Reverse Causation Bias Research Articles

Early-Life Environmental Exposures and Childhood Obesity: An Exposome-Wide Approach.

Background:Chemical and nonchemical environmental exposures are increasingly suspected to influence the development of obesity, especially during early life, but studies mostly consider single exposure groups.Objectives:Our study aimed to systematically assess the association between a wide array of early-life environmental exposures and childhood obesity, using an exposome-wide approach.Methods:The HELIX (Human Early Life Exposome) study measured child body mass index (BMI), waist circumference, skinfold thickness, and body fat mass in 1,301 children from six European birth cohorts age 6–11 y. We estimated 77 prenatal exposures and 96 childhood exposures (cross-sectionally), including indoor and outdoor air pollutants, built environment, green spaces, tobacco smoking, and biomarkers of chemical pollutants (persistent organic pollutants, metals, phthalates, phenols, and pesticides). We used an exposure-wide association study (ExWAS) to screen all exposure–outcome associations independently and used the deletion-substitution-addition (DSA) variable selection algorithm to build a final multiexposure model.Results:The prevalence of overweight and obesity combined was 28.8%. Maternal smoking was the only prenatal exposure variable associated with higher child BMI (z-score increase of 0.28, 95% confidence interval: 0.09, 0.48, for active vs. no smoking). For childhood exposures, the multiexposure model identified particulate and nitrogen dioxide air pollution inside the home, urine cotinine levels indicative of secondhand smoke exposure, and residence in more densely populated areas and in areas with fewer facilities to be associated with increased child BMI. Child blood levels of copper and cesium were associated with higher BMI, and levels of organochlorine pollutants, cobalt, and molybdenum were associated with lower BMI. Similar results were found for the other adiposity outcomes.Discussion:This first comprehensive and systematic analysis of many suspected environmental obesogens strengthens evidence for an association of smoking, air pollution exposure, and characteristics of the built environment with childhood obesity risk. Cross-sectional biomarker results may suffer from reverse causality bias, whereby obesity status influenced the biomarker concentration. https://doi.org/10.1289/EHP5975

CT scans in childhood predict subsequent brain cancer: Finite mixture modelling can help separate reverse causation scans from those that may be causal

BackgroundExcess brain cancers observed after computed tomography (CT) scans could be caused by ionizing radiation. However, as scans are often used to investigate symptoms of brain cancer, excess cancers could also be due to reverse causation bias. We used finite mixture models (FMM) to differentiate CT exposures that are plausibly causal from those due to reverse causation. MethodsPersons with at least one CT scan exposure and a subsequent diagnosis of brain cancer were selected from a cohort of 11 million young Australians. We fitted FMMs and used the posterior probability to inform the choice of exclusion periods. We validated our findings using a separate clinical dataset describing the time between first symptoms and brain cancer diagnosis (pre-diagnostic symptomatic interval; PSI). ResultsThe cohort included 1028 persons with a diagnosed brain tumor and exposed to a total of 1,450 CT scans. The best-fitting model was a generalized linear mixture model using the exponential distribution with three latent classes and two covariates (age at exposure and year of exposure). The 99th percentile classifier cutoff was 18.9 months. The sample-size weighted mean of the 99th percentile of the PSI, derived from clinical data, was 15.6 months. ConclusionsTo minimize reverse causation bias in studies of CT scan and brain cancer, the optimal exclusion period is one to two years (depending on the choice of classifier). This information will inform the interpretation of current and future studies.

Causal effects of physical activity and sedentary behaviour on health deficits accumulation in older adults.

