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The parametric g-formula is a causal inference method that appropriately adjusts for time-varying confounding affected by prior exposure. Like all parametric methods, it assumes correct model specification, usually assessed by comparing the observed outcome with the simulated outcome under no intervention (natural course). However, it is unclear how to evaluate natural course performance and whether other variables should also be considered. We reviewed current practices for evaluating model misspecification in applications of parametric g-formula. To illustrate the pitfalls of current practices, we then applied the parametric g-formula to examine cardiovascular disease mortality in relation to occupational exposure in the United Autoworkers-General Motors cohort (UAW-GM), comparing 20 parametric model sets and qualitatively assessing natural course performance for all time-varying variables over follow-up. We found that current practices of evaluating model misspecification are often insufficient, increasing risk of bias and statistical cherry picking. Based on our motivational analyses of the UAW-GM cohort, good natural course performance of the outcome does not guarantee good simulations of other covariates; poor predictions of exposures and covariates may still exist. We recommend reporting natural course performance for all time-varying variables at all time-points. Objective criteria for evaluating model misspecification in parametric g-formula need to be developed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In previous studies, investigators have reported increased risks of specific cancers associated with exposure to metalworking fluids (MWFs). In this report we broadly examine the incidence of 14 types of cancer, with a focus on digestive, respiratory, and hormonal cancers, in the United Auto Workers-General Motors (UAW-GM) cohort, a cohort of workers exposed to MWFs (1973-2015). The cohort included 39,132 workers followed for cancer incidence. Cox models yielded estimates of adjusted hazard ratios, with categorical variables for lagged cumulative exposure to 3 types of MWF (straight, soluble, and synthetic). We fitted penalized splines to examine the shape of the exposure-response relationships. There were 7,809 incident cancer cases of interest. Oil-based straight and soluble MWFs were each modestly associated with all cancers combined. Exposure-response patterns were consistent with prior reports from this cohort, and results for splined exposures generally reflected their categorically modeled counterparts. We found significantly increased incidence of stomach and kidney cancer with higher levels of straight MWF exposure and increased rectal and prostate cancer with increasing water-based synthetic MWF exposure. Only non-Hodgkin lymphoma and prostate cancer were associated with soluble MWF. All results for colon and lung cancers were null. Our results provide updated evidence for associations between MWF exposure and incidence of several types of cancer., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although air pollution is an important risk factor for stroke, few studies have considered the impact of workplace exposure to particulate matter (PM). We examined implications of exposure to PM composed of metalworking fluids (MWFs) for stroke mortality in the United Autoworkers-General Motors cohort. Cox proportional hazards models with age as the timescale were used to estimate the association of cumulative straight, soluble, and synthetic MWF exposure with stroke mortality, controlling for sex, race, plant, calendar year, and hire year. Among 38,553 autoworkers followed during 1941-1995, we identified 114 ischemic stroke deaths and 113 hemorrhagic stroke deaths. Overall stroke mortality risk was increased among workers in the middle exposure category for straight MWF (hazard ratio (HR) = 1.31, 95% confidence interval (CI): 0.87, 1.98) and workers in the highest exposure category for synthetic MWF (HR = 1.94, 95% CI: 1.13, 3.16) compared with workers who had no direct exposure. Ischemic stroke mortality risk was increased among workers in the highest exposure categories for straight MWF (HR = 1.45, 95% CI: 0.83, 2.52) and synthetic MWF (HR = 2.39, 95% CI: 1.39, 4.50). We observed no clear relationship between MWF exposure and hemorrhagic stroke mortality. Our results support a potentially important role for occupational PM exposures in stroke mortality and indicate the need for further studies of PM exposure and stroke in varied occupational settings., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diesel exhaust is a suggested risk factor for ischemic heart disease (IHD), but evidence from cohorts using quantitative exposure metrics is limited. We examined the impact of respirable elemental carbon (REC), a key surrogate for diesel exhaust, and respirable dust (RD) on IHD mortality, using data from the Diesel Exhaust in Miners Study in the United States. Using data from a cohort of male workers followed from 1948-1968 until 1997, we fitted Cox proportional hazards models to estimate hazard ratios for IHD mortality for cumulative and average intensity of exposure to REC and RD. Segmented linear regression models allowed for nonmonotonicity. Hazard ratios for cumulative and average REC exposure declined relative to the lowest exposure category before increasing to 0.79 and 1.25, respectively, in the highest category. Relative to the category containing the segmented regression change points, hazard ratios for the highest category were 1.69 and 1.54 for cumulative and average REC exposure, respectively. Hazard ratios for RD exposure increased across the full exposure range to 1.33 and 2.69 for cumulative and average RD exposure, respectively. Tests for trend were statistically significant for cumulative REC exposure (above the change point) and for average RD exposure. Our findings suggest excess risk of IHD mortality in relation to increased exposure to REC and RD.

