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1.  Body mass index and mortality in an ethnically diverse population: the Multiethnic Cohort Study 
European journal of epidemiology  2012;27(7):489-497.
Body mass index (BMI) has been strongly related to overall mortality, but the consistency of this association across diverse ethnic groups and the effects of early adult BMI versus BMI in later adulthood have not been adequately studied. A prospective analysis was performed using data from 183,211 adults aged 45–75 who enrolled the population-based Multiethnic Cohort Study by completing a questionnaire that included self-reported weight and height information in 1993–1996. Participants were African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites living in Hawaii and California. During an average 12.5 years of follow-up, 35,664 deaths were identified. To control for confounding caused by conditions that lead to weight loss and mortality, we excluded participants with a history of cancer or heart disease, who ever smoked, and who died within the first 3 years of follow-up. An increased risk of mortality was observed in participants with a BMI ≥ 27.5 in both men and women compared with the reference category of BMI 23.0–24.9; a BMI ≥ 35.0 carried a greater risk of mortality in men than in women. Although the findings were generally similar across ethnic groups, the association of higher BMI with mortality in Latino men appeared to be weaker than in the other groups. A BMI of 25.0–34.9 at age 21 showed a stronger positive association, with no further increase in risk for a BMI ≥ 35.0, than did BMI in later adulthood. These results indicate that the association of BMI with mortality is generally consistent across sex and ethnic groups, with some variation in the strength of the effect. Most notably, the effect of overweight in young adulthood appears to be much stronger than that of overweight in later adulthood on mortality in later life. This emphasizes the importance of weight management in childhood and adolescence.
PMCID: PMC4494097  PMID: 22644110
Body mass index; Cohort studies; Mortality; Multiethnic population; Obesity
2.  The impact of exposure-biased sampling designs on detection of gene-environment interactions in case-control studies with potential exposure misclassification 
European journal of epidemiology  2014;30(5):413-423.
With limited funding and biological specimen availability, choosing an optimal sampling design to maximize power for detecting gene-by-environment (G-E) interactions is critical. Enriched sampling is often used to select subjects with rare exposures for genotyping to enhance power for tests of G-E effects. However, exposure misclassification (MC) combined with biased sampling can affect characteristics of tests for G-E interaction and joint tests for marginal association and G-E interaction. Here, we characterize the impact of exposure-biased sampling under conditions of perfect exposure information and exposure MC on properties of three methods for conducting these tests.
We assess the power, Type I error, bias, and mean squared error of case-only, case-control, and empirical Bayes methods for testing G-E interaction and a joint marginal G (or E) effect and G-E interaction across three biased sampling schemes. Properties are evaluated via simulation. We also consider the role of gene-environment independence.
With perfect exposure information, enriched sampling schemes enhance power as compared to random selection of subjects irrespective of exposure prevalence but yield bias in estimation of the G-E interaction and marginal E parameters. G-E independence affects the relative properties of the interaction detection methods, with the case-only approach suffering most severely. Exposure MC distorts the relative performance of sampling designs when compared to the case of perfect exposure information.
Those conducting G-E studies should be aware of exposure MC properties and the prevalence of exposure when choosing an ideal sampling scheme and method for detecting G-E interactions and joint effects.
PMCID: PMC4256150  PMID: 24894824
sampling design; gene-environment interaction; interaction; genetic epidemiology; case-control; exposure misclassification
3.  Perinatal Risk Factors for Wilms Tumor in a Swedish National Cohort 
European journal of epidemiology  2014;29(3):191-197.
Perinatal risk factors including high birth weight have been associated with Wilms tumor in case-control studies. However, these findings have seldom been examined in large cohort studies, and the specific contributions of gestational age at birth and fetal growth remain unknown.
We conducted the largest population-based cohort study to date consisting of 3,571,574 persons born in Sweden in 1973-2008, followed up for Wilms tumor incidence through 2009 to examine perinatal risk factors.
