• Home
  • News
  • Calendar
  • About DF/HCC
  • Membership
  • Visitor Center
 

Member Resources

Publications

International Journal of Epidemiology

International Journal of Epidemiology - RSS feed of current issue

Most childhood interventions (vaccines, micronutrients) in low-income countries are justified by their assumed effect on child survival. However, usually the interventions have only been studied with respect to their disease/deficiency-specific effects and not for their overall effects on morbidity and mortality. In many situations, the population-based effects have been very different from the anticipated effects; for example, the measles-preventive high-titre measles vaccine was associated with 2-fold increased female mortality; BCG reduces neonatal mortality although children do not die of tuberculosis in the neonatal period; vitamin A may be associated with increased or reduced child mortality in different situations; effects of interventions may differ for boys and girls. The reasons for these and other contrasts between expectations and observations are likely to be that the immune system learns more than specific prevention from an intervention; such training may enhance or reduce susceptibility to unrelated infections. INDEPTH member centres have been in an ideal position to document such additional non-specific effects of interventions because they follow the total population long term. It is proposed that more INDEPTH member centres extend their routine data collection platform to better measure the use and effects of childhood interventions. In a longer perspective, INDEPTH may come to play a stronger role in defining health research issues of relevance to low-income countries.








SummaryThe PROmotion of Breastfeeding Intervention Trial (PROBIT) is a multicentre, cluster-randomized controlled trial conducted in the Republic of Belarus, in which the experimental intervention was the promotion of increased breastfeeding duration and exclusivity, modelled on the Baby-friendly hospital initiative. Between June 1996 and December 1997, 17 046 mother–infant pairs were recruited during their postpartum hospital stay from 31 maternity hospitals, of which 16 hospitals and their affiliated polyclinics had been randomly assigned to the arm of PROBIT investigating the promotion of breastfeeding and 15 had been assigned to the control arm, in which breastfeeding practices and policies in effect at the time of randomization was continued. Of the mother–infant pairs originally recruited for the study, 16 492 (96.7%) were followed at regular intervals until the infants were 12 months of age (PROBIT I) for the outcomes of breastfeeding duration and exclusivity; gastrointestinal and respiratory infections; and atopic eczema. Subsequently, 13 889 (81.5%) of the children from these mother–infant pairs were followed-up at age 6.5 years (PROBIT II) for anthropometry, blood pressure (BP), behaviour, dental health, cognitive function, asthma and atopy outcomes, and 13 879 (81.4%) children were followed to the age of 11.5 years (PROBIT III) for anthropometry, body composition, BP, and the measurement of fasted glucose, insulin, adiponectin, insulin-like growth factor-I, and apolipoproteins. The trial registration number for Current Controlled Trials is ISRCTN37687716 and that for ClinicalTrials.gov is NCT01561612. Proposals for collaboration are welcome, and enquires about PROBIT should be made to an executive group of the study steering committee (M.S.K., R.M.M., and E.O.). More information, including information about how to access the trial data, data collection documents, and bibliography, is available at the trial website (http://www.bristol.ac.uk/social-community-medicine/projects/probit/).


The advent of effective combination antiretroviral therapy (ART) in 1996 resulted in fewer patients experiencing clinical events, so that some prognostic analyses of individual cohort studies of human immunodeficiency virus-infected individuals had low statistical power. Because of this, the Antiretroviral Therapy Cohort Collaboration (ART-CC) of HIV cohort studies in Europe and North America was established in 2000, with the aim of studying the prognosis for clinical events in acquired immune deficiency syndrome (AIDS) and the mortality of adult patients treated for HIV-1 infection. In 2002, the ART-CC collected data on more than 12,000 patients in 13 cohorts who had begun combination ART between 1995 and 2001. Subsequent updates took place in 2004, 2006, 2008, and 2010. The ART-CC data base now includes data on more than 70 000 patients participating in 19 cohorts who began treatment before the end of 2009. Data are collected on patient demographics (e.g. sex, age, assumed transmission group, race/ethnicity, geographical origin), HIV biomarkers (e.g. CD4 cell count, plasma viral load of HIV-1), ART regimen, dates and types of AIDS events, and dates and causes of death. In recent years, additional data on co-infections such as hepatitis C; risk factors such as smoking, alcohol and drug use; non-HIV biomarkers such as haemoglobin and liver enzymes; and adherence to ART have been collected whenever available. The data remain the property of the contributing cohorts, whose representatives manage the ART-CC via the steering committee of the Collaboration. External collaboration is welcomed. Details of contacts are given on the ART-CC website (www.art-cohort-collaboration.org).


