Background: Probabilistic bias and Bayesian analyses are important tools for bias correction, particularly when required parameters are nonidentifiable. Negative controls are another tool; they can be used to detect and correct for confounding. Our goals are to present conditions that assure identifiability of certain causal effects and to describe and illustrate a probabilistic bias analysis and related Bayesian analysis that use a negative control exposure. Methods: Using potential-outcome models, we characterized assumptions needed for identification of causal effects using a dichotomous, negative control exposure when residual confounding exists. We defined bias parameters, characterized their relationships with the negative control and with specified causal effects, and described the corresponding probabilistic-bias and Bayesian analyses. We present analytic examples using data on hormone therapy and suicide attempts among transgender people. To address possible confounding by healthcare utilization, we used prior TdaP (tetanus–diphtheria–pertussis) vaccination as a negative control exposure. Results: Hormone therapy was weakly associated with risk (risk ratio (RR) = 0.9). The negative control exposure was associated with risk (RR = 1.7), suggesting confounding. Based on an assumed prior distribution for the bias parameter, the 95% simulation interval for the distribution of confounding-adjusted RR was (0.17, 1.6), with median 0.5; the 95% credibility interval was similar. Conclusion: We used dichotomous negative control exposure to identify causal effects when a confounder was unmeasured under strong assumptions. It may be possible to relax assumptions and the negative control exposure could prove helpful for probabilistic bias analyses and Bayesian analyses.

Background: Prescribed agricultural burning is a common land management practice, but little is known about the health effects from the resulting smoke exposure. Objective: To examine the association between smoke from prescribed burning and cardiorespiratory outcomes in the U.S. state of Kansas. Methods: We analyzed a zip code-level, daily time series of primary cardiorespiratory emergency department (ED) visits for February–May (months when prescribed burning is common in Kansas) in the years 2009–2011 (n=109,220). Given limited monitoring data, we formulated a measure of smoke exposure using non-traditional datasets, including fire radiative power and locational attributes from remote sensing data sources. We then assigned a population-weighted potential smoke impact factor (PSIF) to each zip code, based on fire intensity, smoke transport, and fire proximity. We used Poisson generalized linear models to estimate the association between PSIF on the same day and in the past 3 days and asthma, respiratory including asthma, and cardiovascular ED visits. Results: During the study period, prescribed burning took place on approximately 8 million acres in Kansas. Same-day PSIF was associated with a 7% increase in the rate of asthma ED visits when adjusting for month, year, zip code, meteorology, day of week, holidays, and correlation within zip codes (rate ratio [RR]: 1.07; 95% confidence interval [CI]: 1.01, 1.13). Same-day PSIF was not associated with a combined outcome of respiratory ED visits (RR [95% CI]: 0.99 [0.97, 1.02]), or cardiovascular ED visits (RR [95% CI]: 1.01 [0.98, 1.04]). There was no consistent association between PSIF during the past 3 days and any of the outcomes. Significance: These results suggest an association between smoke exposure and asthma ED visits on the same day. Elucidating these associations will help guide public health programs that address population-level exposure to smoke from prescribed burning. Impact Statement: In this time series study, we examined the health effects of smoke exposure from prescribed agricultural burning in Kansas. Our findings suggest an association between smoke from prescribed burning and emergency department visits for asthma, but not for cardiovascular outcomes.

One potential mechanism by which diet and lifestyle may affect chronic disease risk and subsequent mortality is through chronic systemic inflammation. In this study, we investigated whether the inflammatory potentials of diet and lifestyle, separately and combined, were associated with all-cause, all-CVD and all-cancer mortality risk. We analysed data on 18 484 (of whom 4103 died during follow-up) Black and White men and women aged ≥45 years from the prospective REasons for Geographic and Racial Differences in Stroke study. Using baseline (2003-2007) Block 98 FFQ and lifestyle questionnaire data, we constructed the previously validated inflammation biomarker panel-weighted, 19-component dietary inflammation score (DIS) and 4-component lifestyle inflammation score (LIS) to reflect the overall inflammatory potential of diet and lifestyle. From multivariable Cox proportional hazards models, the hazards ratios (HR) and their 95 % CI for the DIS-all-cause mortality and LIS-all-cause mortality risk associations were 1·32 (95 % CI (1·18, 1·47); P for trend < 0·01) and 1·25 (95 % CI (1·12, 1·38); P for trend < 0·01), respectively, among those in the highest relative to the lowest quintiles. The findings were similar by sex and race and for all-cancer mortality, but weaker for all-CVD mortality. The joint HR for all-cause mortality among those in the highest relative to the lowest quintiles of both the DIS and LIS was 1·91 (95 % CI 1·57, 2·33) (P for interaction < 0·01). Diet and lifestyle, via their contributions to systemic inflammation, separately, but perhaps especially jointly, may be associated with higher mortality risk among men and women.