There were 443 Wilms tumor cases identified in 66.3 million person-years of follow-up. After adjusting for gestational age and other perinatal factors, high fetal growth was associated with increased risk of Wilms tumor among girls (hazard ratio per 1 standard deviation [SD], 1.36; 95% CI, 1.20-1.54; P<0.001), but not boys (1.10; 95% CI, 0.97-1.25; P=0.14) (Pinteraction=0.02). Among girls, high fetal growth was associated with disease onset before age 5 years (odds ratio per 1 SD, 1.47; 95% CI, 1.28-1.69; P<0.001), but not beyond (1.00; 95% CI, 0.76-1.31; P=0.99). No clear associations were found for gestational age at birth or other perinatal factors.
In this large cohort study, high fetal growth was associated with Wilms tumor before age 5 years among girls. These findings suggest that early-life growth factor pathways for Wilms tumor may be more common among girls than boys. Further elucidation of these mechanisms may reveal better targets for prevention or treatment of specific subtypes of Wilms tumor.
PMCID: PMC4461217  PMID: 24510487
fetal development; gestational age; risk factors; Wilms tumor
4.  The Bangladesh Risk of Acute Vascular Events (BRAVE) Study: objectives and design 
European Journal of Epidemiology  2015;30(7):577-587.
During recent decades, Bangladesh has experienced a rapid epidemiological transition from communicable to non-communicable diseases. Coronary heart disease (CHD), with myocardial infarction (MI) as its main manifestation, is a major cause of death in the country. However, there is limited reliable evidence about its determinants in this population. The Bangladesh Risk of Acute Vascular Events (BRAVE) study is an epidemiological bioresource established to examine environmental, genetic, lifestyle and biochemical determinants of CHD among the Bangladeshi population. By early 2015, the ongoing BRAVE study had recruited over 5000 confirmed first-ever MI cases, and over 5000 controls “frequency-matched” by age and sex. For each participant, information has been recorded on demographic factors, lifestyle, socioeconomic, clinical, and anthropometric characteristics. A 12-lead electrocardiogram has been recorded. Biological samples have been collected and stored, including extracted DNA, plasma, serum and whole blood. Additionally, for the 3000 cases and 3000 controls initially recruited, genotyping has been done using the CardioMetabochip+ and the Exome+ arrays. The mean age (standard deviation) of MI cases is 53 (10) years, with 88 % of cases being male and 46 % aged 50 years or younger. The median interval between reported onset of symptoms and hospital admission is 5 h. Initial analyses indicate that Bangladeshis are genetically distinct from major non-South Asian ethnicities, as well as distinct from other South Asian ethnicities. The BRAVE study is well-placed to serve as a powerful resource to investigate current and future hypotheses relating to environmental, biochemical and genetic causes of CHD in an important but under-studied South Asian population.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-015-0037-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4516898  PMID: 25930055
Non-communicable diseases; Cardiovascular disease; Coronary heart disease; Myocardial infarction; Risk factors; Arsenic; Genetics; Bangladesh; South Asia; BRAVE
5.  The global impact of non-communicable diseases on macro-economic productivity: a systematic review 
European Journal of Epidemiology  2015;30(5):357-395.
Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Medline, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case–control, cross-sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured in DALYs, productivity costs, and labor market participation, including unemployment, return to work and sick leave. From 4542 references, 126 studies met the inclusion criteria, many of which focused on the impact of more than one NCD on productivity. Breast cancer was the most common (n = 45), followed by stroke (n = 31), COPD (n = 24), colon cancer (n = 24), DM (n = 22), lung cancer (n = 16), CVD (n = 15), cervical cancer (n = 7) and CKD (n = 2). Four studies were from the WHO African Region, 52 from the European Region, 53 from the Region of the Americas and 16 from the Western Pacific Region, one from the Eastern Mediterranean Region and none from South East Asia. We found large regional differences in DALYs attributable to NCDs but especially for cervical and lung cancer. Productivity losses in the USA ranged from 88 million US dollars (USD) for COPD to 20.9 billion USD for colon cancer. CHD costs the Australian economy 13.2 billion USD per year. People with DM, COPD and survivors of breast and especially lung cancer are at a higher risk of reduced labor market participation. Overall NCDs generate a large impact on macro-economic productivity in most WHO regions irrespective of continent and income. The absolute global impact in terms of dollars and DALYs remains an elusive challenge due to the wide heterogeneity in the included studies as well as limited information from low- and middle-income countries.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-015-0026-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4457808  PMID: 25837965
Noncommunicable diseases; Productivity; Return to work absenteeism; Systematic review
6.  Effects of obesity and hormone therapy on surgically-confirmed fibroids in postmenopausal women 
European Journal of Epidemiology  2015;30(6):493-499.
