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The relationship of parents' cigarette smoking to outcome of pregnancy—implications as to the problem of inferring causation from observed associations. Amer J Epidem 1971;93:443–456. Nearly 10 000 white and more than 3000 black women were interviewed early in pregnancy on a variety of medical, genetic, environmental, and behavior variables. The increase in the incidence of low-birth-weight among infants of smoking mothers was confirmed. However, a number of paradoxical findings were observed which raise doubts as to causation. Thus, no increase in neonatal mortality was noted. Rather, the neonatal mortality rate and the risk of congenital anomalies of low-birthweight infants were considerably lower for smoking than for nonsmoking mothers. These favorable results cannot be explained by differences in gestational age, nor does a "displacement" hypothesis appear reasonable. Among other findings which could not easily be explained: The healthiest low-birth-weight infants were found for couples where the wife smoked and her husband did not smoke; the most vulnerable were produced by couples where the wife did not smoke and the husband smoked. There were great differences in mode-of-life characteristics between smokers and nonsmokers. The latter were more likely to use contraceptive methods, to plan the baby, less likely to drink coffee and hard liquor, and in general appeared to live at a much slower and moderate pace than the smokers. Most puzzling difference is that of age at menarche, which was lower for smoking mothers. These paradoxical findings raise doubts and argue against the proposition that cigarette smoking acts as an exogenous factor which interferes with intrauterine development of the fetus.








This is the first comprehensive cohort study of the health of older people ever conducted in Iran. The aim of this project is to investigate the health status of older people in Amirkola in the northern part of Iran, near the Caspian Sea. The Amirkola Health and Ageing Project (AHAP) is mainly concerned with geriatric medical problems, such as falling, bone fragility and fractures, cognitive impairment and dementia, poor mobility and functional dependence. It is planned that all participants will be re-examined after 2 years. Data are collected via questionnaire, examinations and venepuncture. AHAP started in April 2011 and 1616 participants had been seen by 18 July 2012, the end of the baseline stage of this study. The participation rate was 72.3%. The prevalence of self-reported hypertension (41.2%) and diabetes mellitus (23.3%) are high. Only 14.4% of older people considered their health as excellent or good in comparison with others at this age. The prevalence of osteoporosis (T score ≤ –2.5) was 57.4% in women and 16.1% in men, and 38.2 % of older people were vitamin D deficient (<20 ng/ml). Researchers interested in using the information are invited to contact the principal investigator Seyed Reza Hosseini (hosseinim46@yahoo.com).



The Motorik-Modul (MoMo) Longitudinal Study aims to contribute to long-term improvement in the health of German children and adolescents by focusing on: (i) the development of physical fitness and physical activity (including period effects); (ii) the individual and physical/social environmental determinants of the development of physical fitness and physical activity; and (iii) the impact of physical fitness and physical activity on the development of physical and mental health. The MoMo Longitudinal Study began with a nationwide representative sample of 4529 children and adolescents who ranged in age from 4–17 years at the study baseline (2003–2006). The first survey wave of the MoMo Longitudinal Study was conducted between 2009 and 2012, with two subsequent survey waves to be conducted between 2014 and 2016 and 2018 and 2020, respectively. The MoMo Longitudinal Study includes a physical fitness test profile, a physical activity questionnaire, and subjective and objective measures of health from the German Health Interview and Examination Survey (KiGGS). Data access is provided on request (alexander.woll@kit.edu). For further information, including a complete list of publications please visit www.motorik-modul.de.


The Andhra Pradesh Children and Parents Study (APCAPS) was originally established to study the long-term effects of early-life undernutrition on risk of cardiovascular disease. Its aims were subsequently expanded to include trans-generational influences of other environmental and genetic factors on chronic diseases in rural India. It builds on the Hyderabad Nutrition Trial (HNT) conducted in 1987–90 to compare the effects on birthweight of a protein-calorie supplement for pregnant women and children. The index children of HNT and their mothers were retraced and examined in 2003–05, and the children re-examined as young adults aged 18–21 years in 2009–10. The cohort was expanded to include both parents and siblings of the index children in a recently completed follow-up conducted in 2010–12 (N = ~6225 out of 10 213 participants). Recruitment of the remaining residents of these 29 villages (N = ~55 000) in Ranga Reddy district of Andhra Pradesh is now under way. Extensive data on socio-demographic, lifestyle, medical, anthropometric, physiological, vascular and body composition measures, DNA, stored plasma, and assays of lipids and inflammatory markers on APCAPS participants are available. Details of how to access these data are available from the corresponding author.


