Comparison of the Inverse Probability of Treatment Weighted (IPTW) Estimator With a Naïve Estimator in the Analysis of Longitudinal Data With Time-Dependent Confounding: A Simulation Study

A simulation study was conducted to compare estimates from a naïve estimator, using standard conditional regression, and an IPTW (Inverse Probability of Treatment Weighted) estimator, to true causal parameters for a given MSM (Marginal Structural Model). The study was extracted from a larger epidemiological study (Longitudinal Study of Effects of Physical Activity and Body Composition on Functional Limitation in the Elderly, by Tager et. al [accepted, Epidemiology, September 2003]), which examined the causal effects of physical activity and body composition on functional limitation. The simulation emulated the larger study in terms of the exposure and outcome variables of interest-- physical activity (LTPA), body composition (LNFAT), and physical limitation (PF), but used one time-dependent confounder (HEALTH) to illustrate the effects of estimating causal effects in the presence of time-dependent confounding. In addition to being a time-dependent confounder (i.e. predictor of exposure and outcome over time), HEALTH was also affected by past treatment. Under these conditions, naïve estimates are known to give biased estimates of the causal effects of interest (Robins, 2000). The true causal parameters for LNFAT (-0.61) and LTPA (-0.70) were obtained by assessing the log-odds of functional limitation for a 1-unit increase in LNFAT and participation in vigorous exercise in an ideal experiment in which the counterfactual outcomes were known for every possible combination of LNFAT and LTPA for each subject. Under conditions of moderate confounding, the IPTW estimates for LNFAT and LTPA were -0.62 and -0.94, respectively, versus the naïve estimates of -0.78 and -0.80. For increased levels of confounding of the LNFAT and LTPA variables, the IPTW estimates were -0.60 and -1.28, respectively, and the naïve estimates were -0.85 and -0.87. The bias of the IPTW estimates, particularly under increased levels of confounding, was explored and linked to violation of particular assumptions regarding the IPTW estimation of causal parameters for the MSM

Temporal and Spatial Patterns of Ambient Endotoxin Concentrations in Fresno, California

BackgroundEndotoxins are found in indoor dust generated by human activity and pets, in soil, and adsorbed onto the surfaces of ambient combustion particles. Endotoxin concentrations have been associated with respiratory symptoms and the risk of atopy and asthma in children.ObjectiveWe characterized the temporal and spatial variability of ambient endotoxin in Fresno/Clovis, California, located in California's Central Valley, to identify correlates and potential predictors of ambient endotoxin concentrations in a cohort of children with asthma [Fresno Asthmatic Children's Environment Study (FACES)].MethodsBetween May 2001 and October 2004, daily ambient endotoxin and air pollutants were collected at the central ambient monitoring site of the California Air Resources Board in Fresno and, for shorter time periods, at 10 schools and indoors and outdoors at 84 residences in the community. Analyses were restricted to May-October, the dry months during which endotoxin concentrations are highest.ResultsDaily endotoxin concentration patterns were determined mainly by meteorologic factors, particularly the degree of air stagnation. Overall concentrations were lowest in areas distant from agricultural activities. Highest concentrations were found in areas immediately downwind from agricultural/pasture land. Among three other measured air pollutants [fine particulate matter, elemental carbon (a marker of traffic in Fresno), and coarse particulate matter (PMc)], PMc was the only pollutant correlated with endotoxin. Endotoxin, however, was the most spatially variable.ConclusionsOur data support the need to evaluate the spatial/temporal variability of endotoxin concentrations, rather than relying on a few measurements made at one location, in studies of exposure and and respiratory health effects, particularly in children with asthma and other chronic respiratory diseases

Plasma Biomarker Concentrations Associated With Return to Sport Following Sport-Related Concussion in Collegiate Athletes—A Concussion Assessment, Research, and Education (CARE) Consortium Study

Importance: Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective: To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants: This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association–Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial–Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures: A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results: The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury, <14 days RTS vs ≥14 days RTS: −0.65 [0.12] pg/mL vs −0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs ≥14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance: The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC.This publication was made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded, in part by the NCAA and the Department of Defense. The US Army Medical Research Acquisition Activity, 820 Chandler St, Ft Detrick, MD 21702, is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program under award No. W81XWH-14-2-0151

Reduced Exercise Tolerance and Pulmonary Capillary Recruitment with Remote Secondhand Smoke Exposure

