Abstract
Mediation analysis allows decomposing a total effect into a direct effect of the exposure on the outcome and an indirect effect operating through a number of possible hypothesized pathways. ...Recent studies have provided formal definitions of direct and indirect effects when multiple mediators are of interest and have described parametric and semiparametric methods for their estimation. Investigating direct and indirect effects with multiple mediators, however, can be challenging in the presence of multiple exposure-mediator and mediator-mediator interactions. In this paper we derive a decomposition of the total effect that unifies mediation and interaction when multiple mediators are present. We illustrate the properties of the proposed framework in a secondary analysis of a pragmatic trial for the treatment of schizophrenia. The decomposition is employed to investigate the interplay of side effects and psychiatric symptoms in explaining the effect of antipsychotic medication on quality of life in schizophrenia patients. Our result offers a valuable tool to identify the proportions of total effect due to mediation and interaction when more than one mediator is present, providing the finest decomposition of the total effect that unifies multiple mediators and interactions.
Abstract
The overall effect of an exposure on an outcome, in the presence of a mediator with which the exposure may interact, can be decomposed into four components that correspond to the portion of ...the effect that is due: (i) to neither mediation nor interaction; (ii) to just interaction (but not mediation); (iii) to both mediation and interaction; and (iv) to just mediation (but not interaction). This four-way decomposition unifies methods to attribute effects to interactions and methods that assess mediation. We introduce the Stata command med4way to estimate the causal contrasts that arise in this decomposition. Med4way is implemented as a Stata stand-alone command requiring Stata version 10 or higher (StataCorp, College Station, TX, USA), and allows estimating the four-way decomposition using parametric regression models. Med4way can be used when the outcome is continuous, dichotomous, count or survival time, and the mediator is continuous or binary. The command accommodates cohort and case-control designs. We present two examples of application of the command to gain insight on important public health problems. In the first application, we employ med4way to investigate the role of birth outcomes in explaining the effect of maternal exposure to manganese on child neurodevelopment. In the second application, we investigate the role of stage at diagnosis in explaining income disparities in colorectal cancer survival. The command is freely available on GitHub https://github.com/anddis/med4way and has been published under General Public License (GPL) version 3.
Prior work has shown that both short and long sleep predict mortality. However, sleep duration decreases with age and this may affect the relationship of sleep duration with mortality. The purpose of ...the present study was to assess whether the association between sleep duration and mortality varies with age. Prospective cohort study. 43,863 individuals (64% women), recruited in September 1997 during the Swedish National March and followed through record-linkages for 13 years. Sleep duration was self-reported and measured using the Karolinska Sleep Questionnaire, and grouped into 4 categories: ≤5, 6, 7 (reference) and ≥8 h. Up to 2010 3548 deaths occurred. Multivariable Cox proportional hazards regression models with attained age as time scale were fitted to estimate mortality rate ratios. Among individuals <65 years, short (≤5 h) and long (≥8 h) sleep duration showed a significant relationship with mortality (HR 1.37, 95% CI 1.09-1.71, and HR 1.27, 95% CI 1.08-1.48). Among individuals 65 years or older, no relationships between sleep duration and mortality were observed. The effect of short and long sleep duration on mortality was highest among young individuals and decreased with increasing age. The results suggest that age plays an important role in the relationship between sleep duration and mortality.
We have previously investigated whether urinary concentrations of bisphenol A (BPA), parabens, and phthalate metabolites were individually associated with reproductive outcomes among women undergoing ...in vitro fertilization (IVF) treatment. However, humans are typically exposed to many man-made chemicals simultaneously. Thus, investigating one chemical at a time may not represent the effect of mixtures.
To investigate whether urinary concentrations of BPA, parabens, and phthalate metabolite mixtures are associated with reproductive outcomes among women undergoing IVF.