To examine the association between body mass index (BMI), use of menopausal hormone therapy (HT), and incidence of uterine fibroids in postmenopausal women, 610,604 postmenopausal women without prior hysterectomy or diagnosis of fibroids were followed as part of a large United Kingdom prospective cohort study. We used Cox regression models to calculate adjusted relative risks (RRs) of surgically-confirmed fibroids (defined as a hospital admission with uterine fibroids as a primary diagnosis with a related surgical procedure), in relation to BMI and use of HT. During an average of 11.4 years of follow-up, 3561 women were admitted to hospital with surgically-confirmed fibroids. Five-year incidence rates decreased with age, from 0.50 % (1 in 200 women) at age 50–54, to 0.11 % (1 in 1000 women) at age 75–79. The 5-year rate in postmenopausal women aged 50–54 was about a quarter that seen in premenopausal women of the same age (1 in 200 vs. 1 in 50). Compared with normal weight women, obese women had a RR of surgically-detected fibroids of 1.46 (95 % CI 1.33–1.59; p < 0.0001). HT use was associated with a RR of 2.33 (95 % CI 2.18–2.49; p < 0.0001) in ever versus never users. When we analysed HT use and BMI together, obese vs. normal weight never users had a RR of 2.00 (95 % CI 1.77–2.26): the highest risks were seen in women who were obese and had ever used HT, RR = 3.30 (95 % CI 2.88–3.79). Uterine fibroids continue to occur in postmenopausal women; obesity and hormone therapy use are important modifiable risk factors.
PMCID: PMC4485678  PMID: 25784364
Uterine leiomyoma; Fibroids; Postmenopausal; BMI; HRT; Million Women Study
7.  Preeclampsia in pregnancy and later use of antihypertensive drugs 
European Journal of Epidemiology  2015;30(6):501-508.
We explored the association between preeclampsia and later use of antihypertensive drugs in a population-based study with data from the Medical Birth Registry of Norway and the Norwegian Prescription Database. The study cohort consisted of 980,000 women having 2.1 million pregnancies during 1967–2012. Hazard ratios (HRs) with 95 % confidence intervals (95 % CI) were estimated in multivariate time-dependent Cox proportional hazards regression models. Overall, the HR of later use of antihypertensive drugs was 2.0 (95 % CI 2.0–2.0) in women with one preeclamptic pregnancy compared to women without preeclamptic pregnancies. The HR increased by increasing number of preeclamptic pregnancies, both term and preterm pregnancies. In women with two or more preeclamptic pregnancies, the HR was 2.8 (2.7–3.0). The overall HR after 40 years of follow-up for women with one preeclamptic pregnancy was 1.3 (1.2–1.4) and for two or more preeclamptic pregnancies the HR was 1.6 (1.1–2.1). The first 5 years after the first birth, the HR of being dispensed antihypertensive drugs was higher in preterm [8.4 (7.7–9.1)] than term preeclamptic pregnancies [4.3(4.0–4.6)]. However, after 10 years, this difference was no longer present. The HR of later use of antihypertensive drugs increased with the number of preeclamptic pregnancies, and in the first 10 years the HR was higher after a preterm than a term preeclamptic pregnancy. Although the HR decreased with time since first birth, the risk was still elevated after 40 years.