Background: When comparing mammography-screening participants and nonparticipants, estimates of reduction in breast-cancer mortality may be biased by poor baseline comparability. We used negative controls to detect uncontrolled confounding. Methods: We designed a closed cohort of Danish women invited to a mammographyscreening programme at age 50-52 years in Copenhagen or Funen from 1991 through 2001. We included women with a normal screening result in their first-invitation round. Based on their second-invitation round, women were divided into participants and nonparticipants and followed until death, emigration or 31 December 2014, whichever came first. We estimated hazard ratios (HRs) of death from breast cancer, causes other than breast cancer and external causes. We added dental-care participation as an exposure to test for an independent association with breast-cancer mortality. We adjusted for civil status, parity, age at first birth, educational attainment, income and hormone use. Results: Screening participants had a lower hazard of breast-cancer death [HR 0.47, 95% confidence interval (CI) 0.32, 0.69] compared with non-participants. Participants also had a lower hazard of death from other causes (HR 0.43, 95% CI 0.39, 0.46) and external causes (HR 0.35, 95% CI 0.23, 0.54). Reductions persisted after covariate adjustment. Dental-care participants had a lower hazard of breast-cancer death (HR 0.75, 95% CI 0.56, 1.01), irrespective of screening participation. Conclusions: Negative-control associations indicated residual uncontrolled confounding when comparing breast-cancer mortality among screening participants and nonparticipants.

Background: Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC-rs4588∗A (Thr436Lys) variant encoding the Vitamin D-binding protein-2 (DBP2) isoform, which may affect Vitamin D status and bioavailability. Methods: We analyzed data from 1710 incident CRC cases and 1649 incidence-density-matched controls nested within three prospective cohorts of mostly Caucasians. Study-specific incidence rate ratios (RRs) for associations of prediagnostic, season-standardized 25(OH)D concentrations according to DBP2 isoform with CRC were estimated using multivariable unconditional logistic regression and were pooled using fixed-effects models. All statistical significance tests were two-sided. Results: The odds of having 25(OH)D concentrations less than 50nmol/L (considered insufficient by the Institute of Medicine) were 43% higher for each DBP2-encoding variant (rs4588∗A) inherited (per DBP2 odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.27 to 1.62, Ptrend = 1.2 x 10T8). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (>50nmol/L), relative to deficient (<30nmol/L), were associated with a 53% lower CRC risk among individuals with the DBP2 isoform (RR = 0.47, 95% CI = 0.33 to 0.67), but with a non-statistically significant 12% lower risk among individuals without it (RR = 0.88, 95% CI = 0.61 to 1.27) (Pheterogeneity.01). Conclusions: Our results suggest that the 25(OH)D-CRC association may differ by DBP isoform, and those with a DBP2-encoding genotype linked to Vitamin D insufficiency may particularly benefit from adequate 25(OH)D for CRC prevention.

Background: Chronically higher inflammation, likely contributed to by dietary and lifestyle exposures, may increase risk for colorectal cancer (CRC). To address this, we investigated associations of novel dietary (DIS) and lifestyle (LIS) inflammation scores with incident CRC in the prospective National Institutes of Health-American Association of Retired Persons Diet and Health Study (N=453 465). Methods: The components of our previously developed and externally validated 19-component DIS and 4-component LIS were weighted based on their strengths of associations with a panel of circulating inflammation biomarker concentrations in a diverse subset (N=639) of participants in the REasons for Geographic and Racial Differences in Stroke Study cohort. We calculated the components and applied their weights in the National Institutes of Health-American Association of Retired Persons cohort at baseline, summed the weighted components (higher scores reflect a higher balance of proinflammatory exposures), and investigated associations of the scores with incident CRC using Cox proportional hazards regression. All statistical tests were two-sided. Results: Over a mean 13.5 years of follow-up, 10 336 participants were diagnosed with CRC. Among those in the highest relative to the lowest DIS and LIS quintiles, the multivariable-adjusted hazards ratios (HRs) and their 95% confidence intervals (CIs) were HR = 1.27 (95% CI = 1.19 to 1.35; Ptrend < .001) and 1.38 (95% CI = 1.30 to 1.48; Ptrend < .001), respectively. The associations were stronger among men and for colon cancers. The hazards ratio for those in the highest relative to the lowest joint DIS and LIS quintile was HR = 1.83 (95% CI = 1.68 to 1.99; Pinteraction < .001). Conclusions: Aggregates of proinflammatory dietary and lifestyle exposures may be associated with higher risk for CRC.

Background Exposure to traffic pollution has been linked to numerous adverse health endpoints. Despite this, limited data examining traffic exposures during realistic commutes and acute response exists. Objectives: We conducted the Atlanta Commuters Exposures (ACE-1) Study, an extensive panel-based exposure and health study, to measure chemically-resolved in-vehicle exposures and corresponding changes in acute oxidative stress, lipid peroxidation, pulmonary and systemic inflammation and autonomic response. Methods We recruited 42 adults (21 with and 21 without asthma) to conduct two 2-h scripted highway commutes during morning rush hour in the metropolitan Atlanta area. A suite of in-vehicle particulate components were measured in the subjects’ private vehicles. Biomarker measurements were conducted before, during, and immediately after the commutes and in 3 hourly intervals after commutes. Results At measurement time points within 3 h after the commute, we observed mild to pronounced elevations relative to baseline in exhaled nitric oxide, C-reactive-protein, and exhaled malondialdehyde, indicative of pulmonary and systemic inflammation and oxidative stress initiation, as well as decreases relative to baseline levels in the time-domain heart-rate variability parameters, SDNN and rMSSD, indicative of autonomic dysfunction. We did not observe any detectable changes in lung function measurements (FEV1, FVC), the frequency-domain heart-rate variability parameter or other systemic biomarkers of vascular injury. Water soluble organic carbon was associated with changes in eNO at all post-commute time-points (p < 0.0001). Conclusions Our results point to measureable changes in pulmonary and autonomic biomarkers following a scripted 2-h highway commute.