This prospective cohort study included 420 women contributing 648 IVF cycles who provided up to two urine samples per cycle prior to oocyte retrieval (N = 1145) between 2006 and 2017 at the Massachusetts General Hospital Fertility Center, and had available urine biomarker data. Urinary concentrations of BPA, parabens, and phthalate metabolites were quantified using isotope-dilution tandem mass spectrometry. Intermediate and clinical end-points of IVF treatments were abstracted from electronic medical records. Principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) were used to identify main patterns of BPA, parabens, and phthalate metabolites concentrations. We used generalized linear mixed models to evaluate the association between PCA-derived factor scores, in quartiles, and IVF outcomes, using random intercepts to account for multiple IVF cycles and adjusting for known confounders. Because of temporal trends in exposure, we conducted a sensitivity analysis restricted to women who underwent IVF cycles in the earlier years of study (2006–2012).
Urinary concentrations of BPA, parabens, and most phthalate metabolites were significantly lower during the second half of the study period (2013–2017) than during the first half (2006–2012). None of the three factors derived from the PCA di(2-ethylhexyl) phthalate (DEHP), non-DEHP, and paraben was associated with IVF outcomes in the main analyses. Similarly, BKRM analyses did not identify any associations of individual urinary concentrations of BPA, paraben and phthalate metabolites with IVF outcomes while accounting for correlation between exposures. However, in sensitivity analyses restricted to women who underwent IVF cycles from 2006 to 2012, where concentrations of most phthalates and phenols were higher, there were decreases in implantation, clinical pregnancy, and live birth across quartiles of the DEHP factor. Specifically, women in the highest quartile of the DEHP factor had, on average, lower probabilities of implantation (−22% p, trend = 0.08), clinical pregnancy (−24% p, trend = 0.14), and live birth (−38% p, trend = 0.06) compared to women in the lowest quartile. Among this group of women, BKMR results did not identify any single contributor driving the decreased probabilities of live birth within the DEHP factor.
We confirmed that women undergoing IVF are concurrently exposed to multiple endocrine disrupting chemicals (EDCs). While we found no overall significant associations, we observed diminished pregnancy success with specific clusters of chemicals among women who underwent IVF cycles in earlier years of study, when urinary concentrations of these EDCs were higher.
•We used novel approaches to evaluate chemical mixtures among women undergoing IVF.•Factor scores reflecting DEHP, non-DEHP, and paraben concentrations were calculated.•These scores did not show associations with reproductive outcomes or live birth.•For IVF cycles before 2012, higher DEHP scores were linked to lower birth rates.
Background
Short‐term exposures to fine (<2.5 μm aerodynamic diameter) ambient particulate‐matter (PM) have been related with increased blood pressure (BP) in controlled‐human exposure and ...community‐based studies. However, whether coarse (2.5 to 10 μm) PM exposure increases BP is uncertain. Recent observational studies have linked PM exposures with blood DNA hypomethylation, an epigenetic alteration that activates inflammatory and vascular responses. No experimental evidence is available to confirm those observational data and demonstrate the relations between PM, hypomethylation, and BP.
Methods and Results
We conducted a cross‐over trial of controlled‐human exposure to concentrated ambient particles (CAPs). Fifteen healthy adult participants were exposed for 130 minutes to fine CAPs, coarse CAPs, or HEPA‐filtered medical air (control) in randomized order with ≥2‐week washout. Repetitive‐element (Alu, long interspersed nuclear element‐1 LINE‐1) and candidate‐gene (TLR4, IL‐12, IL‐6, iNOS) blood methylation, systolic and diastolic BP were measured pre‐ and postexposure. After adjustment for multiple comparisons, fine CAPs exposure lowered Alu methylation (β‐standardized=−0.74, adjusted‐P=0.03); coarse CAPs exposure lowered TLR4 methylation (β‐standardized=−0.27, adjusted‐P=0.04). Both fine and coarse CAPs determined significantly increased systolic BP (β=2.53 mm Hg, P=0.001; β=1.56 mm Hg, P=0.03, respectively) and nonsignificantly increased diastolic BP (β=0.98 mm Hg, P=0.12; β=0.82 mm Hg, P=0.11, respectively). Decreased Alu and TLR4 methylation was associated with higher postexposure DBP (β‐standardized=0.41, P=0.04; and β‐standardized=0.84, P=0.02; respectively). Decreased TLR4 methylation was associated with higher postexposure SBP (β‐standardized=1.45, P=0.01).
Conclusions
Our findings provide novel evidence of effects of coarse PM on BP and confirm effects of fine PM. Our results provide the first experimental evidence of PM‐induced DNA hypomethylation and its correlation to BP.