Increasing physical activity (PA) and reducing sedentary behaviour (SB) have been associated with healthy ageing, but their effects when adjusted for reverse causation and selection bias remain unclear. A deficits accumulation (DA) index based on the number and severity of 51 health deficits (0-100%) was calculated at baseline and three biannual follow-up visits, in a representative cohort of 3228 community-dwelling older adults in Spain. Average differences in DA index by previous recreational PA, household PA, mentally-active SB and passive SB were estimated using marginal structural models with inverse probability of exposure and censoring weights. Compared with participants with previous recreational PA of 10-19.9 metabolic equivalent hours/week (MET-hours/week), average differences in DA index (95% confidence intervals) were 0.19 (-1.09, 1.48), 0.69 (-0.23, 1.61), -0.66 (-1.34, 0.02), -0.87 (-1.59, -0.13) and -0.55 (-1.37, 0.28) for 0, 0.1-9.9, 20-29.9, 30-39.9 and ≥40 MET-hours/week, respectively (P for trend = 0.006). Household PA showed no effect on subsequent DA after adjusting for reverse causation. Women, but not men, who spent 7-14.9, 15-20.9 and ≥21 h/week on mentally active SB had DA decreases of 0.09 (-1.00, 1.19), 1.08 (-0.28, 2.45) and 2.17 (0.58, 3.75), respectively, compared with 1-6.9 h/week (P for trend = 0.005); whereas women who spent 3-3.9, 4-4.9 and ≥5 h/day on passive SB showed DA increases of 0.41 (-0.52, 1.35), 1.35 (0.13, 2.57) and 2.13 (0.78, 3.47), respectively, compared with 2-2.9 h/day (P for trend = 0.001). The proposed methodology allows estimation of the causal effects of PA and SB on ageing, by simulating a random assignment in which all subjects have the same probability of exposure.

Mandatory CSR expenditure and stock return

Purpose India has mandated corporate social responsibility (CSR) expenditure under Section 135 of the Indian Companies Act, 2013 – the first national jurisdiction to do so. The purpose of this paper is to examine the impact of mandated CSR expenditure on firms’ stock returns by using actual CSR spending data, whereas the previous studies mostly focus on voluntary CSR proxied by CSR scores. Design/methodology/approach The authors estimate their baseline regression by using ordinary least squares(OLS) method. Although the baseline regression involving CSR expenditure and stock returns using ordinary least squares method are estimated, endogeneity and reverse causality biases are addressed by using two-stage least squares and generalized method of moments approaches. These approaches contribute mitigating endogeneity bias and biases associated with unobserved heterogeneity and simultaneity. Findings The findings document that mandatory CSR expenditure has a negative impact on firms’ stock returns which supports the “shareholders” expense’ view. This result remain robust after controlling for endogeneity bias and the use of both standard and robust test statistics. The authors however observe that this result holds for the firms with actual CSR expenditure equal to the mandated amount but does not hold for the firms with actual CSR expenditure greater than the mandated amount. Therefore, the authors provide evidence that CSR expenditure’s impact on stock returns depends on whether firms simply comply the regulation or voluntarily chose an amount of CSR expenditure above the mandated amount. Originality/value The primary contribution is to present a valid and robust evidence of negative effect of mandated CSR spending on firms’ stock returns when the mandatory CSR spending rule is already in place. This study contributes by examining the impact of mandated CSR spending on stock during post-implementation period (2015-2017), whereas other studies by Dharampala and Khanna (2018); Kapoor and Dhamija (2017); and Mukherjee et al. (2018) mainly examined the impact of legislation on Indian CSR. The authors use mandated actual CSR expenditure, whereas previous studies mostly focus on voluntary CSR proxied by CSR scores.

Pesticide residue intake from fruits and vegetables and fecundability in a North American preconception cohort study

