overall, epidemiologic research offers no consistent or convincing evidence of a causal relationship between exposure to Agent Orange or TCDD and prostate cancer. More accurate exposure assessment is needed in large epidemiologic studies to rule out a causal association more conclusively.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-014-9931-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-014-9931-2
PMCID: PMC4197347  PMID: 25064616
Prostate cancer; TCDD; Dioxin; Agent Orange; Veterans; Epidemiology
13.  Quantifying the health benefits of chronic disease prevention: a fresh approach using cardiovascular disease as an example 
European Journal of Epidemiology  2014;29(9):605-612.
Current methods of determining the proportion of people who benefit from a preventive intervention and the years of life gained can underestimate the former and overestimate the latter. We describe how to overcome these errors, using two examples relating to the prevention of myocardial infarction (MI) and stroke, one using a specified polypill daily from age 50 and another reducing salt intake in the population. Standard life table analysis was used to calculate the person-years of life gained without an MI or stroke, based on estimates of the incidence of these disorders in England and Wales. The proportion of individuals who benefit was taken as everyone who would, without treatment, have an MI or stroke (holistic model), rather than limiting the benefit to the proportion calculated from the relative risk reduction (reductionist model), as is current practice. Under the holistic model, 33 % of people who take the polypill from age 50 benefit, gaining, on average, 8 years of life without an MI or stroke (19 % and 14 years under the reductionist model). Estimates for reducing salt intake by 6 g/day are 33 % and 2.8 years respectively under the holistic model (6 % and 16 years under the reductionist model). In the prevention of disorders such as stroke by reducing exposure to causal factors such as blood pressure, the use of a holistic model corrects the underestimation of the proportion of people who benefit and the overestimation of their years of life gained associated with current methods.
doi:10.1007/s10654-014-9932-1
PMCID: PMC4160564  PMID: 25063437
Relative risk reduction; Absolute risk reduction; Health benefits; Polypill; Statins; Blood pressure lowering drugs; Salt intake reduction
14.  Sex differences in health and mortality in Moscow and Denmark 
European journal of epidemiology  2014;29(4):243-252.
In high income countries females outlive men, although they generally report worse health, the so-called male–female health-survival paradox. Russia has one of the world’s largest sex difference in life expectancy with a male disadvantage of more than 10 years. We compare components of the paradox between Denmark and Moscow by examining sex differences in mortality and several health measures. The Human Mortality Database and the Russian Fertility and Mortality Database were used to examine sex differences in all-cause death rates in Denmark, Russia, and Moscow in 2007–2008. Self-reported health data were obtained from the Study of Middle-Aged Danish Twins (n = 4,314), the Longitudinal Study of Aging Danish Twins (n = 4,731), and the study of Stress, Aging, and Health in Russia (n = 1,800). In both Moscow and Denmark there was a consistent female advantage at ages 55–89 years in survival and a male advantage in self-rated health, physical functioning, and depression symptomatology. Only on cognitive tests males performed similarly to or worse than women. Nevertheless, Muscovite males had more than twice higher mortality at ages 55–69 years compared to Muscovite women, almost double the ratio in Denmark. The present study showed that despite similar directions of sex differences in health and mortality in Moscow and Denmark, the male–female health-survival paradox is very pronounced in Moscow suggesting a stronger sex-specific disconnect between health indicators and mortality among middle-aged and young-old Muscovites.
doi:10.1007/s10654-014-9893-4
PMCID: PMC4090601  PMID: 24668060
Sex differences; Cross-national comparison; Health; Mortality; Russia; Denmark
15.  A tradition and an epidemic: determinants of the campylobacteriosis winter peak in Switzerland 
European Journal of Epidemiology  2014;29(7):527-537.
Campylobacteriosis is the most frequently reported food borne infection in Switzerland. We investigated determinants of infections and illness experience in wintertime. A case–control study was conducted in Switzerland between December 2012 and February 2013. Cases were recruited among laboratory-confirmed campylobacteriosis patients. Population-based controls were matched according to age group, sex and canton of residence. We determined risk factors associated with campylobacteriosis, and help seeking behaviour and illness perception. The multivariable analysis identified two factors associated with an increased risk for campylobacteriosis: consumption of meat fondue (matched odds ratio [mOR] 4.0, 95 % confidence interval [CI] 2.3–7.1) and travelling abroad (mOR 2.7, 95 % CI 1.1–6.4). Univariable analysis among meat fondue consumers revealed chicken as the type of meat with the highest risk of disease (mOR 3.8, 95 % CI 1.1–13.5). Most frequently reported signs and symptoms among patients were diarrhoea (98 %), abdominal pain (81 %), fever (66 %), nausea (44 %) and vomiting (34 %). The median perceived disease severity was 8 on a 1-to-10 rating scale. Patients reported a median duration of illness of 7 days and 14 % were hospitalised. Meat fondues, mostly “Fondue chinoise”, traditionally consumed during the festive season in Switzerland, are the major driver of the epidemic campylobacteriosis peak in wintertime. At these meals, individual handling and consumption of chicken meat may play an important role in disease transmission. Laboratory-confirmed patients are severely ill and hospitalisation rate is considerable. Public health measures such as decontamination of chicken meat and improved food handling behaviour at the individual level are urgently needed.