RATIONALE: Flight attendants who worked on commercial aircraft before the smoking ban in flights (pre-ban FAs) were exposed to high levels of secondhand smoke (SHS). We previously showed never-smoking pre-ban FAs to have reduced diffusing capacity (Dco) at rest. METHODS: To determine whether pre-ban FAs increase their Dco and pulmonary blood flow (Qc) during exercise, we administered a symptom-limited supine-posture progressively increasing cycle exercise test to determine the maximum work (watts) and oxygen uptake (VO2) achieved by FAs. After 30 min rest, we then measured Dco and Qc at 20, 40, 60, and 80 percent of maximum observed work. RESULTS: The FAs with abnormal resting Dco achieved a lower level of maximum predicted work and VO2 compared to those with normal resting Dco (mean±SEM; 88.7±2.9 vs. 102.5±3.1%predicted VO2; p = 0.001). Exercise limitation was associated with the FAs' FEV(1) (r = 0.33; p = 0.003). The Dco increased less with exercise in those with abnormal resting Dco (mean±SEM: 1.36±0.16 vs. 1.90±0.16 ml/min/mmHg per 20% increase in predicted watts; p = 0.020), and amongst all FAs, the increase with exercise seemed to be incrementally lower in those with lower resting Dco. Exercise-induced increase in Qc was not different in the two groups. However, the FAs with abnormal resting Dco had less augmentation of their Dco with increase in Qc during exercise (mean±SEM: 0.93±0.06 vs. 1.47±0.09 ml/min/mmHg per L/min; p<0.0001). The Dco during exercise was inversely associated with years of exposure to SHS in those FAs with ≥10 years of pre-ban experience (r = -0.32; p = 0.032). CONCLUSIONS: This cohort of never-smoking FAs with SHS exposure showed exercise limitation based on their resting Dco. Those with lower resting Dco had reduced pulmonary capillary recruitment. Exposure to SHS in the aircraft cabin seemed to be a predictor for lower Dco during exercise

Associations between respiratory illnesses and secondhand smoke exposure in flight attendants: A cross-sectional analysis of the Flight Attendant Medical Research Institute Survey

Abstract Background Secondhand tobacco smoke (SHS) is associated with increased risk of respiratory illness, cancer, and cardiovascular disease. Prior to smoking bans on airlines in the late 1980s, flight attendants were exposed to a significant amount of SHS. In the present study, we examine associations between flight attendant SHS exposure and development of respiratory illnesses and cardiovascular disease. Methods Between December 2006 and October 2010, three hundred sixty-two flight attendants completed an online questionnaire with information regarding experience as a flight attendant, medical history, smoking history, and SHS exposure. Rates of illnesses in flight attendants were compared with an age and smoking history matched population sample from NHANES 2005-2006. Logistic regression analysis was used to examine the association of reported medical conditions and pre-ban years of exposure. Results Compared with the sample from NHANES 2005-2006, flight attendants had increased prevalence of chronic bronchitis (11.7% vs. 7.2%, p &lt; 0.05), emphysema/COPD (3.2% vs. 0.9%, p &lt; 0.03), and sinus problems (31.5% vs. 20.9%, p &lt; 0.002), despite a lower prevalence of medical illnesses including high blood pressure, diabetes, high cholesterol, heart failure, cancer, and thyroid disease. Amongst flight attendants who reported never smoking over their lifetimes, there was not a significant association between years of service as a flight attendant in the pre-smoking ban era and illnesses. However, in this same group, there was a significantly increased risk of daily symptoms (vs. no symptoms) of nasal congestion, throat, or eye irritation per 10-year increase of years of service as a flight attendant prior to the smoking ban (OR 2.14, 95% CI 1.41 - 3.24). Conclusions Flight attendants experience increased rates of respiratory illnesses compared to a population sample. The frequency of symptoms of nasal congestion, throat or eye irritation is associated with occupational SHS exposure in the pre-smoking ban era

Applications of Causal Inference Methodology to Questions of Age-Related Changes in Physical and Cognitive Function in Elderly Populations