Intake of conventionally-grown fruits and vegetables with higher levels of pesticide residue contamination has been associated with poorer semen quality and lower probability of live birth among couples undergoing fertility treatment. We examined the association between dietary intake of pesticide residues and fecundability, the per cycle probability of conception, in a preconception cohort of pregnancy planners. We enrolled women aged 21–45 years who were attempting to conceive without use of fertility treatment into Pregnancy Study Online (PRESTO) from June 2013 through September 2019. Participants completed a baseline questionnaire on demographics, lifestyle factors, and medical and reproductive histories, and bimonthly follow-up questionnaires for up to 12 months or until reported conception. Ten days after baseline, participants completed the National Cancer Institute’s Diet History Questionnaire II, a validated food frequency questionnaire. Using data from the USDA Pesticide Data Program, we classified fruits and vegetables as having high or low pesticide residues using a validated method. We examined the relation between greater intake of high- and low-pesticide residue fruits and vegetables with fecundability using proportional probabilities regression models, adjusted for potential confounders and accounting for consumption of organic produce. We restricted our analysis to 5234 women who had been attempting conception for ≤6 cycles at study entry, and further stratified by pregnancy attempt time at study entry (<3 vs. 3–6 cycles) to evaluate potential for reverse causation. Intakes of high- and low-pesticide residue fruits and vegetables were not appreciably related to fecundability in the full sample, or among women trying to conceive for <3 cycles at study entry. However, among women trying to conceive for 3–6 cycles at study entry, both high- and low-pesticide residue fruit and vegetable intakes were strongly inversely related to fecundability, indicating potential reverse causation bias. These results do not support the hypothesis that intake of pesticide residues from conventionally-grown fruits and vegetables is harmful to fertility, although non-differential exposure misclassification may have attenuated our findings.

Accelerometer-measured physical activity and sedentary time in a cohort of US adults followed for up to 13 years: the influence of removing early follow-up on associations with mortality

BackgroundObservational studies linking physical activity with mortality are susceptible to reverse causation bias from undiagnosed and prevalent diseases. Researchers often attempt to deal with reverse causation bias by excluding deaths occurring within the first 1 or 2 years from the analysis, but it is unclear if excluding deaths within this time-frame is sufficient to remove bias.MethodsWe examined associations between total and intensity-specific physical activity and sedentary time with all-cause mortality in a prospective cohort of 3542 individuals from the 2003–2006 NHANES cycles. In order to yield measures of association hypothesized as minimally influenced by reverse causation bias the primary analysis excluded individuals with < 5 years of follow-up. Accelerometer-measured physical activity was linked with recently updated vital status from the National Death Index with a median follow-up of 10.8 years.ResultsHazard ratios (95% confidence intervals) were 0.74 (0.53, 1.04), 0.52 (0.37, 0.73), and 0.61 (0.38, 1.01) for ascending quartiles of total physical activity against the least active reference. Hazard ratios for ascending moderate-to-vigorous physical activity quartiles against the reference were 0.67 (0.47, 1.96), 0.67 (0.47, 0.95), and 0.68 (0.39, 1.18). Associations for light intensity physical activity and sedentary time were smaller in magnitude and all confidence intervals included unity. Total activity and moderate-to-vigorous physical activity hazard ratios from analyses only excluding deaths within the first 2 years were inflated by 13 and 26% relative to analysis restricted to ≥5 years of follow-up.ConclusionsThe pattern of associations suggested total physical activity and moderate-to-vigorous physical activity were associated with lower mortality after more than 10 years of follow-up and excluding the first 5 years of observation time to minimize the impact of reverse causation bias. Excluding deaths within the first 2 years appeared insufficient to minimize the impact of reserve causation bias.

Abstract MP77: Associations Between Atrial Cardiopathy and Cerebral Amyloid: The Aric Pet Study