The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort with inclusions ongoing since 1989. The research objectives focus mainly on mid- and long-term clinical outcomes and therapeutic strategies, as well as severe AIDS and non-AIDS morbidities, and public health issues relative to HIV infection. FHDH also serves to describe HIV-infected patients receiving hospital care in France. FHDH includes data on more than 120 000 HIV-infected patients from 70 French general or university hospitals distributed throughout France. Patients are eligible for inclusion if they are infected by HIV-1 or HIV-2 and give their written informed consent. Standardized variables are collected at each outpatient visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed or a change in biological markers is noted, and/or at least every 6 months. Since its inception, variables collected in FHDH include demographic characteristics, HIV-related biological markers, the date and type of AIDS and non AIDS-defining events, antiretroviral treatments and the date and causes of death, as reported in the medical records. Since 2005, data have also been collected on: co-infection with hepatitis B or C virus; alcohol and tobacco use; and non HIV-related biomarkers. Anyone can submit a research project by completing a standardized form available on the FHDH website (http://www.ccde.fr/_fold/fl-1385734776-429.pdf) or from the corresponding author, describing the context and objectives of the study. All projects are reviewed by the scientific committee.


This is an update of the 2004 Pelotas Birth Cohort profile, originally published in 2011. In view of the high prevalence of overweight and mental health problems among Brazilian children, together with the availability of state-of-the-art equipment to assess body composition and diagnostic tests for mental health in childhood, the main outcomes measured in the fifth follow-up (mean age 6.8 years) included child body composition, mental health and cognitive ability. A total of 3722 (90.2%) of the original mothers/carers were interviewed and their children examined in a clinic where they underwent whole-body dual X-ray absorptiometry (DXA), air displacement plethysmography and a 3D photonic scan. Saliva samples for DNA were obtained. Clinical psychologists applied the Development and Well-Being Assessment questionnaire and the Wechsler Intelligence Scale for Children to all children. Results are being compared with those of the two earlier cohorts to assess the health effects of economic growth and full implementation of public policies aimed at reducing social inequalities in the past 30 years. For further information visit the programme website at [http://www.epidemio-ufpel.org.br/site/content/coorte_2004/questionarios.php]. Applications to use the data should be made by contacting 2004 cohort researchers and filling in the application form available at [http://www.epidemio-ufpel.org.br/site/content/estudos/formularios.php].


The PATHS Data Resource is a unique database comprising data that follow individuals from the prenatal period to adulthood. The PATHS Resource was developed for conducting longitudinal epidemiological research into child health and health equity. It contains individual-level data on health, socioeconomic status, social services and education. Individuals’ data are linkable across these domains, allowing researchers to follow children through childhood and across a variety of sectors. PATHS includes nearly all individuals that were born between 1984 and 2012 and registered with Manitoba’s universal health insurance programme at some point during childhood. All PATHS data are anonymized. Key concepts, definitions and algorithms necessary to work with the PATHS Resource are freely accessible online and an interactive forum is available to new researchers working with these data. The PATHS Resource is one of the richest and most complete databases assembled for conducting longitudinal epidemiological research, incorporating many variables that address the social determinants of health and health equity. Interested researchers are encouraged to contact [mchp_access@cpe.umanitoba.ca] to obtain access to PATHS to use in their own programmes of research.


The Muzaffarpur-TMRC Health and Demographic Surveillance System (HDSS), established in 2007, was developed as an enlargement of the scope of a research collaboration on the project Visceral Leishmaniasis in Bihar, which had been ongoing since 2005. The HDSS is located in a visceral leishmaniasis (VL)-endemic area in the Muzaffarpur district of Bihar state in India. It is the only HDSS conducting research on VL, which is a vector-borne infectious disease transmitted by female phlebotomine sandflies and is fatal if left untreated. Currently the HDSS serves a population of over 105 000 in 66 villages. The HDSS collects data on vital events including pregnancies, births, deaths, migration and marriages, as well as other socio-economic indicators, at regular intervals. Incident VL cases are identified. The HDSS team is experienced in conducting both qualitative and quantitative studies, sample collection and rapid diagnostic tests in the field. In each village, volunteers connect the HDSS team with the community members. The Muzaffarpur-TMRC HDSS provides opportunities for studies on VL and other neglected tropical diseases (NTDs) and their interaction with demographic events such as migration. Queries related to research collaborations and data sharing can be sent to Dr Shyam Sundar at [drshyamsundar@hotmail.com].


