Estimating Causal Effects of Occupational Exposures

Estimates of the risk of occupational exposures are typically based on observational workplace studies that are subject to bias due to the healthy worker survivor effect (HWSE), a ubiquitous process that results in the healthiest workers accruing the most exposure. This body of work is concerned with the estimation of causal effects of occupational exposures from observational workplace studies, in the context of the HWSE. We estimate the effect of cumulative exposure to straight, soluble, and synthetic metalworking fluids (MWFs) on the incidence of colon cancer in the United Autoworkers-General Motors (UAW-GM) cohort. We use longitudinal targeted minimum loss-based estimation (TMLE) to compute the 25-year risk difference if always exposed above compared to if always exposed below an exposure cutoff while at work. Exposure cutoffs were selected a priori at the median of exposed person-years among colon cancer cases. Risk differences are 0.038 (95% CI = 0.022 to 0.054), 0.002 (95% CI = -0.016 to 0.019), and 0.008 (95% CI = 0.002 to 0.014) for straight, soluble, and synthetic MWFs, respectively. By control of the time-varying confounding on the casual pathway that characterizes the HWSE, TMLE estimated effects that were undetectable in earlier reports. Most workers in UAW-GM were hired decades before the reporting of incident cancers began. Incident cancers that occurred before the start of reporting were left filtered. We show that if ignored, left filtering can lead to downward bias in exposure effect estimates. Further, we propose a novel delayed-entry adjusted Kaplan-Meier estimator that controls for time-varying confounding, and permits delayed risk-set entry. The estimator results in little bias in simulated datasets when the outcome is sufficiently rare. In addition to dynamic (realistic) interventions that assign exposure according to workers' employment status, causal contrasts can be defined under static (etiologic) interventions that additionally prevent leaving work. Causal effect estimates of the two classes of interventions can differ substantially. While ideally the choice of intervention would be driven by the research question, in practice it may be dictated by the available data. Furthermore, when estimates of the long-term etiologic effects of occupational exposures are not available, guidelines for exposure limits may be based on studies that estimated effects of realistic interventions. In a simulation study we investigate the conditions under which the two effect measures are comparable, and identify factors that drive the differences between the two

The impact of functional limitations on long-term outcomes among African-American and white women with breast cancer: a cohort study

OBJECTIVES: We examined the impact of functional limitations and functional decline during the first year following breast cancer diagnosis on the risk of mortality from breast cancer and other causes among African-American and white women, respectively. DESIGN: The Health and Functioning in Women (HFW) cohort study. SETTING: Detroit, Michigan, USA. PARTICIPANTS: A total of 162 African-American and 813 white women aged 40–84 years with newly diagnosed breast cancer identified through the Metropolitan Detroit Cancer Surveillance System over a 7-month period between 1984 and 1985 and followed for up to 28 years (median 11 years). OUTCOME MEASURES: Risk of mortality from breast cancer and other causes. RESULTS: Statistically significant increases in the risk of other-cause mortality were found for each unit increase in the number of self-reported functional limitations (HR=1.08, 95% CI 1.03 to 1.14), 0 vs ≥1 functional limitations (HR=1.47, 95% CI 1.13 to 1.91), difficulty in pushing or pulling large objects (HR=1.34, 95% CI 1.04 to 1.73), writing or handling small objects (HR=1.56, 95% CI 1.00 to 2.44), and walking half a mile (HR=1.60, 95% CI 1.19 to 2.14). Functional limitations and functional decline did not explain racial disparities in the survival of this cohort. Functional decline was associated with increased risk of other-cause mortality in women with regional and remote disease but not in women with localised disease. Whereas measures of functional limitation were not associated with breast cancer-specific mortality, each unit of functional decline (HR=1.17, 95% CI 1.05 to 1.31) and decline in the ability to sit ≥1 h (HR=2.06, 95% CI 1.13 to 3.76) were associated with increased risk of breast cancer-specific mortality. Measures of functional decline were associated with increased risk of breast cancer mortality in overweight and obese women, but not in women of normal weight. CONCLUSIONS: Whereas functional limitations were associated with increased risk of other-cause mortality, functional decline was associated with increased risk of breast cancer mortality

The impact of functional limitations on long-term outcomes among African-American and white women with breast cancer: a cohort study.

