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International Journal of Epidemiology

International Journal of Epidemiology - RSS feed of current issue






Today we take for granted the idea of global health, of disease as an international event. Increasingly, we assume as well that the international spread of disease can be traced to human travel patterns as well as to recurring environmental conditions. Perversely, the idea of ‘global health’ and its inverse, global disease, owes little to the three-dimensional imaging of the planet and almost everything to the two-dimensional plane of the map. Here the idea of global disease is traced from its beginnings in the 18th century to its 19th-century introduction in maps of the first cholera pandemic. This global perspective, and the responsibilities it promoted among civil officials, can be seen in modern studies of cancer, influenza and other conditions with both environmental foundations and international presence.


We investigated respiratory pathogens in a prospective cohort study of young children living in the Peruvian Andes. In the study we assessed viral respiratory infections among young children, and explored interactions of viruses with common respiratory bacteria, especially Streptococcus pneumoniae. Through weekly household visits, data were collected on the signs and symptoms of acute respiratory illness (ARI), nasal samples were collected to test for viruses during episodes of ARI, and nasopharyngeal samples were collected on a monthly basis to monitor bacterial colonisation. We also collected data on vaccination coverage, patterns of social mixing, geographic information, and environmental and socio-demographic variables. Understanding the interaction of respiratory viruses with bacteria and its impact on the burden and severity of ARIs in rural areas of developing countries is critical to designing strategies for preventing such infections. Investigators interested in more details about this study or in accessing these resources should contact Dr. Carlos G. Grijalva at Vanderbilt University (carlos.grijalva@vanderbilt.edu).


The Limache cohort was set up to assess the programming and life course events hypotheses in relation to cardiovascular risk factors and chronic respiratory conditions, especially asthma, in the context of an unprecedented economic growth in Chile. The cohort was a representative sample of 1232 participants born between 1974 and 1978 in the hospital of Limache. The study includes data collected at birth, during the 1st year of life, at 22 to 28 years (collected between 2000 and 2002) and at 32 to 38 years (collected between 2010 and 2012). The data collected include anthropometric measurements at birth, 1st year of life and in adulthood, socio-economic and demographic data, lifestyle information including smoking, alcohol consumption and food intake, respiratory symptoms, lung function, broncho-reactivity to methacholine and skin prick reaction to eight allergens, measurement of cardiovascular risk factors and information on common mental health, mainly in the most recent study. The principal researchers welcome collaborative projects, especially those that will compare similar data sets in other settings [E-mail: hamigo@med.uchile.cl].


The Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) Study was established in 2009 to investigate the associations of sex steroids, inflammation, environmental and psychosocial factors with cardio-metabolic disease risk in men. The study population consists of 2569 men from the harmonisation of two studies: all participants of the Florey Adelaide Male Ageing Study (FAMAS) and eligible male participants of the North West Adelaide Health Study (NWAHS). The cohort has so far participated in three stages of the MAILES Study: MAILES1 (FAMAS Wave 1, from 2002–2005, and NWAHS Wave 2, from 2004–2006); MAILES2 (FAMAS Wave 2, from 2007–2010, and NWAHS Wave 3, from 2008–2010); and MAILES3 (a computer-assisted telephone interview (CATI) survey of all participants in the study, conducted in 2010). Data have been collected on a comprehensive range of physical, psychosocial and demographic issues relating to a number of chronic conditions (including cardiovascular disease, diabetes, arthritis and mental health) and health-related risk factors (including obesity, blood pressure, smoking, diet, alcohol intake and inflammatory markers), as well as on current and past health status and medication. Initial approaches or enquiries regarding the study can be made to either the principal investigator (gary.wittert@adelaide.edu.au) or the project coordinator (sean.martin@adelaide.edu.au).


The Japan Diabetes Complications Study, a randomised lifestyle intervention study of type 2 diabetes conducted at 59 institutes throughout Japan that enrolled 2033 eligible patients from January 1995 to March 1996, was directed at: (i) determining the incidence and progression rates of complications of diabetes; (ii) exploring clinical risk factors for complications of diabetes; and (iii) determining the association between lifestyle factors, including diet and physical activity, and complications of diabetes, in addition to comparing, in a randomised manner, the effects on type 2 diabetes of an extensive lifestyle intervention and conventional treatment. The protocol for the study originally specified four study populations according to primary outcomes, consisting of: (1) a macroangiopathy group (N = 1771); (ii) a nephropathy group (N = 1607); (iii) a retinopathy-incident group (N = 1221); and (iv) a retinopathy-progression group (N = 410). The primary outcomes were: (i) development of retinopathy; (ii) progression of retinopathy; (iii) development of overt nephropathy; and (iv) occurrence of macroangiopathic events including proven coronary heart disease and stroke. The study was originally planned to follow patients for 8 years, and an extended follow-up is ongoing. Information about primary outcomes, laboratory tests, and other clinical variables for each patient was collected at a central data centre through an annual report from each investigator. Additionally, extensive lifestyle surveys were conducted at baseline and 5 years after the beginning of the study intervention in both the intervention and conventional treatment groups. A description of the occurrence of complications of diabetes and of all-cause mortality, provided in this paper, demonstrated a clear gender-based difference in cardiovascular disease and all-cause mortality. The data set of the study is not freely available, but collaborative ideas are welcome. Potential collaborators should discuss ideas informally with the principal investigator by e-mail.