Background: Tobacco smoking has been associated with cardiovascular risk factors including adverse serum lipid levels, central obesity and higher resting heart rate, but lower blood pressure and body mass index (BMI). We used a Mendelian randomization approach to study whether these associations may be causal. If smoking affects cardiovascular risk factors then rs1051730 T alleles, predictors of increased smoking quantity, should be associated with cardiovascular risk factors among smokers, but not among never smokers.

Methods: Among 56 625 participants of a population-based study, we estimated associations of rs1051730 T alleles with cardiovascular risk factors and examined whether the associations differed by smoking status.

Results: Rs1051730 T alleles were associated with lower BMI and waist and hip circumferences and higher resting heart rate and estimated glomerular filtration rate (eGFR), and the associations were strongest among current smokers (P interaction 5 x 10–9 to 0.01). Rs1051730 T alleles were associated with lower systolic blood pressure and pulse pressure and higher HDL cholesterol concentrations, but these associations did not robustly differ by smoking status. There were no convincing associations of rs1051730 T alleles with waist-hip ratio, diastolic blood pressure and non-fasting serum concentrations of non-HDL cholesterol, triglycerides, glucose and C-reactive protein.

Conclusions: This Mendelian randomization analysis provides evidence that smoking may cause lower BMI and waist and hip circumferences and higher resting heart rate and eGFR. The findings further suggest that smoking is not a major determinant of waist-hip ratio or adverse blood pressure, serum lipid or glucose levels.



Background: High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality.

Methods: We studied 55 568 individuals including 32 823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses.

Results: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend <0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with –13 base pairs (–18, –8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (–10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (–3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality.

Conclusions: High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association.



Background: Disturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established.

Methods: We studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C->T) by instrumental variable and triangulation analysis, separately and using meta-analysis.

Results: Median (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 µmol/l (6.7,10.8) and 2642 g (379) in the PMNS and 6.0 µmol/l (5.1,7.1) and 2871 g (443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration—PMNS: –22 g/SD [95% confidence interval (CI): (–50, 5), adjusted for gestational age and offspring gender]; Parthenon: –57 g (–92, –21); meta-analysis: –40 g (–62, –17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: –46 g (–102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: –78 g (–170, 15); meta-analysis: –61 g (–111, –10)]. Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight.

Conclusions: Our findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growth.



Background: Suicide is higher among economically inactive and unemployed persons than employed persons. This paper investigates differences in this relationship by sex and age over the period 2001 to 2010 in Australia. It also examines changes in suicide among employed, unemployed and economically inactive persons during the recession of 2007–09.

Method: Suicide data from the National Coroners Information System were utilised for this retrospective study. Negative binomial and Poisson regression was used to estimate the association between suicide and employment status and to investigate differences in suicide rates over the period of the recession (2007–09) compared with the year before the recession (2006).

Results: Results suggest that during 2001–10 economically inactive/unemployed males had a suicide rate ratio (RR) of 4.62 [95% confidence interval (CI) 4.10, 5.19; P < 0.001] compared with employed males (RR = 1.00), whereas economically inactive/unemployed females had a suicide RR of 8.44 compared with employed females (95% CI 7.38, 9.67; P < 0.001). There was an increase in suicide among both employed (7% rise in 2007, P = 0.003) and economically inactive/unemployed males during the GFC (22% in 2008, P < 0.001). Suicide also increased among economically inactive/unemployed females (12% in 2007, P = 0.03; 19% in 2008, P = 0.001) but not among employed females.

Conclusions: These results suggest the need for adequate policy and social welfare responses to ameliorate the effects of the economic recession on the working age population. Particularly, these should target unemployed and economically inactive men and women in Australia, who may be at higher risk of suicide than previously thought.


Aim: To examine whether late-career job loss increased depression among older workers approaching retirement in the USA and Europe.

Methods: Longitudinal data came from the Health and Retirement Survey and the Survey of Health, Ageing, and Retirement in Europe. Workers aged 50 to 64 years in 13 European countries and the USA were assessed biennially from 2006 to 2010. Individual fixed effects models were used to test the effect of job loss on depressive symptoms, controlling for age, sex, physical health, initial wealth and socio-demographic factors.