Similar to other industrialized countries, Germany's population is ageing. Whereas some people enjoy good physical and cognitive health into old age, others suffer from a multitude of age-related disorders and impairments which reduce life expectancy and affect quality of life. To identify and characterize the factors associated with ‘healthy’ vs. ‘unhealthy’ ageing, we have launched the Berlin Aging Study II (BASE-II), a multidisciplinary and multi-institutional project that ascertains a large number of ageing-related variables from a wide range of different functional domains. Phenotypic assessments include factors related to geriatrics and internal medicine, immunology, genetics, psychology, sociology and economics. Baseline recruitment of the BASE-II cohort was recently completed and has led to the sampling of 1600 older adults (age range 60–80 years), as well as 600 younger adults (20–35 years) serving as the basic population for in-depth analyses. BASE-II data are linked to the German Socio-Economic Panel Study (SOEP), a long-running panel survey representative of the German population, to estimate sample selectivity. A major goal of BASE-II is to facilitate collaboration with other research groups by freely sharing relevant phenotypic and genotypic data with qualified outside investigators.


The Gubbio Study is a prospective epidemiological study on the population residing in the city of Gubbio, Italy. Original objectives of the study were the control of hypertension and the role of cellular electrolyte handling in hypertension. Other objectives were added during the 30-year activity of the study. The original target cohort consists of individuals aged ≥ 5 years residing within the medieval walls of the city. To complete family genealogies, individuals residing outside the city were also included. Three active screenings (exams) were conducted. A total of 5376 individuals (response rate 92%) participated in Exam 1 which was performed in 1983–86. Follow-up exams were completed between 1989–92 and 2001–2007. Data categories included demographics, personal and family medical history, lifestyle habits, education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry and special investigations on cellular electrolyte handling. Electrocardiogram, echocardiogram, 24-h ambulatory blood pressure and uroflowmetry were performed in selected subgroups defined by age and/or sex. Data about hospitalizations, mortality and causes of death were collected starting from completion of Exam 1. The study shared the data with other studies.


The main aim of the Gezondheid en Levens Omstandigheden Bevolking Eindhoven en omstreken (GLOBE) study (the letters of whose name represent the first letters of the Dutch acronym for Health and Living Conditions of the Population of Eindhoven and surroundings) is to quantitatively assess mechanisms and factors explaining socio-economic inequalities in health in the Netherlands. Baseline data for the study were collected by postal survey in 1991 among 18 973 respondents ranging in age from 15–75 years from the city of Eindhoven and its surrounding municipalities. Subsamples (total N = 5667) were interviewed and/or surveyed in 1991, 1997, 2004 (also including a new sample), and most recently in 2011. Information was asked on indicators of socio-economic position, a range of potential explanatory factors (material, behavioural, psychosocial, and environmental) and health outcomes. From 2004 onwards, special emphasis was given to the identification of physical, social, and cultural environmental factors in the explanation of socio-economic inequalities in health behaviours. Information from the baseline postal survey onwards can and has been linked to several registries of causes of death, hospital admissions, and cancer. Researchers are cordially invited to contact the project leader (f.vanlenthe@erasmusmc.nl) to propose research based on the data.


As the number and proportion of very old people in the population increase, there is a need for improved knowledge about their health and living conditions. The SWEOLD interview surveys are based on random samples of the population aged 77+years. The low non-response rates, the inclusion of institutionalized persons and the use of proxy informants for people unable to be interviewed directly ensure a representative portrayal of this age group in Sweden. SWEOLD began in 1992 and has been repeated in 2002, 2004 and 2011. The survey is based on another national survey, the Swedish Level of Living Survey (LNU), started in 1968 with 10-year follow-up waves. This longitudinal design provides additional data collected when SWEOLD participants were in middle age and early old age. The SWEOLD interviews cover a wide range of areas including health and health behaviour, work history, family, leisure activities and use of health and social care services. Socio-economic factors include education, previous occupation and available cash margin. Health indicators include symptoms, diseases, mobility and activities of daily living (ADL). In addition to self-reported data, the interview includes objective tests of lung function, physical function, grip strength and cognition. The data have been linked to register data, for example for income and mortality follow-ups. Data are available to the scientific community on request. More information about the study, data access rules and how to apply for data are available at the website (www.sweold.se).