The European Prospective Investigation of Cancer (EPIC) is a 10-country collaborative study in which EPIC-Norfolk is one of the UK centres. EPIC-Norfolk examined 25 639 men and women resident in East Anglia (aged 40–79 years), between 1993 and 1997. The EPIC collaboration was set up to examine the dietary determinants of cancer, but the remit in the EPIC-Norfolk cohort was broadened from the outset to include determinants of other health conditions and chronic diseases. EPIC-Norfolk completed a third round of health examinations (EPIC-Norfolk 3 or 3HC) in December 2011, on 8623 participants in the age range 48–92 years. EPIC-Norfolk focused on objective measures of cognitive function, physical capability and visual health, adapting this existing mid-life cohort to the current need to investigate healthy and independent living for ageing societies. With a wealth of longitudinal data and a biobank (including DNA) collected at up to three separate time points, EPIC-Norfolk offers the unique opportunity to investigate the association of lifestyle and biological factors, including genetic exposures, with a range of health outcomes in middle and later life. Information for data access can be found on the study website, details as given in this cohort profile.


The Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) cohort is a census of all identified HIV-positive individuals in the province of British Columbia. It was formed through the linkage of nine provincial treatment, surveillance and administrative databases. This open cohort allows for bidirectional analyses from 1996 onward and is refreshed annually. Extensive data collection for cohort members includes demographic information, detailed clinical and laboratory data, complete prescription drug use including antiretroviral agents, and information on health service utilization encompassing inpatient and outpatient care, addictions treatment and palliative care. This cohort provides an unprecedented opportunity to evaluate, over an extended time period, patterns and determinants of key outcomes including engagement in the cascade of HIV care from diagnosis to treatment to viral suppression as well as monitoring trends in medical costs, health outcomes and other key healthcare delivery indicators at a population level with wide-ranging, high-quality data. The overall purpose of these activities is to enable the development and implementation of strategically targeted interventions to improve access to testing, care and treatment for all HIV-positive individuals living in British Columbia. As a programme of the Ministry of Health, the STOP HIV/AIDS Evaluation Evaluation Team welcomes input from all stakeholders and possible partners via contact with the Director of Operations for the British Columbia Centre for excellence in HIV AIDS, Ms. Irene Day (iday@cfenet.ubc.ca).


In this paper we update the profile of the 1993 Pelotas (Brazil) Birth Cohort Study, with emphasis on a shift of priority from maternal and child health research topics to four main categories of outcome variables, collected throughout adolescence: (i) mental health; (ii) body composition; (iii) risk factors for non-communicable diseases (NCDs); (iv) human capital. We were able to trace 81.3% (n = 4106) of the original cohort at 18 years of age. For the first time, the 18-years visit took place entirely on the university premises, in a clinic equipped with state-of-the-art equipment for the assessment of body composition. We welcome requests for data analyses from outside scientists. For more information, refer to our website (http://www.epidemio-ufpel.org.projetos_de_pesquisas/estudos/coorte_1993) or e-mail the corresponding author.


Every 3 years, the Australian Government conducts a developmental census across the entire population of children in their first year of full-time schooling (median age 5 years). The first developmental census was conducted in 2009, including 261 147 children, and in 2012 data were collected on 289 973 children—representing 97.5% and 96.5% of the estimated eligible population, respectively. The questionnaire is completed by teachers on the basis of at least 1 month’s knowledge of the child, including aspects of physical, social, emotional, language and cognitive development, as well as data on special needs. Teachers are also asked to include details of the child’s care arrangements and attendance in early education programmes in the years preceding school. Demographic and geographical data are recorded at the individual and area levels. Aggregate data are publicly available and microdata (including data for linkage studies) can be applied for via (www.aedidata.com.au).


The Kombewa Health and Demographic Surveillance System (HDSS) grew out of the Kombewa Clinical Research Centre in 2007 and has since established itself as a platform for the conduct of regulated clinical trials, nested studies and local disease surveillance. The HDSS is located in a rural part of Kisumu County, Western Kenya, and covers an area of about 369 km2 along the north-eastern shores of Lake Victoria. A dynamic cohort of 141 956 individuals drawn from 34 718 households forms the HDSS surveillance population. Following a baseline survey in 2011, the HDSS continues to monitor key population changes through routine biannual household surveys. The intervening period between set-up and baseline census was used for preparatory work, in particular Global Positioning System (GPS) mapping. Routine surveys capture information on individual and households including residency, household relationships, births, deaths, migrations (in and out) and causes of morbidity (syndromic incidence and prevalence) as well as causes of death (verbal autopsy). The Kombewa HDSS platform is used to support health research activities, that is clinical trials and epidemiological studies evaluating diseases of public health importance including malaria, HIV and global emerging infectious diseases such as dengue fever. Formal data request and proposed collaborations can be submitted at Kombewadssdata@usamru-k.org.


Background: Mass drug treatment with azithromycin (MDA) is part of the WHO-endorsed ‘SAFE’ strategy for trachoma control in endemic communities. MDA has been associated with reduced trachoma prevalence and short-term reductions in other bacterial infections, but can also lead to increased circulation of macrolide-resistant bacteria.