Results: Job loss was associated with a 4.78% [95% confidence interval (CI): 0.823% to 8.74%] increase in depressive symptoms in the USA compared with a 3.35% (95% CI: 0.486% to 6.22%) increase in Europe. Job loss due to a worker’s unexpected firm closure increased depression scores in both the USA (beta = 28.2%, 95% CI: 8.55% to 47.8%) and Europe (beta = 7.50%, 95% CI: 1.25% to 13.70%), but pooled models suggested significantly stronger effects for US workers (P < 0.001). American workers who were poorer before the recession experienced significantly larger increases in depressive symptoms compared with wealthier US workers (beta for interaction = –0.054, 95% CI: –0.082 to –0.025), whereas pre-existing wealth did not moderate the impact of job loss among European workers.

Conclusions: Job loss is associated with increased depressive symptoms in the USA and Europe, but effects of job loss due to plant closure are stronger for American workers. Wealth mitigates the impact of job loss on depression in the USA more than in Europe.



Background: Research on future labour market marginalization following suicide attempt at young age is scarce. We investigated the effects of suicide attempts on three labour market outcomes: unemployment, sickness absence and disability pension.

Methods: We conducted a prospective cohort study based on register linkage of 1 613 816 individuals who in 1994 were 16–30 years old and lived in Sweden. Suicide attempters treated in inpatient care during the 3 years preceding study entry, i.e. 1992–94 (N = 5649) were compared with the general population of the same age without suicide attempt between 1973 and 2010 (n = 1 608 167). Hazard ratios (HRs) for long-term unemployment (>180 days), sickness absence (>90 days) and disability pension in 1995–2010 were calculated by Cox regression models, adjusted for a number of parental and individual risk markers, and stratified for previous psychiatric inpatient care not due to suicide attempt.

Results: The risks for unemployment [HR 1.58; 95% confidence interval (CI) 1.52–1.64], sickness absence (HR 2.16; 2.08–2.24) and disability pension (HR 4.57; 4.34–4.81) were considerably increased among suicide attempters. There was a dose-response relationship between number of suicide attempts and the risk of disability pension, for individuals both with or without previous psychiatric hospitalizations not due to suicide attempts. No such relationship was present with regard to unemployment.

Conclusions: This study highlights the strong association of suicide attempts with future marginalization from the labour market, particularly for outcomes that are based on a medical assessment. Studies that focus only on unemployment may largely underestimate the true detrimental impact of suicide attempt on labour market marginalization.


Background: South Africa is experiencing a health and social transition including an ageing population and an HIV epidemic. We report mortality experience of an older rural South African population.

Methods: Individual survey data and longer-term demographic data were used to describe factors associated with mortality. Individuals aged 50 years and over (n = 4085) answered a health and quality of life questionnaire in 2006 and were followed for 3 years thereafter. Additional vital events and socio-demographic data were extracted from the Agincourt Health and Demographic Surveillance System from 1993 to 2010, to provide longer-term trends in mortality. Cox regression analysis was used to determine factors related to survival.

Results: In 10 967 person-years of follow-up between August 2006 and August 2009, 377 deaths occurred. Women had lower mortality {hazard ratio [HR] 0.35 [95% confidence interval (CI) 0.28–0.45]}. Higher mortality was associated with being single [HR 1.48 (95% CI 1.16–1.88)], having lower household assets score [HR 1.79 (95% CI 1.28–2.51)], reporting greater disability [HR 2.40 (95% CI 1.68–3.42)] and poorer quality of life [HR 1.59 (95% CI 1.09–2.31)]. There was higher mortality in those aged under 69 as compared with those 70 to 79 years old. Census data and cause specific regression models confirmed that this was due to deaths from HIV/TB in the younger age group.

Conclusions: Mortality due to HIV/TB is increasing in men, and to some extent women, aged over 50. Policy makers and practitioners should consider the needs of this growing and often overlooked group.


Background: Age at natural menopause (ANM) is considered a marker of biological ageing and is increasingly recognized as a sentinel for chronic disease risk in later life. Socioeconomic position (SEP) and lifestyle factors are thought to be associated with ANM.