PMCID: PMC4485699  PMID: 25784365
Preeclampsia; Antihypertensive drugs; Prescriptions; Population-based registries
8.  Prevalence of refractive error in Europe: the European Eye Epidemiology (E3) Consortium 
European Journal of Epidemiology  2015;30(4):305-315.
To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E3) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia ≤−0.75 diopters (D), high myopia ≤−6D, hyperopia ≥1D and astigmatism ≥1D. Meta-analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those ≥25 and <90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4–30.9], high myopia 2.7 % (95 % CI 2.69–2.73), hyperopia 25.2 % (95 % CI 25.0–25.4) and astigmatism 23.9 % (95 % CI 23.7–24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8–52.5) in 25–29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-015-0010-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4385146  PMID: 25784363
Refractive error; Myopia; Epidemiology; Prevalence; Consortium
9.  Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors 
European Journal of Epidemiology  2015;30(7):543-552.
Finding individual-level data for adequately-powered Mendelian randomization analyses may be problematic. As publicly-available summarized data on genetic associations with disease outcomes from large consortia are becoming more abundant, use of published data is an attractive analysis strategy for obtaining precise estimates of the causal effects of risk factors on outcomes. We detail the necessary steps for conducting Mendelian randomization investigations using published data, and present novel statistical methods for combining data on the associations of multiple (correlated or uncorrelated) genetic variants with the risk factor and outcome into a single causal effect estimate. A two-sample analysis strategy may be employed, in which evidence on the gene-risk factor and gene-outcome associations are taken from different data sources. These approaches allow the efficient identification of risk factors that are suitable targets for clinical intervention from published data, although the ability to assess the assumptions necessary for causal inference is diminished. Methods and guidance are illustrated using the example of the causal effect of serum calcium levels on fasting glucose concentrations. The estimated causal effect of a 1 standard deviation (0.13 mmol/L) increase in calcium levels on fasting glucose (mM) using a single lead variant from the CASR gene region is 0.044 (95 % credible interval −0.002, 0.100). In contrast, using our method to account for the correlation between variants, the corresponding estimate using 17 genetic variants is 0.022 (95 % credible interval 0.009, 0.035), a more clearly positive causal effect.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-015-0011-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4516908  PMID: 25773750
Mendelian randomization; Instrumental variable; Causal inference; Published data; Two-sample Mendelian randomization; Summarized data
10.  Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: the Generation R Study 
European Journal of Epidemiology  2015;30(4):317-330.
Genome-wide association studies (GWAS) have been successful in identifying loci associated with a wide range of complex human traits and diseases. Up to now, the majority of GWAS have focused on European populations. However, the inclusion of other ethnic groups as well as admixed populations in GWAS studies is rapidly rising following the pressing need to extrapolate findings to non-European populations and to increase statistical power. In this paper, we describe the methodological steps surrounding genetic data generation, quality control, study design and analytical procedures needed to run GWAS in the multiethnic and highly admixed Generation R Study, a large prospective birth cohort in Rotterdam, the Netherlands. Furthermore, we highlight a number of practical considerations and alternatives pertinent to the quality control and analysis of admixed GWAS data.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-015-9998-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4385148  PMID: 25762173
Genome-wide association studies; Quality control GWAS; Genomic imputation; Admixed population; Multiethnic study
11.  Postmenopausal hormone therapy and the risk of rheumatoid arthritis: results from the Swedish EIRA population-based case-control study 
European Journal of Epidemiology  2015;30(5):449-457.