Methods: We prospectively monitored macrolide resistance in fecal E. coli collected from young children participating in the PRET+ Study in rural Tanzania. MDA was administered in four villages with >10% trachoma prevalence. Four nearby communities with lower trachoma prevalence served as controls. Rectal swabs were collected during cross-sectional surveys performed at baseline, 1, 3 and 6 months after MDA. Fecal E. coli isolates were screened for macrolide susceptibility using disc diffusion and minimum inhibitory concentration methods. Cross-sectional and longitudinal differences in resistance prevalence by MDA exposure were compared using t-tests and logistic regression.

Results: There was no difference in the proportion of individuals carrying azithromycin-resistant E. coli at baseline (0.21 vs 0.16, P > 0.05). Azithromycin resistance carriage prevalence remained stable over follow-up in non-MDA villages but increased sharply in MDA villages (0.61 at 1 month, 0.42 at 3 months and 0.31 at 6 months). MDA exposure was highly associated with azithromycin resistance carriage at 1 month post-MDA (OR 15.27, P < 0.001) and subsequent surveys. Younger age and recent diarrhoea were also associated with increased odds of resistance (P < 0.01).

Conclusions: MDA resulted in significantly increased prevalence of macrolide resistance in E. coli. Although MDA is effective for trachoma elimination, it has costs; it is essential to monitor antimicrobial resistance following MDA.


Background: Factors associated with Mycobacterium tuberculosis (Mtb) strain success over time in high burdened communities are unknown.

Methods: Mtb isolates collected over 10 years from sputum-positive tuberculosis (TB) patients resident in the study site underwent IS6110-based restriction fragment length polymorphism analysis. Clinical, demographic and social data were extracted from clinic records and interviewer-administered questionnaires. Strains were defined as persistently successful, transiently successful or unsuccessful based on the average number of cases per year and their continued presence over time.

Results: Genotyping data were available on 789 TB cases. Of the 311 distinct Mtb strains (≥6 bands) identified, 247 were categorized as unsuccessful strains, 12 transiently successful and 10 persistently successful strains. Strain success was not associated with age, gender, antiretroviral use or social factors. Persistently successful strains were less likely to be drug-resistant compared with transiently successful strains [odds ratio (OR): 0.13; 95% confidence interval (CI): 0.04 – 0.5]. Persistently successful strains were positively associated with host HIV-infection compared with unsuccessful strains, but this finding was not robust in sensitivity analyses.

Conclusions: Pathogen characteristics appear to play a greater role in Mtb strain success compared with social or host factors. This study supports the need for further investigations into the role of pathogen characteristics in strain success.


Background: Although the risks of adverse pregnancy outcomes associated with anti-D antibodies are well-recognized, much less is known concerning alloimmunization with other red blood cell antibodies detected during routine maternal screening. To date, most reports of adverse pregnancy outcomes associated with non-anti-D antibodies have been from small case studies. The aim of this study was to examine the associations of maternal alloimmunization with specific red blood cell antibodies and the risks of preterm birth and stillbirth in the Swedish population.

Methods: All antibody screening, outcome and covariate data were obtained through linkages of Swedish national health and data registers. Follow-up in these population-based registers was available up to 31 December 2002. The final study sample consisted of 1 022 569 singleton births from 668 952 mothers during 1987–2002.

Results: In total, 1.3% of the 1 022 569 study pregnancies were alloimmunized. In adjusted logistic regression models, compared with having no antibodies, alloimmunization with anti-D, anti-E, anti-C and anti-c was associated with increased risk of both stillbirth and preterm birth. In addition, anti-Kell was associated with increased risk of preterm birth and anti-Lea with increased risk of stillbirth. Compared with firstborn children, risk of preterm birth associated with alloimmunization was greater in subsequent births

Conclusions: In the largest study to date, alloimmunization with Rhesus, K- and -Lea red blood cell antibodies increased the risk of preterm birth and/or stillbirth. The association of anti-Lea with stillbirth was an unexpected finding. Further study of the consequences of non-anti-D alloimmunization is warranted.


Background: Folic acid-containing multivitamins have been associated with a reduced risk of preterm birth. We examined whether periconceptional use of folic acid alone reduced this risk.

Methods: Data were derived from a large population-based cohort study conducted in China to evaluate the prevention of neural tube defects with folic acid supplementation. The sample comprised 207 936 singleton live births delivered at gestational ages of 20–42 weeks to women from two provinces in southern China. Healthcare workers recorded folic acid intake prospectively each month. Gestational age calculation was based on the first day of the last menstrual period. Preterm births were categorized into three clinical subtypes: iatrogenic preterm birth, preterm premature rupture of membranes (PPROM) and spontaneous preterm birth. Logistic regression was used to evaluate the association between folic acid use and the risk of preterm birth, adjusting for potential confounders.

Results: The incidence of preterm birth was significantly lower among folic acid users (5.28%) than among non-users (6.10%). Folic acid use showed a 14% risk reduction for preterm birth overall [adjusted risk ratio (RR) = 0.86, 95% confidence interval (CI) 0.82–0.90]. This association was strongest for spontaneous preterm birth (adjusted RR = 0.81, 95% CI 0.78–0.86) and was not significant for iatrogenic preterm birth (adjusted RR = 0.97, 95% CI 0.88–1.07) or PPROM (adjusted RR = 1.07, 95% CI 0.93–1.23).