Background: Atrial fibrillation (AF) is a risk factor for cognitive decline, perhaps due to silent cerebral infarction, but it is unknown if it also acts on Alzheimer’s Disease (AD)-specific mechanisms, such as deposition of β-amyloid (Aβ). Left atrial changes in structure or function, or atrial cardiopathy, can lead to AF but may cause infarcts independently, and thus might also impact cognition. We hypothesize that Aβ is associated with AF and atrial cardiopathy, independent of AF, when defined similarly to an ongoing clinical trial (ARCADIA). Methods: 321 participants without dementia from the Atherosclerosis Risk in Communities study underwent florbetapir (FBP) PET, electrocardiogram and 2D echocardiography. Atrial cardiopathy was defined as ≥1 of: 1) left atrial volume index (LAVI) &gt;34 ml/m2; 2) P-wave terminal force &gt;5000 uV x ms and 3) serum NT proBNP&gt;250 pg/mL. Cross-sectional associations between global cortical Aβ (&gt;1.2 standardized uptake value ratio (SUVR)) and adjudicated history of atrial fibrillation and atrial cardiopathy, each, were evaluated using multivariable logistic regression. Results: Participants, with mean age 76 y, were 56% female and 42% black. Odds of elevated FBP SUVR was increased for those with atrial cardiopathy (Model 3) and nearly doubled among those with enlarged LAVI that remained significant after sequential adjustment, including AF (Table). There was no significant association between either P-wave terminal force or NT proBNP and elevated FBP SUVR (Table), nor between elevated SUVR and AF. Conclusions: In this cross-sectional analysis of a cohort of healthy, nondemented community-dwelling older individuals, we report a significant association between atrial cardiopathy as well as LAVI and elevated amyloid, by PET, without a similar association in individuals with AF. Potential limitations include reverse causation and survival bias. Ongoing work will help determine if changes in cardiac structure and function precede, or occur simultaneously with amyloid deposition.

Are infectious diseases risk factors for sarcoidosis or a result of reverse causation? Findings from a population-based nested case\u2013control study

Findings from molecular studies suggesting that several infectious agents cause sarcoidosis are intriguing yet conflicting and likely biased due to their cross-sectional design. As done in other inflammatory diseases to overcome this issue, prospectively-collected register data could be used, but reverse causation is a threat when the onset of disease is difficult to establish. We investigated the association between infectious diseases and sarcoidosis to understand if they are etiologically related. We conducted a nested case–control study (2009–2013) using incident sarcoidosis cases from the Swedish National Patient Register (n = 4075) and matched general population controls (n = 40,688). Infectious disease was defined using inpatient/outpatient visits and/or antimicrobial dispensations starting 3 years before diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression and tested for robustness assuming the presence of reverse causation bias. The aOR of sarcoidosis associated with history of infectious disease was 1.19 (95% confidence interval [CI] 1.09, 1.29; 21% vs. 16% exposed cases and controls, respectively). Upper respiratory and ocular infections conferred the highest OR. Findings were similar when we altered the infection definition or varied the infection-sarcoidosis latency period (1–7 years). In bias analyses assuming one in 10 infections occurred because of preclinical sarcoidosis, the observed association was completely attenuated (aOR 1.02; 95% CI 0.90, 1.15). Our findings, likely induced by reverse causation due to preclinical sarcoidosis, do not support the hypothesis that common symptomatic infectious diseases are etiologically linked to sarcoidosis. Caution for reverse causation bias is required when the real disease onset is unknown.

The More the Merrier? The Causal Effect of High Fertility on Later-Life Loneliness in Eastern Europe

Levels of later-life loneliness are high in Eastern Europe. We assess whether having more children is protective against later-life loneliness for Eastern-European mothers and fathers. Drawing on Generations and Gender Surveys data of 25,479 parents aged 50–80 from eight Eastern-European countries, we adopt an instrumental approach exploiting parents’ preference for mixed-sex offspring to estimate the causal effect of having additional children on feelings of loneliness. We find that having an additional child has a causal protective effect against loneliness for mothers. Ordinary least squares regression models also show a weak but statistically significant negative association between number of children and later-life loneliness among fathers. However, results of the instrumental variable analyses are inconclusive for this group. We thus do not find statistically significant causal evidence that having an additional child is protective against loneliness for fathers. Our results underline the importance of addressing reverse causality and selection bias when investigating the links between number of children and later-life loneliness, particularly among women. The causal evidence presented here suggests that the trend towards families with fewer children noted in several Eastern-European countries may place new cohorts of older Eastern-Europeans, and in particular Eastern-European women, at risk of stronger feelings of loneliness.