doi:10.1007/s10654-014-9917-0
PMCID: PMC4099532  PMID: 24990236
Campylobacter; Notification system; Case–control study; Switzerland; Gastroenteritis; Food borne diseases
16.  COMPETING RISK BIAS TO EXPLAIN THE INVERSE RELATIONSHIP BETWEEN SMOKING AND MALIGNANT MELANOMA 
European journal of epidemiology  2013;28(7):10.1007/s10654-013-9812-0.
The relationship between smoking and melanoma remains unclear. Among the different results is the paradoxical finding that smoking was shown to be inversely associated with the risk of malignant melanoma in some large cohort and case-control studies, even after control for suspected confounding variables. Smoking is a known risk factor for many non-communicable diseases, including coronary heart disease, stroke, as well as other malignancies; it has been shown to be positively associated with other types of skin cancer, and there remains no clear biologic explanation for a possible protective effect on malignant melanoma. In this paper, we propose a plausible mechanism of bias from smoking-related competing risks that may explain or contribute to the inverse association between smoking and melanoma as spurious. Using directed acyclic graphs for formalization and visualization of assumptions, and Monte Carlo simulation techniques, we demonstrate how published inverse associations might be compatible with selection bias resulting from uncontrolled or unmeasured common causes of competing outcomes of smoking-related diseases and malignant melanoma. We present results from various scenarios assuming a true null as well as a true positive association between smoking and malignant melanoma. Under a true null assumption, we find inverse associations due to the biasing mechanism to be compatible with published results in the literature, especially after the addition of unmeasured confounding variables. This study could be seen as offering a cautionary note in the interpretation of published smoking-melanoma findings.
doi:10.1007/s10654-013-9812-0
PMCID: PMC3864891  PMID: 23700026
Bias (Epidemiology); Melanoma; Smoking
17.  Place of upbringing in early childhood as related to inflammatory bowel diseases in adulthood: a population-based cohort study in Northern Europe 
European Journal of Epidemiology  2014;29(6):429-437.
Background The two inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease, has increased rapidly during the twentieth century, but the aetiology is still poorly understood. Impaired immunological competence due to decreasing biodiversity and altered microbial stimulation is a suggested explanation. Objective Place of upbringing was used as a proxy for the level and diversity of microbial stimulation to investigate the effects on the prevalence of IBD in adulthood. Methods Respiratory Health in Northern Europe (RHINE) III is a postal follow-up questionnaire of the European Community Respiratory Health Survey (ECRHS) cohorts established in 1989–1992. The study population was 10,864 subjects born 1945–1971 in Denmark, Norway, Sweden, Iceland and Estonia, who responded to questionnaires in 2000–2002 and 2010–2012. Data were analysed in logistic and Cox regression models taking age, sex, smoking and body mass index into consideration. Results Being born and raised on a livestock farm the first 5 years of life was associated with a lower risk of IBD compared to city living in logistic (OR 0.54, 95 % CI 0.31; 0.94) and Cox regression models (HR 0.55, 95 % CI 0.31; 0.98). Random-effect meta-analysis did not identify geographical difference in this association. Furthermore, there was a significant trend comparing livestock farm living, village and city living (p < 0.01). Sub-analyses showed that the protective effect was only present among subjects born after 1952 (OR 0.25, 95 % CI 0.11; 0.61). Conclusion This study suggests a protective effect from livestock farm living in early childhood on the occurrence of IBD in adulthood, however only among subjects born after 1952. We speculate that lower microbial diversity is an explanation for the findings.
doi:10.1007/s10654-014-9922-3
PMCID: PMC4065648  PMID: 24916994
Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Microbial exposure; Rural/urban environments; Hygiene hypothesis
18.  Does celiac disease influence survival in lymphoproliferative malignancy? 
European journal of epidemiology  2013;28(6):10.1007/s10654-013-9789-8.