Conclusions: Daily intake of 400 μg folic acid alone during the periconceptional period was associated with a reduced risk of spontaneous preterm birth.


Background: Fetal growth characteristics are used to identify influences of several maternal characteristics and to identify individuals at increased risk of adverse outcomes. The extent to which fetal growth characteristics track in different trimesters is not known.

Methods: In a population-based prospective cohort study among 8636 pregnant women, we examined the extent to which fetal growth characteristics track, are influenced by maternal socio-demographic and lifestyle related determinants and are associated with birth outcomes. Fetal growth was assessed in each trimester and at birth.

Results: Correlation coefficient between first-trimester crown-rump length and birthweight was r = 0.12 (P-value < 0.05). Correlation coefficients for fetal-head circumference, (femur) length and (estimated) fetal weight ranged from r = 0.16 to r = 0.30 (all P-values < 0.05) between second trimester and birth and from r = 0.36 to r = 0.58 (all P-values < 0.05) between third trimester and birth, and were highest for (estimated) fetal weight. Correlation coefficients for (estimated) fetal weight tended to be lower among overweight mothers, as compared with normal weight mothers, but were not influenced by other maternal characteristics. First, second and third-trimester fetal growth characteristics were associated with risks of preterm birth and small size for gestational age at birth,with the strongest associations present in third trimester.

Conclusion: Fetal growth characteristics track moderately throughout gestation, with stronger tracking coefficients present in later pregnancy. Tracking coefficients were not materially influenced by maternal socio-demographic and lifestyle characteristics. First, second and third trimester fetal growth characteristics were associated with the risk of adverse birth outcomes.


Background: Fetuses-at-risk denominators are commonly used in research on preterm stillbirth, but applications to postnatal outcomes such as preterm infant mortality are controversial. We evaluated whether biased associations between maternal risk factors and preterm infant mortality caused by stratification by preterm birth could be avoided using fetuses-at-risk risk ratios.

Methods: Data included 3 277 570 births drawn from the linked live birth-death file for Canada from 1990 through 2005. We used maternal age as the risk factor, and estimated the association with stillbirth, early neonatal, late neonatal and postneonatal mortality by gestational interval (22–24, 25–27, 28–31, 32–36, ≥37 weeks). Models were run using (i) log-binomial regression stratified by preterm gestational age, and (ii) unstratified log-binomial regression using fetuses-at-risk denominators.

Results: Extremes of maternal age were associated with higher mortality among term births. Among preterm births, the stratified model suggested a protective, null or attenuated association of extremes of maternal age with stillbirth, early, late and post neonatal mortality. The unstratified fetuses-at-risk model, however, resulted in the expected higher risk of mortality at extremes of maternal age for all outcomes.

Conclusions: Fetuses-at-risk regression can avoid paradoxical associations between maternal exposures and mortality of infants born early in gestation, caused by preterm birth stratification bias. The fetuses-at-risk approach can be extended through the first year of life, or potentially beyond, depending on the outcome and presence of unmeasured confounders associated with preterm birth.


Background: We aimed to establish the association between adverse childhood experiences (maltreatment and household dysfunction) and pubertal maturation, which is associated with later health outcome(s).

Methods: The 1958 British birth cohort (n = 17 638) includes all born in one week, March 1958, followed up to mid adulthood. Pubertal stage was rated by medical personnel at 11 and 16 years of age (y). Childhood maltreatment (neglect or abuse) and household dysfunction scores were constructed from information ascertained in childhood and at 45 y.

Results: Childhood neglect, assessed at 7 y, was associated with late pubertal development on several markers after adjusting for early life circumstances: relative risk ratio (RRRadjusted) was 1.13 (95% CI: 1.06,1.21) and 1.06 (1.00,1.12) for late menarche and breast development (females) per unit increase in neglect score ranging 0–7, respectively; 1.14 (1.08,1.20) for late voice change and 1.07 (1.02,1.13) for pubic hair growth (males). The RRRadjusted for late pubic hair (females) and genitalia and facial hair (males) development was 1.04 (P = 0.052 to 0.085). Abuse score (0–3, for physical, sexual or psychological abuse) was associated in females with late menarche [RRRadjusted = 1.17 (1.01,1.36)] and in males with late pubic hair growth [RRRadjusted = 1.16 (1.01,1.34)] per unit increase, but not with other pubertal markers. Neither score (neglect or abuse) was associated with early puberty, but sexual abuse was associated with early [RRRadjusted = 1.86 (1.06,3.29)] as well as late menarche [RRRadjusted = 1.66 (1.02,2.71)] and witnessing abuse with early genitalia development [RRRadjusted = 1.57 (1.02,2.41)]. Household dysfunction score was not associated consistently with pubertal markers.

Conclusions: Cumulative neglect by 7 y was associated with delayed development of several pubertal markers. The underlying role of pubertal development in linking childhood neglect with future adult health warrants further consideration.