Exchange Rates and Domestic Credit-Can Macroprudential Policy Reduce the Link?

This paper examines empirically the role of macroprudential policy in addressing the effects of external shocks on financial stability. In a sample of 62 economies over the period of 2000: Q1-2016: Q4, our dynamic panel regressions show that an appreciation of the local exchange rate is associated with a subsequent increase in the domestic credit gap, while a prior tightening of macroprudential policies dampens this effect. These results are strong for small open economies, and robust when we explicitly account for potential simultaneity and reverse causality biases. We also examine a feedback effect where strong domestic credit pulls in additional cross-border funding, potentially further increasing systemic risk, and find that targeted capital controls can play a complementary role in alleviating this effect.

Impact of follow-up time and analytical approaches to account for reverse causality on the association between physical activity and health outcomes in UK Biobank.

BackgroundThe advent of very large cohort studies (n > 500 000) has given rise to prospective analyses of health outcomes being undertaken after short (<4 years) follow-up periods. However, these studies are potentially at risk of reverse causality bias. We investigated differences in the associations between self-reported physical activity and all-cause and cardiovascular disease (CVD) mortality, and incident CVD, using different follow-up time cut-offs and methods to account for reverse causality bias.MethodsData were from n = 452 933 UK Biobank participants, aged 38–73 years at baseline. Median available follow-up time was 7 years (for all-cause and CVD mortality) and 6.1 years (for incident CVD). We additionally analysed associations at 1-, 2- and 4-year cut-offs after baseline. We fit up to four models: (1) adjusting for prevalent CVD and cancer, (2) excluding prevalent disease, (3) and (4) Model 2 excluding incident cases in the first 12 and 24 months, respectively.ResultsThe strength of associations decreased as follow-up time cut-off increased. For all-cause mortality, Model 1 hazard ratios were 0.73 (0.69–0.78) after 1 year and 0.86 (0.84–0.87) after 7 years. Associations were weaker with increasing control for possible reverse causality. After 7-years follow-up, the hazard ratios were 0.86 (0.84–0.87) and 0.88 (0.86–0.90) for Models 1 and 4, respectively. Associations with CVD outcomes followed similar trends.ConclusionsAs analyses with longer follow-up times and increased control for reverse causality showed weaker associations, there are implications for the decision about when to analyse a cohort study with ongoing data collection, the interpretation of study results and their contribution to meta-analyses.

Does Poorer Pulmonary Function Accelerate Arterial Stiffening?

Whether poorer pulmonary function accelerates progression of arterial stiffness remains unknown as prior observational studies have not examined longitudinal changes in arterial stiffness in relation to earlier pulmonary function. Data (N=5342, 26% female) were drawn from the Whitehall II cohort study. Participants completed repeated assessments of forced expiratory volume in 1 second (FEV1, L) and carotid-femoral pulse wave velocity (cf-PWV, m/s) over 5 years. The effect of FEV1 on later cf-PWV and its progression was estimated using linear mixed-effects modeling. Possible explanatory mechanisms, such as mediation by low-grade systemic inflammation, common-cause explanation by preexisting cardiometabolic risk factors, and reverse-causation bias, were assessed. Poorer pulmonary function was associated with later higher cf-PWV and its subsequent progression (cf-PWV 5-year change 0.09, 95% CI 0.03–0.17 per SD lower FEV1) after adjustment for age, sex, ethnicity, heart rate, and mean arterial pressure. Decrease in pulmonary function was associated with later higher cf-PWV (0.17, 95% CI 0.04–0.30 in the top compared to bottom quartile of decline in FEV1). There was no evidence to support mediation by circulating CRP (C-reactive protein) or IL (interleukin)-6. Furthermore, arterial stiffness was not associated with later FEV1 after accounting for cardiometabolic status. In conclusion, poorer pulmonary function predicted future arterial stiffness. These findings support pulmonary function as a clinically important risk factor for arterial stiffness and provide justification for future intervention studies for pulmonary function based on its relationship with arterial stiffness.