The Bandafassi Health and Demographic Surveillance System (Bandafassi HDSS) is located in south-eastern Senegal, near the borders with Mali and Guinea. The area is 700 km from the national capital, Dakar. The population under surveillance is rural and in 2012 comprised 13 378 inhabitants living in 42 villages. Established in 1970, originally for genetic studies, and initially covering only villages inhabited by one subgroup of the population of the area (the Mandinka), the project was transformed a few years later into a HDSS and then extended to the two other subgroups living in the area: Fula villages in 1975, and Bedik villages in 1980. Data have been collected through annual rounds since the project first began. On each visit, investigators review the composition of all the households, checking the lists of people who were present in each household the previous year and gathering information about births, marriages, migrations and deaths (including their causes) since then. One specific feature of the Bandafassi HDSS is the availability of genealogies.


Background: Size at birth has taken on renewed significance due to its now well-established association with many health and health-related outcomes in both the immediate perinatal period and across the entire life course. Optimizing fetal growth to improve both neonatal survival and population health is the focus of much research and policy development, although most efforts have concentrated on either the period of pregnancy itself or the period immediately preceding it.

Methods: Intergenerational data linked to the Aberdeen Children of the 1950s (ACONF) study were used to examine the influence of grandparental and parental life course biological and social variables on the distribution of offspring size at birth. Guided stepwise multivariable methods and a graphical approach were used to assess the relative importance of these temporally ordered and highly correlated life course measures.

Results: Both distal and proximal grandparental and parental life course biological and social factors predicted offspring size at birth. Inequalities in size at birth, according to adult maternal socioeconomic indicators, were found to be largely generated by the continuity of the social environment across generations, and the inequalities in maternal early life growth were predicted by the adult grandparental social environment during the mother’s early life. Mother’s own size at birth predicted her offspring’s intrauterine growth, independent of her adult biological and social characteristics.

Conclusions: A mother’s childhood social environment and her early growth are both important predictors of her offspring’s size at birth. Population strategies aimed at optimizing size at birth require broader social and intergenerational considerations, in addition to focusing on the health of mothers in the immediate pregnancy period.


Background Cardiovascular risk factors are transmitted from parents to offspring; however, the relative contributions of fathers and mothers remain unclear. If maternal exposures during pregnancy influence offspring through the intrauterine environment, associations between mothers and offspring are expected to be stronger than between fathers and offspring. In this family linkage study we compared father-offspring and mother-offspring associations of several cardiovascular risk factors.

Methods The study population consisted of 36 528 father-mother-offspring trios who participated at one or more surveys of the HUNT Study, Norway in 1984–86, 1995–97 and 2006–08. Parent-offspring associations were assessed using unstandardized and standardized residuals from linear regression analysis, and possible non-paternity was accounted for in sensitivity analyses.

Results Age- and sex-adjusted parent-offspring associations for anthropometric factors, blood pressure, blood lipids, blood glucose and resting heart rate were largely similar between fathers and mothers. Use of standardized values and analyses adjusted for non-paternity further emphasized this similarity.

Conclusions This study found largely similar father-offspring and mother-offspring associations across all cardiovascular risk factors under study, arguing against strong maternal effects transmitted through intrauterine mechanisms.



Background With the greying of the industrialized world has come increased interest in identifying the modifiable lifestyle factors that promote healthy and successful ageing. Whereas many of the behavioural correlates of late-life morbidity and mortality have been identified, relatively little is known about the origins of individual differences in these factors.

Methods A sample of 12 714 twins, including both members of 3806 pairs of known zygosity, ascertained through the Danish Twin Registry and aged 40 to 80 years, completed a self-report assessment of six lifestyle factors associated with ageing: smoking, drinking, diet and physical, social and intellectual activities. Standard biometric methods were used to analyse the twin data and determine the extent to which individual differences in each of the lifestyle factors are heritable.