ObjectivesWe examined the impact of functional limitations and functional decline during the first year following breast cancer diagnosis on the risk of mortality from breast cancer and other causes among African-American and white women, respectively.DesignThe Health and Functioning in Women (HFW) cohort study.SettingDetroit, Michigan, USA.ParticipantsA total of 162 African-American and 813 white women aged 40-84 years with newly diagnosed breast cancer identified through the Metropolitan Detroit Cancer Surveillance System over a 7-month period between 1984 and 1985 and followed for up to 28 years (median 11 years).Outcome measuresRisk of mortality from breast cancer and other causes.ResultsStatistically significant increases in the risk of other-cause mortality were found for each unit increase in the number of self-reported functional limitations (HR=1.08, 95% CI 1.03 to 1.14), 0 vs ≥1 functional limitations (HR=1.47, 95% CI 1.13 to 1.91), difficulty in pushing or pulling large objects (HR=1.34, 95% CI 1.04 to 1.73), writing or handling small objects (HR=1.56, 95% CI 1.00 to 2.44), and walking half a mile (HR=1.60, 95% CI 1.19 to 2.14). Functional limitations and functional decline did not explain racial disparities in the survival of this cohort. Functional decline was associated with increased risk of other-cause mortality in women with regional and remote disease but not in women with localised disease. Whereas measures of functional limitation were not associated with breast cancer-specific mortality, each unit of functional decline (HR=1.17, 95% CI 1.05 to 1.31) and decline in the ability to sit ≥1 h (HR=2.06, 95% CI 1.13 to 3.76) were associated with increased risk of breast cancer-specific mortality. Measures of functional decline were associated with increased risk of breast cancer mortality in overweight and obese women, but not in women of normal weight.ConclusionsWhereas functional limitations were associated with increased risk of other-cause mortality, functional decline was associated with increased risk of breast cancer mortality

Smoking and mortality after breast cancer diagnosis: the health and functioning in women study.

We examined the effect of smoking on long-term mortality from breast cancer and other causes among a cohort of women with breast cancer. A total of 975 women diagnosed with breast cancer and aged 40-84 years were followed for a median follow-up of 11 years in the U.S. Health and Functioning in Women (HFW) study. The impact of the individual smoking status and smoking intensity reported in the first few months following breast cancer diagnosis on the risk of mortality from breast cancer and other causes was examined using Cox proportional hazards models. In this study, former smoking was associated with increased risk of other-cause mortality (hazard ratio [HR] = 1.47, 95% confidence interval [CI]: 1.13-1.90), and the risk doubled with increased intensity (HR for <50 pack-years [py]: 1.36, 95% CI: 1.03-1.79; HR for ≥50 py: 2.45, 95% CI: 1.41-4.23). Current smoking (HR = 2.45, 95% CI: 1.81-3.32) and each additional 10 py smoked (HR = 1.16, 95% CI: 1.11-1.22) were associated with statistically significant increases in the risk of other-cause mortality. The effect of current smoking on other-cause mortality decreased with advancing stage and increasing body mass index (BMI). Breast cancer-specific mortality was associated with current smoking of ≥50 py (HR = 2.36, 95% CI: 1.26-4.44), and each additional 10 py smoked (HR = 1.07, 95% CI: 1.01-1. 14). Current smoking, but not former smoking, was associated with increased risk of breast cancer-specific mortality in women with local disease (HR = 2.32, 95% CI: 1.32-4.09), but not in those with regional and distant disease (HR = 1.10, 95% CI: 0.73-1.68). Our findings suggest that current smoking at the time of breast cancer diagnosis may be associated with increased risk of breast-cancer specific and other-cause mortality, whereas former smoking is associated with increased risk of other-cause mortality. Smoking cessation at the time of diagnosis may lead to better prognosis among women with breast cancer

The impact of functional limitations on long-term outcomes among African-American and white women with breast cancer: a cohort study.