Causal inference methodology represents an analytical framework to evaluate and estimate causal effects based on observational data. This framework can be applied to examine and estimate individual contributions of causal factors in epidemiologic studies of aging. These studies are characterized by complex temporal relationships between these different factors, and confounders of these factors and outcomes of interest (i.e. time-dependent confounding). Unbiased estimation of effects under these conditions lies beyond the scope of conventional statistical methods. Causal inference methods allow for examination and unbiased estimation of population-level (i.e., marginal) effects, and can account for time-dependent confounding. Marginal Structural Models (MSMs) can be used to define causal parameters (i.e., marginal effects) of interest. History-adjusted marginal structural models (HAMSMs), a generalization of MSMs, can be used to define and evaluate marginal effects given time-varying covariates. These models were applied to examine the causal associations between different factors of interest and physical and cognitive functioning outcomes. Estimation procedures were applied (e.g., targeted maximum likelihood estimation, inverse-probability of treatment weights) to address time-dependent confounding in the data and provide unbiased estimates of the effects examined in these models, which would not have been possible with standard statistical methods.Study 1Self-reported leisure-time physical activity (LTPA), based on metabolic equivalents, equal to or greater than public-health recommended-levels, and a measure of body composition (lean: fat mass ratio, L/F), estimated from bioelectric impedance using population-specific prediction equations derived from dual x-ray energy absorptiomery, were examined with respect to a measure of physical function that was based on standard self-report questions. In women 55 and older, a one-unit gain in L/F reduced by 65.5 percent (95% CI: 21.8, 87.4) the report of physical limitation at all four surveys of an 8-year study. A similar reduction was not observed in men; however, there was a 3 percent increase in the report of no limitation at any survey. The effect of high levels of LTPA was a reduction in new physical limitation that occurred at the last survey of 36.8 percent (95% CI: 0.0, 0.92) and 52.7 percent (95% CI: 13.5, 91.9) in men and women, respectively. In summary, higher LTPA appeared to reduce the risk of future functional limitation conditional on the level of functioning established by L/F.Study 2 The association of lifetime household secondhand smoke exposure (SHS) and risk of incident dementia was examined in 970 participants in the Cardiovascular Health Cognition Study who were never-smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. Given prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, interactions between SHS and measures of clinical and subclinical CVD on dementia risk were examined as well. Moderate (16-25 years) and high (&gt;25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with &gt;25 years of SHS exposure and &gt;25% carotid artery stenosis had a three-fold increase (Hazard Ratio, 3.00; 95% Confidence Interval: 1.03, 9.72) in hazard of dementia, compared to subjects with no/low (0-15 years) SHS exposure and ≤ 25% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.Study3Leisure-time physical activity (LTPA), based on metabolic equivalents, was examined with respect to walking speed (WS) that was based on standard protocol. A measure of body composition (Lean:fat mass ratio, L/F) (see Study 1), was included as a surrogate of metabolic function (e.g., glucose tolerance) and as a causal intermediate of LTPA and WS. In sex-specific analyses, the direct effects of LTPA on WS were estimated from four separate surveys of an 8-year study, and pooled. Stratified analyses examined effect estimates in different subgroups (e.g., diabetics vs. non-diabetics). Mean WS increased (2.394 ft/sec vs. 2.238 ft/sec in women; 2.418 ft/sec vs. 2.278 ft/sec in men) with higher LTPA (i.e., greater or equal vs. less than public health recommended levels) and higher L/F (i.e. &gt; median vs. &lt; median). In women, the direct effect of LTPA was an increase in mean WS for &lt; median L/F (2.316 ft/sec vs. 2.238 ft/sec) and &gt; median L/F (2.394 ft/sec vs. 2.316 ft/sec). Similar results were observed for the men. Results of the stratified analysis did not differ from the overall analysis. These results indicate a marginal level of direct protection of LTPA for WS, but underscore the influence of LTPA on metabolic intermediates that affect lower body-function. The application of MSMs and HAMSMs in these different studies illustrate their use to examine causal factors associated with cognitive and physical decline. Moreover, estimation procedures were employed to provide accurate estimates of effects based on these models of physical activity and other factors associated with function in the elderly

Associations between respiratory illnesses and secondhand smoke exposure in flight attendants: A cross-sectional analysis of the Flight Attendant Medical Research Institute Survey

Abstract Background Secondhand tobacco smoke (SHS) is associated with increased risk of respiratory illness, cancer, and cardiovascular disease. Prior to smoking bans on airlines in the late 1980s, flight attendants were exposed to a significant amount of SHS. In the present study, we examine associations between flight attendant SHS exposure and development of respiratory illnesses and cardiovascular disease. Methods Between December 2006 and October 2010, three hundred sixty-two flight attendants completed an online questionnaire with information regarding experience as a flight attendant, medical history, smoking history, and SHS exposure. Rates of illnesses in flight attendants were compared with an age and smoking history matched population sample from NHANES 2005-2006. Logistic regression analysis was used to examine the association of reported medical conditions and pre-ban years of exposure. Results Compared with the sample from NHANES 2005-2006, flight attendants had increased prevalence of chronic bronchitis (11.7% vs. 7.2%, p Conclusions Flight attendants experience increased rates of respiratory illnesses compared to a population sample. The frequency of symptoms of nasal congestion, throat or eye irritation is associated with occupational SHS exposure in the pre-smoking ban era.</p