Association of social contact with dementia and cognition: 28-year follow-up of the Whitehall II cohort study.

BackgroundThere is need to identify targets for preventing or delaying dementia. Social contact is a potential target for clinical and public health studies, but previous observational studies had short follow-up, making findings susceptible to reverse causation bias. We therefore examined the association of social contact with subsequent incident dementia and cognition with 28 years’ follow-up.Methods and findingsWe conducted a retrospective analysis of the Whitehall II longitudinal prospective cohort study of employees of London civil service departments, aged 35–55 at baseline assessment in 1985–1988 and followed to 2017. Social contact was measured six times through a self-report questionnaire about frequency of contact with non-cohabiting relatives and friends. Dementia status was ascertained from three linked clinical and mortality databases, and cognition was assessed five times using tests of verbal memory, verbal fluency, and reasoning. Cox regression models with inverse probability weighting to account for attrition and missingness examined the association between social contact at age 50, 60, and 70 years and subsequent incident dementia. Mixed linear models examined the association of midlife social contact between 45 and 55 years and cognitive trajectory during the subsequent 14 years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, education, health behaviours, employment status, and marital status. Of 10,308 Whitehall II study participants, 10,228 provided social contact data (mean age 44.9 years [standard deviation (SD) 6.1 years] at baseline; 33.1% female; 89.1% white ethnicity). More frequent social contact at age 60 years was associated with lower dementia risk (hazard ratio [HR] for each SD higher social contact frequency = 0.88 [95% CI 0.79, 0.98], p = 0.02); effect size of the association of social contact at 50 or 70 years with dementia was similar (0.92 [95% CI 0.83, 1.02], p = 0.13 and 0.91 [95% CI 0.78, 1.06], p = 0.23, respectively) but not statistically significant. The association between social contact and incident dementia was driven by contact with friends (HR = 0.90 [95% CI 0.81, 1.00], p = 0.05), but no association was found for contact with relatives. More frequent social contact during midlife was associated with better subsequent cognitive trajectory: global cognitive function was 0.07 (95% CI 0.03, 0.11), p = 0.002 SDs higher for those with the highest versus lowest tertile of social contact frequency, and this difference was maintained over 14 years follow-up. Results were consistent in a series of post hoc analyses, designed to assess potential biases. A limitation of our study is ascertainment of dementia status from electronic health records rather than in-person assessment of diagnostic status, with the possibility that milder dementia cases were more likely to be missed.ConclusionsFindings from this study suggest a protective effect of social contact against dementia and that more frequent contact confers higher cognitive reserve, although it is possible that the ability to maintain more social contact may be a marker of cognitive reserve. Future intervention studies should seek to examine whether improving social contact frequency is feasible, acceptable, and efficacious in changing cognitive outcomes.

The Effects of Reverse Causality and Selective Attrition on the Relationship Between Body Mass Index and Mortality in Postmenopausal Women.

Concerns about reverse causality and selection bias complicate the interpretation of studies of body mass index (BMI, calculated as weight (kg)/height (m)2) and mortality in older adults. The objective of this study was to investigate methodological explanations for the apparent attenuation of obesity-related risks in older adults. We used data from 68,132 participants in the Women's Health Initiative (WHI) clinical trial for this analysis. All of the participants were postmenopausal women aged 50-79 years at baseline (1993-1998). To examine reverse causality and selective attrition, we compared rate ratios from inverse probability of treatment- and censoring-weighted Poisson marginal structural models with results from an unweighted adjusted Poisson regression model. The estimated mortality rate ratios and 95% confidence intervals for BMIs of 30.0-34.9, 35.0-39.9 and ≥40.0 were 0.86 (95% confidence interval (CI): 0.77, 0.96), 0.85 (95% CI: 0.72, 0.99), and 0.88 (95% CI: 0.72, 1.07), respectively, in the unweighted model. The corresponding mortality rate ratios were 0.96 (95% CI: 0.86, 1.07), 1.12 (95% CI: 0.97, 1.29), and 1.31 95% CI: (1.08, 1.57), respectively, in the marginal structural model. Results from the inverse probability of treatment- and censoring-weighted marginal structural model were attenuated in low BMI categories and increased in high BMI categories. The results demonstrate the importance of accounting for reverse causality and selective attrition in studies of older adults.