To study the association between postmenopausal hormone therapy (PMH) use and the risk of rheumatoid arthritis (RA) stratifying the cases by the presence/absence of antibodies against citrullinated peptides (ACPA). A subset of the Epidemiological Investigation of RA (EIRA), a population-based case-control study, comprising postmenopausal women aged 50–70 living in Sweden, between 2006 and 2011 was analysed (523 cases and 1057 controls). All participants answered an extensive questionnaire, including questions regarding PMH use and potential confounders (education, smoking, BMI, oral contraceptives, reproductive factors). We calculated odds ratios (OR) of developing ACPA-positive/-negative RA, with 95 % confidence intervals (CI) and adjusted for age, residential area and smoking. Current users of PMH had a decreased risk of ACPA-positive RA compared with never users (OR 0.6, 95 % CI 0.3–0.9). The decreased risk was observed mainly in the age-group 50–59 years (OR 0.3, 95 % CI 0.1–0.8) but not in the age-group 60–70 years (OR 0.8, 95 % CI 0.4–1.4). Among current users of a combined therapy (estrogen plus progestogens) an OR of 0.3 (95 % CI 0.1–0.7) of ACPA-positive RA was observed, while no significant association was found among women who used estrogen only (OR 0.8, 95 % CI 0.5–1.6). No association between PMH use and ACPA-negative RA was found. PMH use might reduce the risk of ACPA-positive RA in post-menopausal women over 50 years of age, but not of ACPA-negative RA. The negative influence of this treatment on the risk of other chronic conditions cannot be overlooked.
PMCID: PMC4457806  PMID: 25762170
Rheumatoid arthritis; Postmenopausal hormone therapy; Antibodies to citrullinated peptides (ACPA); Etiology; Epidemiology
12.  A confidence ellipse for the Net Reclassification Improvement 
European Journal of Epidemiology  2015;30(4):299-304.
The Net Reclassification Improvement (NRI) has become a popular metric for evaluating improvement in disease prediction models through the past years. The concept is relatively straightforward but usage and interpretation has been different across studies. While no thresholds exist for evaluating the degree of improvement, many studies have relied solely on the significance of the NRI estimate. However, recent studies recommend that statistical testing with the NRI should be avoided. We propose using confidence ellipses around the estimated values of event and non-event NRIs which might provide the best measure of variability around the point estimates. Our developments are illustrated using practical examples from EPIC-Potsdam study.
PMCID: PMC4385149  PMID: 25724473
Risk assessment; Risk model; Model comparison; Reclassification; Confidence intervals
14.  Targeted hepatitis C antibody testing interventions: a systematic review and meta-analysis 
European Journal of Epidemiology  2014;30(2):115-129.
Testing for hepatitis C virus (HCV) infection may reduce the risk of liver-related morbidity, by facilitating earlier access to treatment and care. This review investigated the effectiveness of targeted testing interventions on HCV case detection, treatment uptake, and prevention of liver-related morbidity. A literature search identified studies published up to 2013 that compared a targeted HCV testing intervention (targeting individuals or groups at increased risk of HCV) with no targeted intervention, and results were synthesised using meta-analysis. Exposure to a targeted testing intervention, compared to no targeted intervention, was associated with increased cases detected [number of studies (n) = 14; pooled relative risk (RR) 1.7, 95 % CI 1.3, 2.2] and patients commencing therapy (n = 4; RR 3.3, 95 % CI 1.1, 10.0). Practitioner-based interventions increased test uptake and cases detected (n = 12; RR 3.5, 95 % CI 2.5, 4.8; and n = 10; RR 2.2, 95 % CI 1.4, 3.5, respectively), whereas media/information-based interventions were less effective (n = 4; RR 1.5, 95 % CI 0.7, 3.0; and n = 4; RR 1.3, 95 % CI 1.0, 1.6, respectively). This meta-analysis provides for the first time a quantitative assessment of targeted HCV testing interventions, demonstrating that these strategies were effective in diagnosing cases and increasing treatment uptake. Strategies involving practitioner-based interventions yielded the most favourable outcomes. It is recommended that testing should be targeted at and offered to individuals who are part of a population with high HCV prevalence, or who have a history of HCV risk behaviour.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-014-9958-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4366568  PMID: 25385677
Hepatitis C; Testing; Systematic review; Meta-analysis
15.  Fish consumption and mortality in the European Prospective Investigation into Cancer and Nutrition cohort 
Fish is a source of important nutrients and may play a role in preventing heart diseases and other health outcomes. However, studies of overall mortality and cause-specific mortality related to fish consumption are inconclusive. We examined the rate of overall mortality, as well as mortality from ischaemic heart disease and cancer in relation to the intake of total fish, lean fish, and fatty fish in a large prospective cohort including ten European countries. More than 500,000 men and women completed a dietary questionnaire in 1992–1999 and were followed up for mortality until the end of 2010. 32,587 persons were reported dead since enrolment. Hazard ratios and their 99 % confidence interval were estimated using Cox proportional hazard regression models. Fish consumption was examined using quintiles based on reported consumption, using moderate fish consumption (third quintile) as reference, and as continuous variables, using increments of 10 g/day. All analyses were adjusted for possible confounders. No association was seen for fish consumption and overall or cause-specific mortality for both the categorical and the continuous analyses, but there seemed to be a U-shaped trend (p < 0.000) with fatty fish consumption and total mortality and with total fish consumption and cancer mortality (p = 0.046).