Background: Areca nut, more commonly known as betel nut, is the fourth most commonly used addictive substance in the world. Though recent evidence suggests it may play a role in the development of cardiovascular disease, no studies have investigated whether betel nut use is related to subclinical atherosclerosis.

Methods: We evaluated the association between betel nut use and subclinical atherosclerosis in 1206 participants randomly sampled from the Health Effects of Arsenic Longitudinal Study (HEALS). Frequency and duration of betel nut use were assessed at baseline, and carotid IMT was measured on average 6.65 years after baseline.

Results: A positive association was observed between duration and cumulative exposure (function of duration and frequency) of betel nut use and IMT, with above-median use for duration (7 or more years) and cumulative exposure (30 or more quid-years) corresponding to a 19.1 μm [95% confidence interval (CI): 5.3-32.8; P ≤ 0.01] and 16.8 μm (95% CI: 2.9-30.8; P < 0.05) higher IMT in an adjusted model, respectively. This association was more pronounced in men [32.8 μm (95% CI: 10.0-55.7) and 30.9 μm (95% CI: 7.4-54.2)]. There was a synergy between cigarette smoking and above-median betel use such that the joint exposure was associated with a 42.4 μm (95% CI: 21.6-63.2; P ≤ 0.01) difference in IMT.

Conclusion: Betel nut use at long duration or high cumulative exposure levels is associated with subclinical atherosclerosis as manifested through carotid IMT. This effect is especially pronounced among men and cigarette smokers.



Background: Epidemiological studies have observed protective effects of mid-upper arm circumference (MUAC) against all-cause mortality mostly in Western populations. However, evidence on cause-specific mortality is limited.

Methods: The sample included 19 575 adults from a population-based cohort study in rural Bangladesh, who were followed up for an average of 7.9 years for mortality. Cox proportional hazards regression was used to evaluate the effect of MUAC, as well as the joint effect of body mass index (BMI) and MUAC, on the risk of death from any cause, cancer and cardiovascular disease (CVD).

Results: During 154 664 person-years of follow-up, 744 deaths including 312 deaths due to CVD and 125 deaths due to cancer were observed. There was a linear inverse relationship of MUAC with total and CVD mortality. Each 1-cm increase in MUAC was associated a reduced risk of death from any cause [hazard ratio (HR) = 0.85; 95% confidence interval (C), 0.81–0.89) and CVD (HR = 0.87; 95% CI, 0.80–0.94), after controlling for potential confounders. No apparent relationship between MUAC and the risk of death from cancer was observed. Among individuals with a low BMI (<18.5 kg/m2), a MUAC less than 24 cm was associated with increased risk for all-cause (HR = 1.81; 95% CI, 1.52–2.17) and CVD mortality (HR = 1.45; 95% CI, 1.11–1.91).

Conclusions: MUAC may play a critical role on all-cause and CVD mortality in lean Asians.


Background: Some studies have suggested that overweight is associated with lower mortality, but these results may be affected by reverse causality. We analysed how body mass index (BMI) in young adulthood is associated with mortality in the general population and after the diagnoses of coronary heart disease (CHD), stroke and cancer.

Methods: BMI was measured at an average age of 18 years in 734 438 Swedish men born in 1950–65. Diagnoses of CHD, stroke and cancer as well as all-cause mortality were derived from registers covering the whole population, up to 31 December 2010. The follow-up of 24.56 million person-years included 33 067 cases of mortality and 19 843 CHD, 13 578 stroke and 27 365 cancer diagnoses. Hazard ratios (HR) [with 95% confidence intervals (CI)] were estimated by the Cox proportional hazards model.

Results: Higher mortality in the whole cohort (HR = 1.26, 1.21–1.32) as well as after the diagnosis of CHD (HR = 1.33, 1.09–1.63) or cancer (HR = 1.13, 1.01–1.25) was found in moderately overweight men (BMI 25.0–27.4 kg/m2) as compared with normal weight men (BMI 20.1–22.4 kg/m2); for stroke patients the result for the same BMI categories was not statistically significant (HR = 1.17, 0.94–1.45). Mortality increased with increasing weight status and was highest in obese men (BMI >30 kg/m2): HR = 2.17 (2.02–2.34) for the whole cohort, 2.35 (1.81–3.05) after the diagnosis of CHD, 2.08 (1.56–2.77) after stroke and 1.68 (1.40–2.01) after cancer.

Conclusions: Even moderate overweight in young adulthood increases all-cause mortality and mortality after the diagnosis of CHD, stroke and cancer in men. Preventing overweight in young adulthood remains as an important public health issue.


Background: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.

Methods: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n = 50 000) and CVD risk factors (n = 200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.

Results: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR < 0.01). For T2D, we detected one locus adjacent to HNF1B.

Conclusions: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.


Background: Smoking is a major cause of morbidity and mortality. Smoking-related epigenetic biomarkers may open new avenues to better quantify the adverse health effects of smoking, and to better understanding of the underlying mechanisms. We aimed to evaluate the clinical implications of F2RL3 methylation, a novel epigenetic biomarker of smoking exposure disclosed by recent genome-wide methylation studies.