Flexible Modeling of the Association Between Cumulative Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Risk of Cancer in Adults With Congenital Heart Disease.

Adults with congenital heart disease are increasingly being exposed to low-dose ionizing radiation (LDIR) from cardiac procedures. In a recent study, Cohen et al. (Circulation. 2018;137(13):1334-1345) reported an association between increased LDIR exposure and cancer incidence but did not explore temporal relationships. Yet, the impact of past exposures probably accumulates over years, and its strength may depend on the amount of time elapsed since exposure. Furthermore, LDIR procedures performed shortly before a cancer diagnosis may have been ordered because of early symptoms of cancer, raising concerns about reversal causality bias. To address these challenges, we combined flexible modeling of cumulative exposures with competing-risks methodology to estimate separate associations of time-varying LDIR exposure with cancer incidence and all-cause mortality. Among 24,833 patients from the Quebec Congenital Heart Disease Database, 602 had incident cancer and 500 died during a follow-up period of up to 15 years (1995-2010). Initial results suggested a strong association of cancer incidence with very recent LDIR exposures, likely reflecting reverse causality bias. When exposure was lagged by 2 years, an increased cumulative LDIR dose from the previous 2-6 years was associated with increased cancer incidence, with a stronger association for women. These results illustrate the importance of accurate modeling of temporal relationships between time-varying exposures and health outcomes.

The relationship between chronic stress, hair cortisol and hypertension

Inconsistencies in studies of chronic psychosocial stress and hypertension may be explained by the use of stress markers greatly influenced by circadian rhythm and transient stressors. We assessed whether hair cortisol, a marker that captures systemic cortisol over months, was independently associated with hypertension. We measured hair cortisol and blood pressure in 75 consecutive participants in the Survey of the Health of Wisconsin, using an ELISA test. Individuals with values ​≥ ​median (78.1 ​pg/mg) were considered exposed. We used approximate Bayesian logistic regression, with a prior odds ratio of 1.0–4.0, to quantify the multivariate-adjusted hair cortisol-hypertension association. Participants' average age was 46.9 years; 37.3% were male; and 25.3% were hypertensive. Hypertension prevalence was 2.23 times higher in exposed (95% CI: 1.69–3.03). This finding was unlikely explained by differential measurement errors, since we conducted blinded measurements of exposure and outcome. Sensitivity analyses showed the association was unlikely explained by an unmeasured confounder, survival bias, or reverse causality bias. Findings suggest elevated hair cortisol is a risk factor for hypertension. Although feasible, the clinical value of hair cortisol as a tool for hypertension risk stratification or for monitoring the effect of chronic psychosocial stress management interventions is still uncertain.

Importance of vitamin D in acute and critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis

ObjectivesTo estimate the prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency and investigate its association with mortality in children with acute or critical conditions.DesignSystematic review and meta-analysis of observational studies.Data sourcesPubMed, OVID,...

Consumption of Meat, Fish, Dairy Products, and Eggs and Risk of Ischemic Heart Disease.