Results For each of the six lifestyle factors, the estimate of heritability ranged from 32% (95% CI: 19–42%) for the diet scale to 69% (62–72%) for the smoking measure. Biometric estimates of the contribution of the twins’ common rearing environment were uniformly small (≤6%). There was little evidence that standardized biometric estimates varied by gender or age.

Conclusions Individuals likely construct lifestyles in part to complement and reinforce underlying genetically influenced dispositions and talents. The heritable nature of lifestyle factors implies that the behavioural and genetic contributors to ageing processes are not necessarily conceptually distinct but rather reflect the complexity of gene-environment interplay in ageing.


Objectives: To examine the association between maternal prepregnancy weight and child neurodevelopment, and the effect of gestational weight gain.

Methods: Using the U.S. Collaborative Perinatal Project data, 1959–76, a total of 30 212 women with a calculable prepregnancy body mass index (BMI) and gestational weight gain, and term singleton children followed up for more than 7 years were included in this study. Intelligence quotient (IQ) was measured at 7 years of age by Wechsler Intelligence Scales.

Results: Maternal prepregnancy BMI displayed inverted U-shaped associations with child IQ after adjustment for maternal age, maternal education levels, maternal race, marital status, socioeconomic status, smoking during pregnancy, parity and study center. Women with BMI at around 20 kg/m2 appeared to have the highest offspring IQ scores. After controlling for familial factors in the siblings’ sample, maternal obesity (BMI ≥30.0 kg/m2) was associated with lower Full-scale IQ (adjusted ß = –2.0, 95% confidence interval –3.5 to –0.5), and Verbal scale IQ (adjusted ß = –2.5, 95% confidence interval –4.0 to –1.0), using BMI of 18.5–24.9 kg/m2 as the reference category. Compared with children born to normal-weight women who gained 21–25 lb. during pregnancy, those born to obese women who gained more than 40 lb. had 6.5 points deficit in IQ after adjustment for potential confounders.

Conclusions: Maternal prepregnancy obesity was associated with lower child IQ, and excessive weight gain accelerated the association. With obesity rising steadily, these results appear to raise serious public health concerns.


Background: Ultraviolet radiation (UVR) exposure is the main risk factor for cutaneous malignant melanoma (CMM), but its specific effect in infancy is unknown. We examined whether season of birth, a proxy for solar UVR exposure in the first few months of life, is associated with CMM in childhood through young adulthood.

Methods: National cohort study of 3 571 574 persons born in Sweden in 1973–2008, followed up for CMM incidence through 2009 (maximum age 37 years) to examine season of birth and other perinatal factors.

Results: There were 1595 CMM cases in 63.9 million person-years of follow-up. We found a sinusoidal pattern in CMM risk by season of birth (P = 0.006), with peak risk corresponding to birthdates in spring (March–May). Adjusted odds ratios for CMM by season of birth were 1.21 [95% confidence interval (CI), 1.05–1.39; P = 0.008] for spring, 1.07 (95% CI, 0.92–1.24; P = 0.40) for summer and 1.12 (95% CI, 0.96–1.29; P = 0.14) for winter, relative to fall. Spring birth was associated with superficial spreading subtype of CMM (P = 0.02), whereas there was no seasonal association with nodular subtype (P = 0.26). Other CMM risk factors included family history of CMM in a sibling (>6-fold) or parent (>3-fold), female gender, high fetal growth and high paternal education level.

Conclusions: In this large cohort study, persons born in spring had increased risk of CMM in childhood through young adulthood, suggesting that the first few months of life may be a critical period of UVR susceptibility. Sun avoidance in early infancy may play an important role in the prevention of CMM in high-risk populations.


Background The aim of this study was to elucidate the role of gestational age in determining the risk of neonatal morbidity among infants born late preterm (34–36 weeks) and early term (37–38 weeks) compared with those born full term (39–41 weeks) by examining the contribution of gestational age within the context of biological determinants of preterm birth.

Methods This was a retrospective cohort study. The sample included singleton live births with no major congenital anomalies, delivered at 34–41 weeks of gestation to London-Middlesex (Canada) mothers in 2002–11. Data from a city-wide perinatal database were linked with discharge abstract data. Multivariable models used modified Poisson regression to directly estimate adjusted relative risks (aRRs). The roles of gestational age and biological determinants of preterm birth were further examined using mediation and moderation analyses.