Methods: Blood DNA methylation at F2RL3 (also known as PAR-4) was quantified in baseline samples of 3588 participants aged 50–75 years in a large population-based prospective cohort study by MALDI-TOF mass spectrometry. Deaths were recorded during a median follow-up of 10.1 years. The associations of methylation intensity and of smoking with all-cause, cardiovascular, cancer and other mortality were assessed by Cox’s proportional hazards regression, controlling for potential confounding factors.

Results: Lower methylation intensity at F2RL3 was strongly associated with mortality. After adjustment for multiple covariates including smoking, hazard ratios [95% confidence interval (CI)] for death from any cause, cardiovascular disease, cancer or other causes were 2.60 (95% CI, 1.81-3.74), 2.45 (95% CI, 1.28-4.68), 2.94 (95% CI, 1.68-5.14) and 2.39 (95% CI, 1.11-5.16), respectively, in subjects in the lowest quartile of methylation intensity compared with subjects in the highest quartile. The associations with mortality outcomes were much stronger among men than among women. In addition, strong positive associations of smoking with each of the outcomes were substantially weakened, and almost disappeared when controlling for F2RL3 methylation intensity.

Conclusions: F2RL3 methylation is a strong predictor of mortality, including all-cause, cardiovascular, cancer and other mortality. Systemic adverse effects of smoking may be mediated by pathways associated with F2RL3 methylation.


Background: We conducted a meta-analysis in order to investigate whether circulating adiponectin, an insulin-sensitizing hormone produced by adipocytes, is associated with breast cancer risk.

Methods: A systematic literature search was performed in PubMed, Medline, EMBASE, ISI Web of Knowledge and the Cochrane Library. The summary relative risk (SRR) was calculated by pooling the different study-specific estimates using the random effect models. Meta-regression, subgroup and sensitivity analyses were carried out to investigate between-study heterogeneity and to test publication bias.

Results: Data from 15 observational studies, published between 2003 and April 2013 for a total of 4249 breast cancer cases, were analysed. The SRR for the ‘highest’ vs ‘lowest’ adiponectin levels indicated a 34% reduction in breast cancer risk [95% confidence interval (CI): 13%–50%]. Between-study heterogeneity was not substantial (I2 = 53%). Ten studies were included in the dose-response analysis: the SRR for an increase of 3 µg/ml of adiponectin corresponded to a 5% risk reduction (95% CI: 1%–9%). The comparison between ‘highest’ and ‘lowest’ levels of adiponectin showed an inverse association in postmenopausal women (SRR = 0.80; 95% CI: 0.63–1.01) and an indication of an inverse relationship in premenopausal women (SRR = 0.72, 95% CI: 0.30–1.72). No evidence of publication bias was found.

Conclusions: Low circulating adiponectin levels are associated with an increased breast cancer risk. However, properly designed studies are needed to confirm the role of adiponectin as breast cancer biomarker, and clinical trials should be performed to identify those interventions that may be effective in modulating adiponectin levels and reducing breast cancer risk.



Background: Mammographic density (MD) has not been systematically investigated among Chinese women. Breast cancer screening programmes provided detailed information on MD in a large number of asymptomatic women.

Methods: In the Multi-modality Independent Screening Trial (MIST), we estimated the association between MD and its influential factors using logistic regression, adjusting for age, body mass index (BMI) and study area. Differences between Chinese and other ethnic groups with respect to MD were also explored with adjustment for age and BMI.

Results: A total of 28 388 women aged 45 to 65 years, who had been screened by mammography, were enrolled in the study. Of these, 49.2% were categorized as having dense breasts (BI-RADS density 3 and 4) and 50.8% as fatty breasts (BI-RADS density 1 and 2). Postmenopausal status [odds ratio (OR) = 0.66; 95% confidence interval (CI): 0.62–0.70] and higher number of live births (OR = 0.56; 95% CI: 0.46–0.68) were inversely associated with MD, whereas prior benign breast disease (OR = 1.48; 95% CI: 1.40–1.56) and later age at first birth (OR = 1.17; 95% CI: 1.08–1.27) were positively associated with MD. In comparison with the data from the Breast Cancer Surveillance Consortium, we found that women in MIST were more likely to have fatty breasts than Americans (from the Breast Cancer Surveillance Consortium) in the older age group (≥50 years) but more likely to have dense breasts in the younger age group (<50 years).

Conclusions: This study suggests that several risk factors for breast cancer were associated with breast density in Chinese women. Information on the determinants of mammographic density may provide valuable insights into breast cancer aetiology.


Background: Chinese women’s reproductive patterns have changed significantly over the past several decades. However, relatively little is known about the pace and characteristics of these changes either overall or by region and socioeconomic status.

Methods: We examined the cross-sectional data from the China Kadoorie Biobank cohort study that recruited 300 000 women born between 1930 and 1974 (mean age: 51 years) from 10 socially diverse urban and rural regions of China. Temporal trends in several self-reported reproductive characteristics, and effect modification of these trends by area and education (as a surrogate for socioeconomic status), were examined.