ObjectivesWe examined the impact of functional limitations and functional decline during the first year following breast cancer diagnosis on the risk of mortality from breast cancer and other causes among African-American and white women, respectively.DesignThe Health and Functioning in Women (HFW) cohort study.SettingDetroit, Michigan, USA.ParticipantsA total of 162 African-American and 813 white women aged 40-84 years with newly diagnosed breast cancer identified through the Metropolitan Detroit Cancer Surveillance System over a 7-month period between 1984 and 1985 and followed for up to 28 years (median 11 years).Outcome measuresRisk of mortality from breast cancer and other causes.ResultsStatistically significant increases in the risk of other-cause mortality were found for each unit increase in the number of self-reported functional limitations (HR=1.08, 95% CI 1.03 to 1.14), 0 vs ≥1 functional limitations (HR=1.47, 95% CI 1.13 to 1.91), difficulty in pushing or pulling large objects (HR=1.34, 95% CI 1.04 to 1.73), writing or handling small objects (HR=1.56, 95% CI 1.00 to 2.44), and walking half a mile (HR=1.60, 95% CI 1.19 to 2.14). Functional limitations and functional decline did not explain racial disparities in the survival of this cohort. Functional decline was associated with increased risk of other-cause mortality in women with regional and remote disease but not in women with localised disease. Whereas measures of functional limitation were not associated with breast cancer-specific mortality, each unit of functional decline (HR=1.17, 95% CI 1.05 to 1.31) and decline in the ability to sit ≥1 h (HR=2.06, 95% CI 1.13 to 3.76) were associated with increased risk of breast cancer-specific mortality. Measures of functional decline were associated with increased risk of breast cancer mortality in overweight and obese women, but not in women of normal weight.ConclusionsWhereas functional limitations were associated with increased risk of other-cause mortality, functional decline was associated with increased risk of breast cancer mortality

Contrasting Causal Effects of Workplace Interventions

Occupational exposure guidelines are ideally based on estimated effects of static interventions that assign constant exposure over a working lifetime. Static effects are difficult to estimate when follow-up extends beyond employment because their identifiability requires additional assumptions. Effects of dynamic interventions that assign exposure while at work, allowing subjects to leave and become unexposed thereafter, are more easily identifiable but result in different estimates. Given the practical implications of exposure limits, we explored the drivers of the differences between static and dynamic interventions in a simulation study where workers could terminate employment because of an intermediate adverse health event that functions as a time-varying confounder. The two effect estimates became more similar with increasing strength of the health event and outcome relationship and with increasing time between health event and employment termination. Estimates were most dissimilar when the intermediate health event occurred early in employment, providing an effective screening mechanism

The association of early life socioeconomic position on breast cancer incidence and mortality: a systematic review

ObjectivesWe conducted a systematic review of the literature relating early life socioeconomic position (SEP) to breast cancer incidence and mortality from a critical period and life-course trajectory perspective.MethodsPubMed, EMBASE and Web of Science were searched to identify cohort studies that evaluated the impact of early life SEP indicators on the incidence and/or mortality from breast cancer in adulthood.ResultsNine distinct studies evaluated the relationship between early life SEP and breast cancer between 1990 and 2016. Five reports assessed breast cancer incidence and five assessed breast cancer mortality as outcomes; one study assessed both incidence and mortality. While lower early life SEP was associated with reduced breast cancer incidence and increased breast cancer mortality in the US, studies conducted in Europe were unable to establish a consistent association.ConclusionsWe found moderate support for the association between early life SEP and incidence and mortality from breast cancer. The impact of early life SEP on breast cancer incidence and mortality appeared to vary between countries. We urge further investigation of the role of lifelong SEP trajectories in breast cancer outcomes

The Healthy Worker Survivor Effect: Target Parameters and Target Populations

Purpose of reviewWe offer an in-depth discussion of the time-varying confounding and selection bias mechanisms that give rise to the healthy worker survivor effect (HWSE).Recent findingsIn this update of an earlier review, we distinguish between the mechanisms collectively known as the HWSE and the statistical bias that can result. This discussion highlights the importance of identifying both the target parameter and the target population for any research question in occupational epidemiology. Target parameters can correspond to hypothetical workplace interventions; we explore whether these target parameters' true values reflect the etiologic effect of an exposure on an outcome or the potential impact of enforcing an exposure limit in a more realistic setting. If a cohort includes workers hired before the start of follow-up, HWSE mechanisms can limit the transportability of the estimates to other target populations. We summarize recent publications that applied g-methods to control for the HWSE, focusing on their target parameters, target populations, and hypothetical interventions