Results Compared with infants born full term, infants born late preterm and early term were at increased risk for neonatal intensive care unit triage/admission [late preterm aRR = 6.14, 95% confidence interval (CI) 5.63, 6.71; early term aRR = 1.54, 95% CI 1.41, 1.68] and neonatal respiratory morbidity (late preterm aRR = 6.16, 95% CI 5.39, 7.03; early term aRR = 1.46, 95% CI 1.29, 1.65). The effect of gestational age was partially explained by biological determinants of preterm birth acting through gestational age. Moreover, placental ischaemia and other hypoxia exacerbated the effect of gestational age on poor outcomes.

Conclusions Poor outcomes among infants born late preterm and early term are not only due to physiological immaturity but also to biological determinants of preterm birth acting through and with gestational age to produce poor outcomes.



Background Infant mortality rates in the US exceed those in all other developed countries and in many less developed countries, suggesting political factors may contribute.

Methods Annual time series on overall, White and Black infant mortality rates in the US were analysed over the 1965–2010 time period to ascertain whether infant mortality rates varied across presidential administrations. Data were de-trended using cubic splines and analysed using both graphical and time series regression methods.

Results Across all nine presidential administrations, infant mortality rates were below trend when the President was a Democrat and above trend when the President was a Republican. This was true for overall, neonatal and postneonatal mortality. Regression estimates show that, relative to trend, Republican administrations were characterized by infant mortality rates that were, on average, 3% higher than Democratic administrations. In proportional terms, effect size is similar for US Whites and Blacks. US Black rates are more than twice as high as White, implying substantially larger absolute effects for Blacks.

Conclusions We found a robust, quantitatively important association between net of trend US infant mortality rates and the party affiliation of the president. There may be overlooked ways by which macro-dynamics of policy impact microdynamics of physiology, suggesting the political system is a component of the underlying mechanism generating health inequality in the USA.





Background: Violent criminality is at least moderately heritable, but the mechanisms behind this remain largely unexplained. Height, a highly heritable trait, may be involved but no study has estimated the effect of height on crime while simultaneously accounting for important demographic, biological and other heritable confounders.

Methods: We linked nationwide, longitudinal registers for 760 000 men who underwent mandatory military conscription from 1980 through 1992 in Sweden, to assess the association between height and being convicted of a violent crime. We used Cox proportional hazard modelling and controlled for three types of potential confounders: physical characteristics, childhood demographics and general cognitive ability (intelligence).

Results: In unadjusted analyses, height had a moderate negative relationship to violent crime; the shortest of men were twice as likely to be convicted of a violent crime as the tallest. However, when simultaneously controlling for all measured confounders, height was weakly and positively related to violent crime. Intelligence had the individually strongest mitigating effect on the height-crime relationship.

Conclusions: Although shorter stature was associated with increased risk of violent offending, our analyses strongly suggested that this relationship was explained by intelligence and other confounding factors. Hence, it is unlikely that height, a highly heritable physical characteristic, accounts for much of the unexplained heritability of violent criminality.


Background: A possible aetiological link between obesity and certain autoimmune diseases (ADs) has been suggested. We investigated the associations between body mass index (BMI, kg/m2) and 43 ADs.

Methods: 75 008 women participating in the Danish National Birth Cohort were followed during a median time of 11 years. Diagnoses on ADs were retrieved from the Danish National Patient Register. Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated adjusting for potential confounders (smoking, alcohol, parity and socio-occupational status).

Results: During follow-up, 2430 women (3.2%) developed a total of 2607 new-onset ADs. Risk of any autoimmune disease was increased in obese women (HR, 1.27; 95% CI, 1.11 to 1.46) compared with normal weight women (18.5–≤25 kg/m2). Obese women (BMI ≥30 kg/m2) were at increased risk of sarcoidosis (HR 3.59; 95% CI, 2.31 to 5.57) and type 1 diabetes mellitus (HR 2.67; 95% CI, 1.71 to 4.17). Risk of dermatitis herpetiformis increased by 14% (95% CI, 1% to 30%) per BMI unit. Conversely, risk of celiac disease and Raynaud’s phenomenon decreased by 7% (95% CI, 1% to 13%) and 12% (95% CI, 4% to 19%) per BMI unit, respectively. Further associations between BMI and risk of psoriasis, rheumatoid arthritis and Crohn’s disease were suggested.