Methods: We performed a systematic review and meta-analyses to determine the overall mean ANM, and the effect of SEP and lifestyle factors on ANM by calculating the weighted mean difference (WMD) and pooling adjusted hazard ratios. We explored heterogeneity using meta-regression and also included unpublished findings from the Australian Longitudinal Study on Women’s Health.

Results: We identified 46 studies across 24 countries. Mean ANM was 48.8 years [95% confidence interval (CI): 48.3, 49.2], with between-study heterogeneity partly explained by geographical region. ANM was lowest among African, Latin American, Asian and Middle Eastern countries and highest in Europe and Australia, followed by the USA. Education was associated with later ANM (WMD middle vs low education 0.30, 95% CI: 0.10, 0.51; high vs low education 0.64, 95% CI 0.26, 1.02). A similar dose-response relationship was also observed for occupation. Smoking was associated with a 1-year reduction of ANM (WMD: -0.91, 95% CI: –1.34, –0.48). Being overweight and moderate/high physical activity were modestly associated with later ANM, but findings were less conclusive.

Conclusions: ANM varies across populations, partly due to differences across geographical regions. SEP and some lifestyle factors are associated with ANM, but further research is needed to examine the impact of the associations between risk factors and ANM on future health outcomes.


Background: Of the 1 billion people with hypertension globally, two-thirds reside in low- and middle-income countries (LMICs). The risk of hypertension in LMICs is thought to be positively associated with socioeconomic status (SES). However, recent studies have provided data inconsistent with this concept. Thus, we assessed the association between SES and hypertension in rural populations of LMICs. Further, we explored whether this association differs according to geographical region.

Methods: Through a search of databases we identified population-based studies that presented risk estimates for the association between SES, or any of its proxies, and hypertension. Meta-analyses were conducted using a random effects model.

Results: Overall, no association was detected between educational status and hypertension, whereas a positive association was observed with income. Interestingly, educational status was inversely associated with hypertension in East Asia {effect size [ES] 0.82 [95% confidence interval (CI) 0.78, 0.87]} but positively associated in South Asia [ES 1.28 (95% CI 1.14, 1.43)]. Higher income, household assets or social class were positively associated with hypertension in South Asia whereas no association was detected in East Asia and Africa. Compared with other occupations, farmers or manual labourers were associated with a lower risk for hypertension. Further, in regions such as Latin America, few studies were identified that fulfilled our inclusion criteria.

Conclusions: We provide evidence that the association between hypertension and SES in rural populations of LMICs in Asia varies according to geographical region. This has important implications for targeting intervention strategies aimed at high-risk populations in different geographical regions.




Background: The level of evidence regarding the association between red and processed meat intakes and breast cancer risk is still low, due to insufficient prospective studies. Moreover, mechanistic data suggest that some antioxidants may modulate this relationship but epidemiological evidence is lacking. Our objectives were to investigate relationships between red and processed meat intakes and breast cancer risk, and to study whether an antioxidant supplementation modulates these associations, which, to our knowledge, has never been investigated before.

Methods: The SU.VI.MAX study was a randomized, double-blind, placebo-controlled trial in which participants received a combination of low-dose antioxidants or a placebo from 1994 to 2002. This observational prospective analysis included 4684 women among whom 190 developed a first incident breast cancer between 1994 and 2007 [mean (range) follow-up = 11.3 (0-13)years]. Baseline dietary data were assessed by repeated dietary records in 1994-1995. Associations between quartiles of red and processed meat intakes and breast cancer risk were characterized by multivariate Cox proportional hazards models.

Results: Breast cancer risk was directly associated with processed meat intake [hazard ratio (HR)Q4vsQ1 = 1.45 (0.92-2.27), Ptrend = 0.03] and this association was stronger when excluding cooked ham [HRQ4vsQ1 = 1.90 (1.18-3.05), Ptrend = 0.005]. In stratified analyses, processed meat intake was directly associated with breast cancer risk in the placebo group only [HRQ4vsQ1 = 2.46 (1.28-4.72), Ptrend = 0.001], but not in the supplemented group [HRQ4vsQ1 = 0.86 (0.45-1.63), Ptrend = 0.7].

Conclusion: Processed meat intake was prospectively associated with increased breast cancer risk. This study also suggests that antioxidants may modulate this association by counteracting the potential pro-carcinogenic effects of processed meat on breast cancer.