Celiac disease (CD) is associated with both lymphoproliferative malignancy (LPM) and increased death from LPM. Research suggests that co-existing autoimmune disease may influence survival in LPM. Through Cox regression we examined overall and cause-specific mortality in 316 individuals with CD+LPM vs. 689 individuals with LPM only. CD was defined as having villous atrophy according to biopsy reports at any of Sweden’s 28 pathology departments, and LPM as having a relevant disease code in the Swedish Cancer Register. During follow-up, there were 551 deaths (CD: n=200; non-CD: n=351). Individuals with CD+LPM were at an increased risk of death compared with LPM-only individuals (adjusted hazard ratio (aHR)=1.23; 95% confidence interval (CI)=1.02–1.48). However, this excess risk was only seen in the first year after LPM diagnosis (aHR=1.76), with HRs decreasing to 1.09 in years 2–5 after LPM diagnosis and to 0.90 thereafter. Individuals with CD and non-Hodgkin lymphoma (NHL) were at a higher risk of any death as compared with NHL-only individuals (aHR=1.23; 95%CI=0.97–1.56). This excess risk was due to a higher proportion of T-cell lymphoma in CD patients. Stratifying for T- and B-cell status, the HR for death in individuals with CD+NHL was 0.77 (95%CI=0.46–1.31
In conclusion, we found no evidence that co-existing CD influences survival in individuals with LPM. The increased mortality in the first year after LPM diagnosis is related to the predominance of T-NHL in CD individuals. Individuals with CD+LPM should be informed that their prognosis is similar to that of individuals with LPM only. However, this study had low statistical power to rule our excess mortality in patients with CD and certain LPM subtypes.
doi:10.1007/s10654-013-9789-8
PMCID: PMC3886816  PMID: 23463575
cancer; celiac; coeliac; death; lymphoproliferative; malignancy mortality
19.  The German National Cohort: aims, study design and organization 
European Journal of Epidemiology  2014;29(5):371-382.
The German National Cohort (GNC) is a joint interdisciplinary endeavour of scientists from the Helmholtz and the Leibniz Association, universities, and other research institutes. Its aim is to investigate the causes for the development of major chronic diseases, i.e. cardiovascular diseases, cancer, diabetes, neurodegenerative/-psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases, and their pre-clinical stages or functional health impairments. Across Germany, a random sample of the general population will be drawn by 18 regional study centres, including a total of 100,000 women and 100,000 men aged 20–69 years. The baseline assessments include an extensive interview and self-completion questionnaires, a wide range of medical examinations and the collection of various biomaterials. In a random subgroup of 20 % of the participants (n = 40,000) an intensified examination (“Level 2”) programme will be performed. In addition, in five of the 18 study centres a total of 30,000 study participants will take part in a magnetic resonance imaging examination programme, and all of these participants will also be offered the intensified Level 2 examinations. After 4–5 years, all participants will be invited for a re-assessment. Information about chronic disease endpoints will be collected through a combination of active follow-up (including questionnaires every 2–3 years) and record linkages. The GNC is planned for an overall duration of 25–30 years. It will provide a major, central resource for population-based epidemiology in Germany, and will help to identify new and tailored strategies for early detection, prediction, and primary prevention of major diseases.
doi:10.1007/s10654-014-9890-7
PMCID: PMC4050302  PMID: 24840228
Population-based cohort; Non-communicable diseases; Chronic infections; Life-style and socio-economic factors; Magnetic resonance imaging; Pre-clinical disease; Functional impairments
20.  Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism 
European Journal of Epidemiology  2014;29(5):325-336.
The mechanism of antihypertensive and lipid-lowering drugs on the human organism is still not fully understood. New insights on the drugs’ action can be provided by a metabolomics-driven approach, which offers a detailed view of the physiological state of an organism. Here, we report a metabolome-wide association study with 295 metabolites in human serum from 1,762 participants of the KORA F4 (Cooperative Health Research in the Region of Augsburg) study population. Our intent was to find variations of metabolite concentrations related to the intake of various drug classes and—based on the associations found—to generate new hypotheses about on-target as well as off-target effects of these drugs. In total, we found 41 significant associations for the drug classes investigated: For beta-blockers (11 associations), angiotensin-converting enzyme (ACE) inhibitors (four assoc.), diuretics (seven assoc.), statins (ten assoc.), and fibrates (nine assoc.) the top hits were pyroglutamine, phenylalanylphenylalanine, pseudouridine, 1-arachidonoylglycerophosphocholine, and 2-hydroxyisobutyrate, respectively. For beta-blockers we observed significant associations with metabolite concentrations that are indicative of drug side-effects, such as increased serotonin and decreased free fatty acid levels. Intake of ACE inhibitors and statins associated with metabolites that provide insight into the action of the drug itself on its target, such as an association of ACE inhibitors with des-Arg(9)-bradykinin and aspartylphenylalanine, a substrate and a product of the drug-inhibited ACE. The intake of statins which reduce blood cholesterol levels, resulted in changes in the concentration of metabolites of the biosynthesis as well as of the degradation of cholesterol. Fibrates showed the strongest association with 2-hydroxyisobutyrate which might be a breakdown product of fenofibrate and, thus, a possible marker for the degradation of this drug in the human organism. The analysis of diuretics showed a heterogeneous picture that is difficult to interpret. Taken together, our results provide a basis for a deeper functional understanding of the action and side-effects of antihypertensive and lipid-lowering drugs in the general population.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-014-9910-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-014-9910-7
PMCID: PMC4050296  PMID: 24816436
Beta-blockers; Angiotensin-converting enzyme inhibitors; Diuretics; Statins; Fibrates; Metabolomics
22.  GOUT AND THE RISK OF PARKINSON’S DISEASE IN DENMARK 
European journal of epidemiology  2013;28(4):359-360.