Conclusions: BMI was found to be associated with several Ads. This was most pronounced between obesity and risk of sarcoidosis and and risk of type 1 diabetes mellitus. These novel findings need confirmation and the possible role of adipose tissue-derived immunological changes in the development of autoimmune reactions needs consideration.


Background: Weight and health behaviours are known to affect physical disability; however the evidence exploring the impact of changes to these lifestyle factors over the life course on disability is inconsistent. We aimed to explore the roles of weight and activity change between mid and later life on physical disability.

Methods: Baseline and 20-year clinical follow-up data were collected from1418 men and women, aged 58–88 years at follow-up, as part of a population-based observational study based in north-west London. At clinic, behavioural data were collected by questionnaire and anthropometry measured. Disability was assessed using a performance-based locomotor function test and self-reported questionnaires on functional limitation and basic activities of daily living (ADLs).

Results: At follow-up, 39% experienced a locomotor dysfunction, 24% a functional limitation and 17% an impairment of ADLs. Weight gain of 10–20% or >20% of baseline, but not weight loss, were associated with increased odds of a functional limitation [odds ratio (OR) 1.69, 95% confidence interval (CI) 1.14-2.49 and OR 2.74, 1.55-4.83, respectively], after full adjustment for covariates. The same patterns were seen for the other disability outcomes. Increased physical activity reduced, and decreased physical activity enhanced the likelihood of disability, independent of baseline behaviours and adiposity. The adverse effects of weight gain appeared to be lessened in the presence of increased later-life physical activity.

Conclusion: Weight and activity changes between mid and later life have strong implications for physical functioning in older groups. These findings reinforce the importance of the maintenance of healthy weight and behaviour throughout the life course, and the need to promote healthy lifestyles across population groups.


Background: Secular trends in cardiovascular risk factors have been described, but few studies have examined simultaneously the effects of both ageing and secular trends within the same cohort.

Methods: Development of cardiovascular risk factors over the past three decades was analysed using serial measurements from 10 308 participants aged from 35 to 80 years over 25 years of follow-up from five clinical examination phases of the Whitehall II study. Changes of body mass index, waist circumference, blood pressure and total and high-density lipoprotein cholesterol distribution characteristics were analysed with quantile regression models in the 57–61 age group. Age-related trajectories of risk factors were assessed by fitting mixed-effects models with adjustment for year of birth to reveal secular trends.

Results: Average body mass index and waist circumference increased faster with age in women than in men, but the unfavourable secular trend was more marked in men. Distributions showed a fattening of the right tail in each consecutive phase, meaning a stronger increase in higher percentiles. Despite the higher obesity levels in younger birth cohorts, total cholesterol decreased markedly in the 57–61 age group along the entire distribution rather than in higher extremes only.

Conclusion: The past three decades brought strong and heterogeneous changes in cardiovascular risk factor distributions. Secular trends appear to modify age-related trajectories of cardiovascular risk factors, which may be a source of bias in longitudinal analyses.


Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans.

Methods: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS).

Results: We found that shorter LTL is associated with increased prospective mortality in middle (30–80 years; hazard ratio (HR) = 0.75, P = 0.001) and highly advanced age (≥90 years; HR = 0.92, P = 0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (β = 0.006, P = 0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n = 8165).

Conclusions: We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity.


Background: HCV coinfection remains a major cause of morbidity and mortality among HIV-infected individuals and its incidence has increased dramatically in HIV-infected men who have sex with men(MSM).

Methods: Hepatitis C virus (HCV) coinfection in the Swiss HIV Cohort Study(SHCS) was studied by combining clinical data with HIV-1 pol-sequences from the SHCS Drug Resistance Database(DRDB). We inferred maximum-likelihood phylogenetic trees, determined Swiss HIV-transmission pairs as monophyletic patient pairs, and then considered the distribution of HCV on those pairs.