Results: The overall mean age at menarche was 15.4 (standard deviation 1.9) years, but decreased steadily over the 45 birth cohorts from 16.1 to 14.3 years, except for an anomalous increase of ~1 year for women exposed to the 1958-61 famine in early adolescence. Similarly large changes were seen for other characteristics: mean parity fell (urban: 4.9 to 1.1; rural: 5.9 to 1.4); mean age at first birth increased (urban: 19.0 to 25.9 years; rural: 18.3 to 23.8 years); and birth spacing increased after 1980 to over 5 years. Breastfeeding declined after 1950 in urban and, after 1980, in rural women; and 68% of urban and 48% of rural women experienced a terminated pregnancy. Mean age at menopause increased from 47.9 to 49.3 years.

Conclusions There have been striking changes in reproductive factors over time and between areas among these Chinese women. Their effects on major chronic diseases should be investigated.


Background: Observational studies suggest that breastfeeding benefits later maternal child-feeding practices, which in turn may contribute to positive eating attitudes. We investigated the effect of a randomized intervention to increase duration and exclusivity of breastfeeding on pre-adolescent eating attitudes.

Methods: Long-term follow-up of the Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster-randomized trial in 31 maternity hospitals and affiliated polyclinics in Belarus. Sites were randomly assigned an experimental intervention to promote longer duration and exclusivity of breastfeeding in mothers who initiated breastfeeding (n = 16 sites), or a control intervention of continuing usual care (n = 15 sites); 17 046 healthy infants were enrolled in 1996–7, of whom 13 751 (80.7%) completed the Children’s Eating Attitude Test (ChEAT) at 11.5 years of age. A ChEAT score ≥22.5 (85th percentile) was used as an indicator of problematic eating attitudes. Analysis was based on intention-to-treat, accounting for clustering within hospitals/clinics.

Results: Compared with the control arm, the experimental intervention substantially increased breastfeeding exclusivity (43.3% vs 6.4% exclusively breastfed at 3 months of age) and duration of any breastfeeding throughout infancy. The proportion of children with ChEAT scores ≥22.5 was lower in the experimental than control arm (boys 11.4% vs 17.2%; girls 18.5% vs 23.4%) [cluster-adjusted odds ratio (OR), boys: 0.44; 95% confidence interval (CI): 0.21,0.93; girls: 0.51; 95% CI: 0.27,0.99). Results were robust to adjustment for potential confounders and using a ChEAT score ≥25.5 (91st percentile) as the outcome (OR: 0.53; 95% CI: 0.28,1.03).

Conclusions: An intervention to improve the duration and exclusivity of breastfeeding among term infants in Belarus was associated with a reduction in problematic eating attitudes at 11.5 years of age.


Background: Blinding patients in clinical trials is a key methodological procedure, but the expected degree of bias due to nonblinded patients on estimated treatment effects is unknown.

Methods: Systematic review of randomized clinical trials with one sub-study (i.e. experimental vs control) involving blinded patients and another, otherwise identical, sub-study involving nonblinded patients. Within each trial, we compared the difference in effect sizes (i.e. standardized mean differences) between the sub-studies. A difference <0 indicates that nonblinded patients generated a more optimistic effect estimate. We pooled the differences with random-effects inverse variance meta-analysis, and explored reasons for heterogeneity.

Results: Our main analysis included 12 trials (3869 patients). The average difference in effect size for patient-reported outcomes was –0.56 (95% confidence interval –0.71 to –0.41), (I2 = 60%, P = 0.004), i.e. nonblinded patients exaggerated the effect size by an average of 0.56 standard deviation, but with considerable variation. Two of the 12 trials also used observer-reported outcomes, showing no indication of exaggerated effects due lack of patient blinding. There was a larger effect size difference in 10 acupuncture trials [–0.63 (–0.77 to –0.49)], than in the two non-acupuncture trials [–0.17 (–0.41 to 0.07)]. Lack of patient blinding also increased attrition and use of co-interventions: ratio of control group attrition risk 1.79 (1.18 to 2.70), and ratio of control group co-intervention risk 1.55 (0.99 to 2.43).

Conclusions: This study provides empirical evidence of pronounced bias due to lack of patient blinding in complementary/alternative randomized clinical trials with patient-reported outcomes.


Background: Despite numerous population-based randomized intervention trials, the impact of such interventions on socioeconomic inequalities has rarely been examined. We used data from a large cluster-randomized trial to assess the impact of a breastfeeding promotion intervention on socioeconomic inequalities in breastfeeding (exclusivity and duration) and in child cognitive ability at early school age.

Methods: The Promotion of Breastfeeding Intervention Trial (PROBIT) randomized 31 Belarusian maternity hospitals and their affiliated polyclinics either to receive a breastfeeding promotion intervention modelled on the WHO/UNICEF Baby-Friendly Hospital Initiative or to continue the standard practices in effect at the time of randomization. We estimated and compared inequalities in discontinuation of exclusive breastfeeding before 3 months and of any breastfeeding before 12 months and in child verbal IQ at age 6.5 years, across maternal education strata between the two intervention arms.

Findings: Socioeconomic inequalities in discontinuing exclusive breastfeeding before 3 months were negligible in the control group. However, graded inequalities by maternal education emerged in the intervention group {relative risk [RR] = 1.12 [95% confidence interval (CI): 1.04, 1.20] for partial university and RR = 1.20 [95% CI: 1.11, 1.31] for secondary education or less vs complete university; risk difference [RD] = 0.06 [95% CI: 0.03, 0.09] and 0.10 [95% CI: 0.06, 0.14], respectively}. For discontinuing any breastfeeding before 12 months, small socioeconomic gradients in the control group were widened in the intervention group (RR = 1.04 and 1.16, respectively, for mothers with secondary education or less). Despite these differential effects on breastfeeding, however, we observed a small, nonsignificant reduction in socioeconomic inequalities in child verbal IQ at age 6.5 years.