Exposure to silica has been linked to excess risk of lung cancer and nonmalignant respiratory disease mortality. In this study we estimated risk for both these outcomes in relation to occupational silica exposure as well as the reduction in risk that would result from hypothetical interventions on exposure in a cohort of exposed workers. Analyses were carried out using data from an all-male study population consisting of 2,342 California diatomaceous earth workers regularly exposed to crystalline silica and followed between 1942 and 2011. We estimated subdistribution risk for each event under the natural course and interventions of interest using the parametric g-formula to adjust for healthy-worker survivor bias. The risk ratio for lung cancer mortality, comparing an intervention in which a theoretical maximum exposure limit was set at 0.05 mg/m3 (the current US regulatory limit) with the observed exposure concentrations, was 0.86 (95% confidence interval: 0.63, 1.22). The corresponding risk ratio for nonmalignant respiratory disease mortality was 0.69 (95% confidence interval: 0.52, 0.93). Our findings suggest that risks from both outcomes would have been considerably lower if historical silica exposures in this cohort had not exceeded current regulatory limits.

Prolonged exposures can have complex relationships with health outcomes, as timing, duration, and intensity of exposure are all potentially relevant. Summary measures such as cumulative exposure or average intensity of exposure may not fully capture these relationships. We applied penalized and unpenalized distributed-lag nonlinear models (DLNMs) with flexible exposure-response and lag-response functions in order to examine the association between crystalline silica exposure and mortality from lung cancer and nonmalignant respiratory disease in a cohort study of 2,342 California diatomaceous earth workers followed during 1942-2011. We also assessed associations using simple measures of cumulative exposure assuming linear exposure-response and constant lag-response. Measures of association from DLNMs were generally higher than those from simpler models. Rate ratios from penalized DLNMs corresponding to average daily exposures of 0.4 mg/m3 during lag years 31-50 prior to the age of observed cases were 1.47 (95% confidence interval (CI): 0.92, 2.35) for lung cancer mortality and 1.80 (95% CI: 1.14, 2.85) for nonmalignant respiratory disease mortality. Rate ratios from the simpler models for the same exposure scenario were 1.15 (95% CI: 0.89, 1.48) and 1.23 (95% CI: 1.03, 1.46), respectively. Longitudinal cohort studies of prolonged exposures and chronic health outcomes should explore methods allowing for flexibility and nonlinearities in the exposure-lag-response.

Little is known about the heart disease risks associated with occupational, rather than traffic-related, exposure to particulate matter with aerodynamic diameter of 2.5 µm or less (PM2.5). We examined long-term exposure to PM2.5 in cohorts of aluminum smelters and fabrication workers in the United States who were followed for incident ischemic heart disease from 1998 to 2012, and we addressed 2 forms of survivor bias. Left truncation bias was addressed by restricting analyses to the subcohort hired after the start of follow up. Healthy worker survivor bias, which is characterized by time-varying confounding that is affected by prior exposure, was documented only in the smelters and required the use of marginal structural Cox models. When comparing always-exposed participants above the 10th percentile of annual exposure with those below, the hazard ratios were 1.67 (95% confidence interval (CI): 1.11, 2.52) and 3.95 (95% CI: 0.87, 18.00) in the full and restricted subcohorts of smelter workers, respectively. In the fabrication stratum, hazard ratios based on conditional Cox models were 0.98 (95% CI: 0.94, 1.02) and 1.17 (95% CI: 1.00, 1.37) per 1 mg/m(3)-year in the full and restricted subcohorts, respectively. Long-term exposure to occupational PM2.5 was associated with a higher risk of ischemic heart disease among aluminum manufacturing workers, particularly in smelters, after adjustment for survivor bias., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)