There is uncertainty about the relevance of animal foods to the pathogenesis of ischemic heart disease (IHD). We examined meat, fish, dairy products, and eggs and risk for IHD in the pan-European EPIC cohort (European Prospective Investigation Into Cancer and Nutrition). In this prospective study of 409 885 men and women in 9 European countries, diet was assessed with validated questionnaires and calibrated with 24-hour recalls. Lipids and blood pressure were measured in a subsample. During a mean of 12.6 years of follow-up, 7198 participants had a myocardial infarction or died of IHD. The relationships of animal foods with risk were examined with Cox regression with adjustment for other animal foods and relevant covariates. The hazard ratio (HR) for IHD was 1.19 (95% CI, 1.06-1.33) for a 100-g/d increment in intake of red and processed meat, and this remained significant after exclusion of the first 4 years of follow-up (HR, 1.25 [95% CI, 1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR, 0.93 [95% CI, 0.89-0.98] per 100-g/d increment), cheese (HR, 0.92 [95% CI, 0.86-0.98] per 30-g/d increment), and eggs (HR, 0.93 [95% CI, 0.88-0.99] per 20-g/d increment); the associations with yogurt and eggs were attenuated and nonsignificant after exclusion of the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish, or milk. In analyses modeling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese, or eggs was associated with ≈20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-high-density lipoprotein cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-high-density lipoprotein cholesterol. Risk for IHD was positively associated with consumption of red and processed meat and inversely associated with consumption of yogurt, cheese, and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It is not clear whether the associations with red and processed meat and cheese reflect causality, but they were consistent with the associations of these foods with plasma non-high-density lipoprotein cholesterol and for red and processed meat with systolic blood pressure, which could mediate such effects.

Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis

ObjectiveTo examine whether physical inactivity is a risk factor for dementia, with attention to the role of cardiometabolic disease in this association and reverse causation bias that arises from changes...

Kidney Dysfunction and the Risk of Developing Aortic Stenosis

BackgroundChronic kidney disease (CKD) and aortic stenosis (AS) share many risk factors. ObjectivesThis study sought to evaluate whether kidney dysfunction is associated with the development of AS in the community. MethodsThe study included 1,121,875 Stockholm citizens without a prior diagnosis of AS from the SCREAM (Stockholm CREAtinine Measurements) project. Estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2) was calculated from serum creatinine. AS incidence during follow-up was ascertained by clinical diagnostic codes. The association between eGFR and AS incidence was estimated with multivariable Cox proportional hazards models. Sensitivity analyses included analysis of possible reverse causation bias by excluding the first 6 months to 2 years after enrollment and excluding individuals with comorbid heart failure. ResultsThe median age was 50 years (interquartile range [IQR]: 36 to 64 years), and 54% of participants were women. Median eGFR was 96 ml/min/1.73 m2 (IQR: 82 to 109 ml/min/1.73 m2), and 66,949 (6.0%) participants had CKD (eGFR <60 ml/min/1.73 m2). During a median follow-up of 5.1 years (IQR: 3.3 to 6.1 years), 5,858 (0.5%) individuals developed AS (incidence rate [IR] 1.13/1,000 person-years). Compared with eGFR >90 (IR 0.34/1,000 person-years), lower eGFR strata were associated with higher hazards of AS: eGFR 60 to 90 ml/min/1.73 m2; IR: 1.88; hazard ratio (HR): 1.14; 95% confidence interval (CI): 1.05 to 1.25; eGFR 45 to 59 ml/min/1.73 m2; IR: 4.61; HR: 1.17; 95% CI: 1.05 to 1.30; eGFR 30 to 44 ml/min/1.73 m2; IR: 6.62; HR: 1.22; 95% CI: 1.07 to 1.39; and eGFR 30 ml/min/1.73 m2; IR: 8.27; HR: 1.56; 95% CI: 1.29 to 1.87. Sensitivity analysis attenuated only slightly the magnitude of the association; individuals with eGFR ≤44 ml/min/1.73 m2 remained at an approximate 20% risk of AS both when excluding events within the 2 years after baseline (HR: 1.22; 95% CI: 1.06 to 1.42) and when excluding participants with heart failure (HR: 1.20; 95% CI: 1.03 to 1.39). ConclusionsCKD, even in moderate to severe stages, is associated with an increased risk of AS.