Conclusions: A population-based intervention to promote breastfeeding slightly widened socioeconomic inequalities in breastfeeding but not those in child cognitive ability.



Background: Debates exist over whether health inequities are bound to rise as population health improves, due to health improving more quickly among the better off, with most analyses focused on mortality data.

Methods: We analysed 50 years of socioeconomic inequities in measured health status among US-born Black and White Americans, using data from the National Health Examination Surveys (NHES) I-III (1959–70), National Health and Nutrition Examination Surveys (NHANES) I-III (1971–94) and NHANES 1999–2008.

Results: Absolute US socioeconomic health inequities for income percentile and education variously decreased (serum cholesterol; childhood height), stagnated [systolic blood pressure (SBP)], widened [body mass index (BMI), waist circumference (WC)] and in some cases reversed (age at menarche), even as on-average values rose (BMI, WC), idled (childhood height) and fell (SBP, serum cholesterol, age at menarche), with patterns often varying by race/ethnicity and socioeconomic measure; similar results occurred for relative inequities. For example, for WC, the adverse 20th (low) vs 80th (high) income percentile gap increased only among Whites (NHES I: 0.71 cm [95% confidence interval (CI) –0.74, 2.16); NHANES 2005–08: 2.10 (95% CI 0.96, 3.62)]. By contrast, age at menarche for girls in the 20th vs 80th income percentile among Black girls remained consistently lower, by 0.34 years (95% CI 0.12, 0.55) whereas among White girls the initial null difference became inverse [NHANES 2005–08: –0.49 years (95% CI –0.86, –0.12; overall P = 0.0015)]. Adjusting for socioeconomic position only modestly altered Black/White health inequities.

Conclusions: Health inequities need not rise as population health improves.


Background: Factors underlying socioeconomic inequalities in mortality are not well understood. This study contributes to our understanding of potential pathways to result in socioeconomic inequalities, by examining alcohol consumption as one potential explanation via comparing socioeconomic inequalities in alcohol-attributable mortality and all-cause mortality.

Methods: Web of Science, MEDLINE, PsycINFO and ETOH were searched systematically from their inception to second week of February 2013 for articles reporting alcohol-attributable mortality by socioeconomic status, operationalized by using information on education, occupation, employment status or income. The sex-specific ratios of relative risks (RRRs) of alcohol-attributable mortality to all-cause mortality were pooled for different operationalizations of socioeconomic status using inverse-variance weighted random effects models. These RRRs were then combined to a single estimate.

Results: We identified 15 unique papers suitable for a meta-analysis; capturing about 133 million people, 3 741 334 deaths from all causes and 167 652 alcohol-attributable deaths. The overall RRRs amounted to RRR = 1.78 (95% confidence interval (CI) 1.43 to 2.22) and RRR = 1.66 (95% CI 1.20 to 2.31), for women and men, respectively. In other words: lower socioeconomic status leads to 1.5–2-fold higher mortality for alcohol-attributable causes compared with all causes.

Conclusions: Alcohol was identified as a factor underlying higher mortality risks in more disadvantaged populations. All alcohol-attributable mortality is in principle avoidable, and future alcohol policies must take into consideration any differential effect on socioeconomic groups.


Background: Global progress in reducing the burden of undernutrition tends to be measured at the population level. It has been hypothesized that population-level improvements may mask widening socioeconomic inequalities, but little attempt has been made to assess whether this is true.

Methods: Original data from 131 demographic health surveys and 48 multiple indicator cluster surveys from 1990 to 2011 were used to examine trends in socioeconomic inequalities in stunting and underweight, as well as the relationship between changes in prevalence and changes in inequality, in 80 countries. Socioeconomic inequality is measured using the corrected concentration index.

Results: Countries with a higher prevalence of stunting tend to have larger socioeconomic inequalities in stunting (Spearman rank correlation = –0.27 P = 0.014). In most countries, there has been no change in inequality in stunting: in 31 out of 53, the 90% confidence intervals around the changes overlap the zero value. In the remaining 22, there was a reduction in inequality in 11 and an increase in 11. The distributional patterns underlying the summary inequality statistics vary considerably across countries, but in most there have been considerable gains to the poorest quintile.

Conclusions: Reductions in the prevalence of undernutrition have generally not been accompanied by widening inequalities. However, inequalities have also not been narrowing. Rather, the picture is one of a strong persistence of existing inequalities. In addition, there are different distributional patterns underlying changes in the summary indices of inequality which will need to be taken into consideration in designing programmes to reach the poor.


The terminology describing missingness mechanisms is confusing. In particular the meaning of ‘missing at random’ is often misunderstood, leading researchers faced with missing data problems away from multiple imputation, a method with considerable advantages. The purpose of this article is to clarify how ‘missing at random’ differs from ‘missing completely at random’ via an imagined dialogue between a clinical researcher and statistician.