doi:10.1007/s10654-013-9791-1
PMCID: PMC3655156  PMID: 23456139
gout; parkinson
23.  Cognitive lifestyle jointly predicts longitudinal cognitive decline and mortality risk 
European Journal of Epidemiology  2014;29(3):211-219.
Cognitive lifestyle measures such as education, occupation, and social engagement are commonly associated with late-life cognitive ability although their associations with cognitive decline tend to be mixed. However, longitudinal analyses of cognition rarely account for death and dropout, measurement error of the cognitive phenotype, and differing trajectories for different population sub-groups. This paper applies a joint latent class mixed model (and a multi-state model in a sensitivity analysis) that accounts for these issues to a large (n = 3,653), population-based cohort, Paquid, to model the relationship between cognitive lifestyle and cognitive decline. Cognition was assessed over a 20-year period using the Mini-Mental State Examination. Three cognitive lifestyle variables were assessed: education, mid-life occupation, and late-life social engagement. The analysis identified four latent sub-populations with class-specific longitudinal cognitive decline and mortality risk. Irrespective of the cognitive trajectory, increased social engagement was associated with a decreased mortality risk. High education was associated with the most favourable cognitive trajectory, and after adjusting for cognitive decline, with an increased mortality risk. Mid-life occupational complexity was also associated with more favourable trajectories but not with mortality risk. To realistically examine the link between cognitive lifestyle and cognitive decline, complex statistical models are required. This paper applies and compares in a sensitivity analysis two such models, and shows education to be linked to a compression of cognitive morbidity irrespective of cognitive trajectory. Furthermore, a potentially modifiable variable, late-life social engagement is associated with a decreased mortality risk in all of the population sub-groups.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-014-9881-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-014-9881-8
PMCID: PMC4003346  PMID: 24577561
Cognitive lifestyle; Mortality; Cognitive decline; Longitudinal modelling
24.  Maternal weight change before pregnancy in relation to birthweight and risks of adverse pregnancy outcomes 
European Journal of Epidemiology  2011;26(10):789-796.
Maternal weight change before pregnancy can be considered an indicator of maternal energy balance and nutritional status before conception, and may be involved in early life programming. We aimed to investigate the association of maternal Weight Change Before Pregnancy (WCBP) with fetal growth and adverse pregnancy outcomes. Data are from the French EDEN mother-child cohort of 1756 mother-child pairs; information on mother’s weight at 20 years, weight just before pregnancy, fetal anthropometry at second and third trimesters, infant’s birthweight and pregnancy complications were recorded. The average annual WCBP between 20 years and start of pregnancy (in kg/year) was categorized as: “Weight Loss” (n=320), “Moderate weight gain” (n=721) and “High weight gain” (n=715). The associations of WCBP with fetal and newborn characteristics and with adverse pregnancy outcomes were analyzed, adjusting for maternal and pregnancy characteristics, including the mother’s prepregnancy BMI. Interactions between WCBP and prepregnancy BMI were tested. Birthweight and estimated fetal weight in the third trimester increased significantly with increasing WCBP in mothers with BMI <25kg/m2. In these mothers, weight loss before pregnancy was associated with a higher risk of newborns small for gestational age (SGA). Whatever the prepregnancy BMI, WCBP was positively associated with a maternal risk of gestational diabetes and hypertension. The ponderal history of mothers before pregnancy can impact on fetal growth and on pregnancy outcomes such as gestational diabetes or hypertension. Our analysis is the first to report that in non-overweight women, those who lost weight before pregnancy are at higher risk of having SGA newborns.
doi:10.1007/s10654-011-9599-9
PMCID: PMC3925097  PMID: 21710259
Adult; Birth Weight; Body Mass Index; Cohort Studies; Female; Fetal Development; France; Gestational Age; Hospitals, Teaching; Humans; Mothers; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Questionnaires; Socioeconomic Factors; Weight Gain; physiology; Weight change; birthweight; adverse pregnancy outcomes

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