•We used PCA and BKMR to evaluate chemical mixtures among men in couples undergoing IVF.•Factor scores reflecting urinary DEHP, non-DEHP/BPA, and paraben were calculated.•Paternal mixtures of DEHP ...metabolites were related to higher infertility treatment failure.•BKMR identified ∑DEHP as the most important contributor to the mixture-outcome association.
Few epidemiologic studies have evaluated the impact of paternal environmental exposures, particularly as mixtures, on couples’ pregnancy outcomes.
We investigated whether mixtures of paternal urinary bisphenol A (BPA), paraben, and phthalates were associated with pregnancy outcomes among couples attending a fertility center.
We included 210 couples undergoing 300 in vitro fertilization (IVF) between 2004 and 2017 in this prospective analysis. We quantified paternal urinary biomarker concentrations in one sample per cycle using isotope-dilution tandem mass spectrometry. We used principal component analysis (PCA) to identify correlations of biomarker concentrations and multivariable Cox proportional hazards models for discrete survival time to estimate the hazard ratios (HRs) and 95% CIs for the associations between PCA-derived factor scores and probability of failing to achieve a live birth. Interactions were also included in the models to examine strength of associations over three vulnerable periods embryo transfer to implantation, implantation to clinical pregnancy, and clinical pregnancy to live birth. Models were adjusted for paternal and maternal ages and body mass indexes, urinary dilution (specific gravity) and year of collection, infertility diagnosis, and other PCA factor scores. Sensitivity analyses with further adjustment for maternal PCA factor scores were performed.
We identified three factors, representing di-2-ethylhexyl phthalate (DEHP) metabolites, BPA and non-DEHP metabolites, and parabens, accounting for 56%, 15% and 10%, respectively, of the total variance explained. An interquartile range (25th and 75th percentiles) increase in the DEHP-related factor score was associated with elevated probability of failing prior to live birth (HR = 1.41, 95% CI: 1.08, 1.81) and the association was stronger between implantation and clinical pregnancy as well as between clinical pregnancy and live birth compared to before implantation. The overall HRs of failure for the BPA/non-DEHP-related and paraben-related factor scores were HR = 1.24 (95% CI: 0.97, 1.59) and HR = 0.99 (95% CI: 0.80, 1.24). We found similar HRs when additionally adjusting for maternal PCA factor scores.
Paternal mixtures of urinary concentrations of DEHP metabolites were related to higher infertility treatment failure.
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Studies suggest a link between pregnancy phthalate exposures and gestational diabetes mellitus (GDM). Few studies have evaluated associations between phthalate biomarkers (individual ...or mixtures) with gradations of maternal glucose intolerance.
In a subset of 606 women participating in LIFECODES pregnancy cohort, a combination of 50-gram 1-h non-fasting glucose load test (GLT) and 100-gram 3-h fasting oral glucose tolerance test was used to determine pregnancy glycemic status (median: 27 weeks gestation): normoglycemia (n = 136), impaired glucose tolerance (IGT) (n = 296), and GDM (n = 174). Nineteen metabolites of phthalates and their replacements were measured during each trimester. We used multivariable logistic regression models to evaluate associations between biomarkers (in quartiles) and maternal glycemic status (GDM v. normoglycemia and IGT v. normoglycemia), adjusting for potential confounders. We also used principal component analysis to evaluate associations jointly accounting for metabolites as chemical mixtures.
Higher 1st trimester mono-3-carboxypropyl phthalate (MCPP) was associated with decreased odds of GDM (Q4 v. Q1: 0.30; 95% CI: 0.13, 0.67) and IGT (Q4 v. Q1 OR: 0.37; 95% CI: 0.17, 0.79). Higher 2nd trimester mono-isobutyl phthalate (MiBP) was associated with increased IGT (Q4 v. Q1 OR: 2.07; 95% CI: 1.06, 4.07), and 2nd trimester mono-3-hydroxybutyl phthalate (MHBP) was non-monotonically associated with increased GDM (Q2 v. Q1 OR: 3.21; 95% CI: 1.54, 6.87). Mixture analyses showed similar associations (Q4 v. Q1 for 2nd trimester dibutyl phthalates metabotlites mixtures OR: 2.08; 95% CI: 1.04, 4.22).