Background: Some studies reported similar effect estimates for the impact of maternal smoking in pregnancy and paternal smoking on childhood obesity, whereas others suggested higher effects for maternal smoking. We performed a meta-analysis to compare the effect of in utero exposure to maternal smoking and that of paternal or household smoking exposure in utero or after birth with mutual adjustment.

Methods: Meta-analysis of observational studies identified in MEDLINE, EMBASE and Web of Knowledge published in 1900–2013. Study inclusion criterion was assessment of the association of maternal smoking during pregnancy and paternal or household smoking (anyone living in the household who smokes) at any time with childhood overweight and obesity. The analyses were based on all studies with mutually adjusted effect estimates for maternal and paternal/household smoking applying a random-effects model.

Results: Data for 109 838 mother/child pairs were reported in 12 studies. The pooled odds ratios (ORs) for overweight 1.33 [95% confidence interval (CI) 1.23;1.44] (n = 6, I2 = 0.00%) and obesity 1.60 (95% CI 1.37;1.88) (n = 4, I2 = 32.47%) for maternal smoking during pregnancy were higher than for paternal smoking: 1.07 (95% CI 1.00;1.16) (n = 6, I2 = 41.34%) and 1.23 (95% CI 1.10;1.38) (n = 4, I2 = 14.61%), respectively. Similar estimates with widely overlapping confidence limits were found for maternal smoking during pregnancy and childhood overweight and obesity: 1.35 (95% CI 1.20;1.51) (n = 3, I2 = 0.00%) and 1.28 (95% CI 1.07;1.54) (n = 3, I2 = 0.00%) compared with household smoking 1.22 (95% CI 1.06;1.39) (n = 3, I2 = 72.14%) and 1.31 (95% CI 1.15;1.50)] (n = 3, I2 = 0.00%).

Conclusions: Higher effect estimates for maternal smoking in pregnancy compared with paternal smoking in mutually adjusted models may suggest a direct intrauterine effect.


Background: Present understanding of increased risk of Epstein-Barr virus (EBV)-related infectious mononucleosis among children of low birth order or small sibships is mainly based on old and indirect evidence. Societal changes and methodological limitations of previous studies call for new data.

Methods: We used data from the Danish Civil Registration System and the Danish National Hospital Discharge Register to study incidence rates of inpatient hospitalizations for infectious mononucleosis before the age of 20 years in a cohort of 2 543 225 Danes born between 1971 and 2008, taking individual sibship structure into account.

Results: A total of 12 872 cases of infectious mononucleosis were observed during 35.3 million person-years of follow-up. Statistical modelling showed that increasing sibship size was associated with a reduced risk of infectious mononucleosis and that younger siblings conferred more protection from infectious mononucleosis than older siblings. In addition to this general association with younger and older siblings, children aged less than 4 years transiently increased their siblings’ infectious mononucleosis risk. Our results were confirmed in an independent sample of blood donors followed up retrospectively for self-reported infectious mononucleosis.

Conclusions: Younger siblings, and to a lesser degree older siblings, seem to be important in the transmission of EBV within families. Apparently the dogma of low birth order in a sibship as being at the highest risk of infectious mononucleosis is no longer valid.


Background: Road traffic crashes are a major cause of death and injury worldwide and are set to increase as low- and middle-income countries motorize. United Nations (UN) and World Health Organization (WHO) road traffic injury prevention efforts depend on support from external organizations, many of which have commercial interests in increasing car use. Because of concerns about conflict of interest, this study objectively assessed the activities of a key WHO collaborator, the Global Road Safety Partnership (GRSP).

Methods: We conducted a quantitative content analysis comparing GRSP publications and the 2004 WHO World Report on Road Traffic Injury Prevention. Dictionaries of terms were constructed for each of the evidence-based interventions detailed in the World Report. Text analysis software was used to generate word frequency counts of those terms to compare the World Report and GRSP documents.

Results: Education, information and publicity featured far more commonly in the GRSP publications than in the WHO World Report [word frequency ratios and 95% confidence intervals: GRSP Newsletter 3.09, 2.53 to 3.78; Around GRSPs World 4.69, 3.76 to 5.87; GRSP Project summaries 3.42, 2.59 to 4.51] On the other hand, compared with the World Report, reducing car use [GRSP Newsletter 0.36, 0.27 to 0.48], minimizing exposure to high-risk scenarios [GRSP Newsletter 0.04, 0.02 to 0.09] and encouraging the use of safer modes of travel [GRSP Newsletter 0.02, 0.01 to 0.08] rarely featured in GRSP publications.