Results: Among the 9748 patients in the SHCS-DRDB with known HCV status, 2768(28%) were HCV-positive. Focusing on subtype B(7644 patients), we identified 1555 potential HIV-1 transmission pairs. There, we found that, even after controlling for transmission group, calendar year, age and sex, the odds for an HCV coinfection were increased by an odds ratio (OR) of 3.2 [95% confidence interval (CI) 2.2, 4.7) if a patient clustered with another HCV-positive case. This strong association persisted if transmission groups of intravenous drug users (IDUs), MSMs and heterosexuals (HETs) were considered separately(in all cases OR >2). Finally we found that HCV incidence was increased by a hazard ratio of 2.1 (1.1, 3.8) for individuals paired with an HCV-positive partner.

Conclusions: Patients whose HIV virus is closely related to the HIV virus of HIV/HCV-coinfected patients have a higher risk for carrying or acquiring HCV themselves. This indicates the occurrence of domestic and sexual HCV transmission and allows the identification of patients with a high HCV-infection risk.


Background The standardized patient approach has proved to be an effective training tool for medical educators. This article explains the process of employing standardized patients in an HIV stigma reduction intervention in healthcare settings in China.

Methods The study was conducted in 40 hospitals in two provinces of China. One year after the stigma reduction intervention, standardized patients made unannounced visits to participating hospitals, randomly approached service providers on duty and presented symptoms related to HIV and disclosed HIV-positive test results. After each visit, the standardized patients evaluated their providers’ attitudes and behaviours using a structured checklist. Standardized patients also took open-ended observation notes about their experience and the evaluation process.

Results Seven standardized patients conducted a total of 217 assessments (108 from 20 hospitals in the intervention condition; 109 from 20 hospitals in the control condition). Based on a comparative analysis, the intervention hospitals received a better rating than the control hospitals in terms of general impression and universal precaution compliance as well as a lower score on stigmatizing attitudes and behaviours toward the standardized patients.

Conclusion Standardized patients are a useful supplement to traditional self-report assessments, particularly for measuring intervention outcomes that are sensitive or prone to social desirability.



Background: Alcohol use disorders (AUD) are highly disabling. Recent studies reported much higher relative risks for all-cause mortality in AUD patients compared with earlier studies. Systematic evidence regarding cause-specific mortality among AUD patients has been unavailable to date.

Methods: Studies were identified through MEDLINE, EMBASE and Web of Science up to August 2012. Following MOOSE guidelines, prospective and historical cohort studies assessing cause-specific mortality risk from AUD patients at baseline compared with the general population were selected. Data on several study characteristics, including AUD assessment, follow-up period, setting, location and cause-specific mortality risk compared with the general population were abstracted. Random-effect meta-analyses were conducted.

Results: Overall, 17 observational studies with 6420 observed deaths among 28 087 AUD patients were included. Pooled standardized mortality ratios (SMRs) after 10 years of follow-up among men were 14.8 (95% confidence interval: 8.7–24.9) for liver cirrhosis, 18.0 (11.2–30.3) for mental disorders, 6.6 (5.0–8.8) for death by injury and around 2 for cancer and cardiovascular diseases. SMRs were substantially higher in women, with fewer studies available. For many outcomes the risk has been increasing substantially over time.

Conclusions: Cause-specific mortality among AUD patients was high in all major categories compared with the general population. There has been a lack of recent research, and future studies should focus on the influence of comorbidities on excess mortality risk among AUD patients. Efforts to reduce these risks should be a priority, given that successful treatment reduces mortality risk substantially for a relatively common psychiatric disease.



Background: Sample size calculations are an important tool for planning epidemiological studies. Large sample sizes are often required in Mendelian randomization investigations.

Methods and results: Resources are provided for investigators to perform sample size and power calculations for Mendelian randomization with a binary outcome. We initially provide formulae for the continuous outcome case, and then analogous formulae for the binary outcome case. The formulae are valid for a single instrumental variable, which may be a single genetic variant or an allele score comprising multiple variants. Graphs are provided to give the required sample size for 80% power for given values of the causal effect of the risk factor on the outcome and of the squared correlation between the risk factor and instrumental variable. R code and an online calculator tool are made available for calculating the sample size needed for a chosen power level given these parameters, as well as the power given the chosen sample size and these parameters.