PMCID: PMC4356893  PMID: 25377533
Mortality; Fish consumption; Cohort; Lean fish; Fatty fish; Multi-centre study
16.  Mortality benefits of population-wide adherence to national physical activity guidelines: a prospective cohort study 
We quantified the mortality benefits and attributable fractions associated with engaging in physical activity across a range of levels, including those recommended by national guidelines. Data were from the Allied Dunbar National Fitness Survey, a population-based prospective cohort comprising 1,796 male and 2,122 female participants aged 16–96 years, randomly selected from 30 English constituencies in 1990. Participants were tagged for mortality at the Office for National Statistics. Cox multivariable regression quantified the association between self-reported achievement of activity guidelines—150 min of at least moderate activity per week, equivalent here to 30 or more 20-min episodes of at least moderate activity per month—and mortality adjusting for age, sex, smoking status, social class, geographical area, anxiety/depression and interview season. There were 1,175 deaths over a median (IQR) of 22.9 (3.9) years follow-up; a mortality rate of 15.2, 95 % confidence interval (CI) 14.4–16.1 per 1,000 person years. Compared with being inactive (no 20-min bouts per month), meeting activity guidelines (30+ bouts) was associated with a 25 % lower mortality rate, adjusting for measured confounders. If everyone adhered to recommended-, or even low-activity levels, a substantial proportion of premature mortality might be avoided (PAF, 95 % CI 20.6, 6.9–32.3 and 8.9, 4.2–13.4 %, respectively). Among a representative English population, adherence to activity guidelines was associated with significantly reduced mortality. Efforts to increase population-wide activity levels could produce large public health benefits and should remain a focus of health promotion efforts.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-014-9965-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4356894  PMID: 25377532
Physical activity; Physical activity guidelines; All-cause mortality; Population health promotion; Attributable fraction
17.  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.
PMCID: PMC4220102  PMID: 25354991
Acute coronary syndrome; Obesity; Obesity paradox; Body mass index
18.  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.
PMCID: PMC4181528  PMID: 22388766
Fibrinogen gene; Tagging SNPs; Haplotypes; Mendelian randomization
19.  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.
PMCID: PMC3844527  PMID: 24037117
socioeconomic status; coronary heart disease; health behaviors; risk factors
20.  Reconsidering the denominator of the attributable proportion for interaction 
European journal of epidemiology  2013;28(10):10.1007/s10654-013-9843-6.
PMCID: PMC3882023  PMID: 24037116
21.  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.
PMCID: PMC4180054  PMID: 22623145
Common mental disorders; Physical activity; Bidirectional association; Longitudinal studies
22.  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.
PMCID: PMC4197377  PMID: 25238720
BiomarCaRE; Biomarker; Cardiovascular Risk Assessment; MORGAM; EU
23.  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.
PMCID: PMC4167007  PMID: 20882324
Correlated outcomes; Marginal models; Family study; Large and inter-related extended families
24.  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.
PMCID: PMC3791322  PMID: 23681776
glioma; birth order; siblings; birth weight; breast feeding
25.  Adult height and head and neck cancer: a pooled analysis within the INHANCE Consortium 
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.
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.
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.
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.
PMCID: PMC4122122  PMID: 24271556

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