Some phthalate biomarkershad trimester-specific associations with glycemic outcomes, with long and short term health implications.
No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip ...fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors.
We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National Osteoporosis Foundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random-effects meta-analysis methods.
223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75–79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2–9·7) followed by physical inactivity (5·5%, 2·1–8·5), history of diabetes (2·8%, 2·1–4·0), and low to average BMI (2·0%, 1·4–2·7), whereas low alcohol consumption (0·01–2·5 g per day) and high BMI had a protective effect.
Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle.
European Community's Seventh Framework Programme.
Higher blood lead levels (BLLs) have been linked to neurologic deficits and impaired growth, but few studies have evaluated their association with timing of sexual maturity or pubertal progression in ...boys.
In a longitudinal cohort of Russian boys enrolled at age 8–9 and followed to adulthood, BLLs were measured at study entry, and pubertal staging (genitalia and pubic hair) and testicular volume (TV) measurements were obtained annually. We used interval-censored regression models to estimate differences between boys with higher BLL (≥5 μg/dL) and lower BLL in mean ages at sexual maturity (genitalia stage 5, pubic hair stage 5, or TV ≥ 20 mL) and duration of pubertal progression (onset to maturity), adjusting for potential confounders. Mediation analyses were conducted to quantify the percent of lead's effect attributable to its association with reduced somatic growth.
Among 481 evaluable boys, 28% had BLL ≥ 5 μg/dL. Adjusted mean ages at sexual maturity were 14.7 years for genitalia, 16.1 for pubic hair, and 13.9 for TV. In adjusted models, boys with BLLs ≥5 μg/dL had later maturity than those with lower levels by 4–5 months depending on pubertal indicator. In mediation analyses, height and body mass index at age 11 accounted for 40–71% of the shift in age at maturity for boys with higher compared to lower BLLs. Higher BLLs were not associated with pace of pubertal progression.
Higher lead levels were associated with later attainment of sexual maturity in males, but not with the duration of pubertal progression. A high proportion of the delay in sexual maturity for boys with higher as compared to lower BLL was shown to be attributable to mediating effects of BLL on reduced growth.
•Higher blood lead has been linked to impaired growth and delayed pubertal onset.•Few studies have addressed the effects of blood lead on age at male sexual maturity.•We found significant delays in maturity among Russian boys with higher lead levels.•This delay was partly due to reduced growth among boys with higher lead levels.•Higher blood lead did not appear to slow pubertal progression.
The use of labor epidural analgesia has been associated with intrapartum fever, known as labor epidural associated fever (LEAF). LEAF is most commonly non-infectious in origin and associated with ...elevated inflammatory cytokines.
The LIFECODES pregnancy cohort was designed to prospectively collect data to evaluate the association of maternal inflammatory biomarkers with preterm birth in women who delivered between 2007 and 2008 at Brigham and Women's Hospital. Our secondary analysis of the data from the cohort identified 182 women for whom inflammatory biomarkers (i.e. interleukin-10, interleukin-1β, interleukin-6, tumor necrosis factor-α and C-reactive protein) collected longitudinally over four prenatal visits was available. Maternal temperature and other clinical variables were abstracted from medical records. The primary outcome, the presence of LEAF, was defined as oral temperature ≥ 38°C (≥100.4°F) after epidural analgesia initiation. Multivariable logistic regression estimated the association between inflammatory biomarker concentrations and the odds of developing an intrapartum fever after adjusting for a number of potential confounders.
Women who developed LEAF were more likely to have a longer duration of epidural analgesia, whereas women who did not develop LEAF were more likely to have induced labor and positive or unknown Group B Streptococcus colonization status. However, no differences were seen by nulliparity, mode of delivery, white blood cell count at admission, baseline temperature, length of rupture of membranes and number of cervical exams performed during labor. Unadjusted and multivariable logistic regression models did not provide evidence for or exclude an association between individual maternal inflammatory biomarkers and the odds of developing LEAF, regardless of visit time-period.
The predictive value of maternal inflammatory biomarkers measured during early- and mid-pregnancy for the risk of developing LEAF cannot be excluded.
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