Conclusions: The sample size required for a given power of Mendelian randomization investigation depends greatly on the proportion of variance in the risk factor explained by the instrumental variable. The inclusion of multiple variants into an allele score to explain more of the variance in the risk factor will improve power, however care must be taken not to introduce bias by the inclusion of invalid variants.


Background: A cross-over trial design is more powerful than a parallel groups design, but requires that treatment effects do not carry over from one period of the trial to the next. We focus here on interventions in chronic disease populations where the control is routine care: in such cases we cannot assume the intervention effect is easily washed out in crossing over from the experimental intervention back to the control.

Methods: We introduce an alternative trial design for these situations, and investigate its performance. One group is assessed before and after the experimental intervention, whereas two other groups provide respective, independent treatment comparisons in each period. We call this a dog-leg design because of the pattern of assessments in the three groups. The dog-leg design is reminiscent of a stepped wedge design, but with a reduced schedule of assessments and with the notable difference that not all groups receive the intervention.

Results: If the correlation between baseline and follow-up is <0.72, the dog-leg design is more efficient than a parallel groups design with a baseline assessment. The dog-leg design also requires fewer assessments in total than a parallel groups design where participants are only assessed once, at follow-up.

Conclusions: The dog-leg design is simple, and has some attractive properties. Though there is a risk of differential attrition in the three arms, the design’s good performance relative to alternatives makes it a useful addition to the methodologist’s toolkit.


Background: We wanted to evaluate the impact of nonblinded outcome assessors on estimated treatment effects in time-to-event trials.

Methods: Systematic review of randomized clinical trials with both blinded and nonblinded assessors of the same time-to-event outcome. Two authors agreed on inclusion of trials and outcomes. We compared hazard ratios based on nonblinded and blinded assessments. A ratio of hazard ratios (RHR) <1 indicated that nonblinded assessors generated more optimistic effect estimates. We pooled RHRs with inverse variance random-effects meta-analysis.

Results: We included 18 trials. Eleven trials (1969 patients) with subjective outcomes provided hazard ratios, RHR 0.88 (0.69 to 1.12), (I2 = 44%, P = 0.06), but unconditional pooling was problematic because of qualitative heterogeneity. Four atypical cytomegalovirus retinitis trials compared experimental oral administration with control intravenous administration of the same drug, resulting in bias favouring the control intervention, RHR 1.33 (0.98 to 1.82). Seven trials of cytomegalovirus retinitis, tibial fracture and multiple sclerosis compared experimental interventions with standard control interventions, e.g. placebo, no-treatment or active control, resulting in bias favouring the experimental intervention, RHR 0.73 (0.57 to 0.93), indicating an average exaggeration of nonblinded hazard ratios by 27% (7% to 43%).

Conclusions: Lack of blinded outcome assessors in randomized trials with subjective time-to-event outcomes causes high risk of observer bias. Nonblinded outcome assessors typically favour the experimental intervention, exaggerating the hazard ratio by an average of approximately 27%; but in special situations, nonblinded outcome assessors favour control interventions, inducing a comparable degree of observer bias in the reversed direction.



Background: We review three common methods to estimate predicted probabilities following confounder-adjusted logistic regression: marginal standardization (predicted probabilities summed to a weighted average reflecting the confounder distribution in the target population); prediction at the modes (conditional predicted probabilities calculated by setting each confounder to its modal value); and prediction at the means (predicted probabilities calculated by setting each confounder to its mean value). That each method corresponds to a different target population is underappreciated in practice. Specifically, prediction at the means is often incorrectly interpreted as estimating average probabilities for the overall study population, and furthermore yields nonsensical estimates in the presence of dichotomous confounders. Default commands in popular statistical software packages often lead to inadvertent misapplication of prediction at the means.

Methods: Using an applied example, we demonstrate discrepancies in predicted probabilities across these methods, discuss implications for interpretation and provide syntax for SAS and Stata.

Results: Marginal standardization allows inference to the total population from which data are drawn. Prediction at the modes or means allows inference only to the relevant stratum of observations. With dichotomous confounders, prediction at the means corresponds to a stratum that does not include any real-life observations.

Conclusions: Marginal standardization is the appropriate method when making inference to the overall population. Other methods should be used with caution, and prediction at the means should not be used with binary confounders. Stata, but not SAS, incorporates simple methods for marginal standardization.