Conclusions: The GRSP focuses on educational interventions, for which there is no evidence of effectiveness. Furthermore, the GRSP does not appear to consider the full range of WHO interventions. As motorization growth has serious negative implications for health, including those associated from physical inactivity, climate change and air and noise pollution, it is imperative that the UN and WHO do not allow business interests to dominate public health interests.


Background: Overt and subclinical hypothyroidism are associated with higher levels of serum creatinine and with increased risk of chronic kidney disease (CKD). The prospective association between thyroid hormones and kidney function in euthyroid individuals, however, is largely unexplored.

Methods: We conducted a prospective cohort study in 104 633 South Korean men and women who were free of CKD and proteinuria at baseline and had normal thyroid hormone levels and no history of thyroid disease or cancer. At each annual or biennial follow-up visit, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxin (FT4) levels were measured by radioimmunoassay. The study outcome was incident CKD, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration creatinine equation.

Results: After a median follow-up of 3.5 years, 1032 participants developed incident CKD. There was a positive association between high-normal levels of TSH and increased risk of incident CKD. In fully-adjusted models including baseline eGFR, the hazard ratio comparing the highest vs the lowest quintiles of TSH was 1.26 [95% confidence interval (CI) 1.02 to 1.55; P for linear trend = 0.03]. In spline models, FT3 levels below 3 pg/ml were also associated with increased risk of incident CKD. There was no association between FT4 levels and CKD.

Conclusions: In a large cohort of euthyroid men and women, high levels of TSH and low levels of FT3, even within the normal range, were modestly associated with an increased risk of incident CKD.


Background: Errors, introduced through poor assessment of physical measurement or because of inconsistent or inappropriate standard operating procedures for collecting, processing, storing or analysing haematological and biochemistry analytes, have a negative impact on the power of association studies using the collected data. A dataset from UK Biobank was used to evaluate the impact of pre-analytical variability on the power of association studies.

Methods: First, we estimated the proportion of the variance in analyte concentration that may be attributed to delay in processing using variance component analysis. Then, we captured the proportion of heterogeneity between subjects that is due to variability in the rate of degradation of analytes, by fitting a mixed model. Finally, we evaluated the impact of delay in processing on the power of a nested case-control study using a power calculator that we developed and which takes into account uncertainty in outcome and explanatory variables measurements.

Results: The results showed that (i) the majority of the analytes investigated in our analysis, were stable over a period of 36 h and (ii) some analytes were unstable and the resulting pre-analytical variation substantially decreased the power of the study, under the settings we investigated.

Conclusions: It is important to specify a limited delay in processing for analytes that are very sensitive to delayed assay. If the rate of degradation of an analyte varies between individuals, any delay introduces a bias which increases with increasing delay. If pre-analytical variation occurring due to delays in sample processing is ignored, it affects adversely the power of the studies that use the data.


In cohort and case-control studies, confounding that arises as a result of differences in the distribution of determinants of the outcome between exposure groups leading to non-exchangeability are addressed by restriction, matching or with statistical models. In case-only studies, this issue is addressed by comparing each individual with his/herself. Although case-only designs use self-matching and only include individuals who develop the outcome of interest, issues of non-exchangeability are identical to those that arise in traditional case-control and cohort studies. In this review, we describe one type of case-only design, the case-crossover design, and discuss how the concept of exchangeability can be used to understand issues of confounding, carryover effects, period effects and selection bias in case-crossover studies.


Recent methodological innovation is giving rise to an increasing number of applied papers in medical and epidemiological journals in which natural direct and indirect effects are estimated. However, there is a longstanding debate on whether such effects are relevant targets of inference in population health. In light of the repeated calls for a more pragmatic and consequential epidemiology, we review three issues often raised in this debate: (i) the use of composite cross-world counterfactuals and the need for cross-world independence assumptions; (ii) interventional vs non-interventional identifiability; and (iii) the interpretational ambiguity of natural direct and indirect effect estimates. We use potential outcomes notation and directed acyclic graphs to explain ‘cross-world’ assumptions, illustrate implications of this assumption via regression models and discuss ensuing issues of interpretation. We argue that the debate on the relevance of natural direct and indirect effects rests on whether one takes as a target of inference the mathematical object per se, or the change in the world that the mathematical object represents. We further note that public health questions may be better served by estimating controlled direct effects.