Background: Children may have differing susceptibility to ambient air pollution concentrations depending on various background characteristics of the children. Methods: Using emergency department (ED) data linked with birth records from Atlanta, Georgia, we identified ED visits for asthma or wheeze among children 2 to 16 years of age from 1 January 2002 through 30 June 2010 (n = 109,758). We stratified by preterm delivery, term low birth weight, maternal race, Medicaid status, maternal education, maternal smoking, delivery method, and history of a bronchiolitis ED visit. Population-weighted daily average concentrations were calculated for 1-hour maximum carbon monoxide and nitrogen dioxide; 8-hour maximum ozone; and 24-hour average particulate matter less than 10 microns in diameter, particulate matter less than 2.5 microns in diameter (PM<inf>2. 5</inf>), and the PM<inf>2. 5</inf> components sulfate, nitrate, ammonium, elemental carbon, and organic carbon, using measurements from stationary monitors. Poisson time-series models were used to estimate rate ratios for associations between 3-day moving average pollutant concentrations and daily ED visit counts and to investigate effect-measure modification by the stratification factors. Results: Associations between pollutant concentrations and asthma exacerbations were larger among children bom preterm and among children bom to African American mothers. Stratification by race and preterm status together suggested that both factors affected susceptibility. The largest estimated effect size (for an interquartile range increase in pollution) was observed for ozone among preterm births to African American mothers: rate ratio = 1.138 (95% confidence interval = 1.077-1.203). In contrast, the rate ratio for the ozone association among full-term births to mothers of other races was 1.025 (0.970-1.083). Conclusions: Results support the hypothesis that children vary in their susceptibility to ambient air pollutants.

Background: Relationships between air quality and health are well-described, but little information is available about the joint associations between particulate air pollution, ambient temperature, and respiratory morbidity. Objectives: We evaluated associations between concentrations of particulate matter ≤ 2.5 μm in diameter (PM2.5) and exacerbation of existing asthma and modification of the associations by ambient air temperature. Methods: Data from 50,356 adult respondents to the Asthma Call-back Survey from 2006–2010 were linked by interview date and county of residence to estimates of daily averages of PM2.5 and maximum air temperature. Associations between 14-day average PM2.5 and the presence of any asthma symptoms during the 14 days leading up to and including the interview date were evaluated using binomial regression. We explored variation by air temperature using similar models, stratified into quintiles of the 14-day average maximum temperature. Results: Among adults with active asthma, 57.1% reported asthma symptoms within the past 14 days, and 14-day average PM2.5 ≥ 7.07 μg/m3 was associated with an estimated 4–5% higher asthma symptom prevalence. In the range of 4.00–7.06 μg/m3 of PM2.5, each 1-μg/m3 increase was associated with a 3.4% [95% confidence interval (CI): 1.1, 5.7] increase in symptom prevalence; across categories of temperature from 1.1 to 80.5°F, each 1-μg/m3 increase was associated with increased symptom prevalence (1.1–44.4°F: 7.9%; 44.5–58.6°F: 6.9%; 58.7–70.1°F: 2.9%; 70.2–80.5°F: 7.3%). Conclusions: These results suggest that each unit increase in PM2.5 may be associated with an increase in the prevalence of asthma symptoms, even at levels as low as 4.00–7.06 μg/m3.

Purpose: Causal effects in epidemiology are almost invariably studied by considering disease incidence even when prevalence data are used to estimate the causal effect. For example, if certain conditions are met, a prevalence odds ratio can provide a valid estimate of an incidence rate ratio. Our purpose and main result are conditions that assure causal effects on prevalence can be estimated in cross-sectional studies, even when the prevalence odds ratio does not estimate incidence. Methods: Using a general causal effect definition in a multivariate counterfactual framework, we define causal contrasts that compare prevalences among survivors from a target population had all been exposed at baseline with that prevalence had all been unexposed. Although prevalence is a measure reflecting a moment in time, we consider the time sequence to study causal effects. Results: Effects defined using a contrast of counterfactual prevalences can be estimated in an experiment and, with conditions provided, in cross-sectional studies. Proper interpretation of the effect includes recognition that the target is the baseline population, defined at the age or time of exposure. Conclusions: Prevalences are widely reported, readily available measures for assessing disabilities and disease burden. Effects on prevalence are estimable in cross-sectional studies but only if appropriate conditions hold.