Visualizing External Validity: Graphical Displays to Inform the Extension of Treatment Effects from Trials to Clinical Practice.

BACKGROUND: In the presence of effect measure modification, estimates of treatment effects from randomized controlled trials may not be valid in clinical practice settings. The development and application of quantitative approaches for extending treatment effects from trials to clinical practice settings is an active area of research. METHODS: In this article, we provide researchers with a practical roadmap and four visualizations to assist in variable selection for models to extend treatment effects observed in trials to clinical practice settings and to assess model specification and performance. We apply this roadmap and visualizations to an example extending the effects of adjuvant chemotherapy (5-fluorouracil vs. plus oxaliplatin) for colon cancer from a trial population to a population of individuals treated in community oncology practices in the United States. RESULTS: The first visualization screens for potential effect measure modifiers to include in models extending trial treatment effects to clinical practice populations. The second visualization displays a measure of covariate overlap between the clinical practice populations and the trial population. The third and fourth visualizations highlight considerations for model specification and influential observations. The conceptual roadmap describes how the output from the visualizations helps interrogate the assumptions required to extend treatment effects from trials to target populations. CONCLUSIONS: The roadmap and visualizations can inform practical decisions required for quantitatively extending treatment effects from trials to clinical practice settings.

Use of personal care product mixtures and incident hormone-sensitive cancers in the Sister Study: A U.S.-wide prospective cohort.

BACKGROUND: Personal care products (PCPs), a source of endocrine-disrupting chemical exposure, may be associated with the risk of hormone-sensitive cancers. Few studies have investigated associations for PCP use with the incidence of hormone-sensitive cancers or considered the joint effect of multiple correlated PCPs. We examined associations between frequently used, or "everyday", PCPs and incident cancers of the breast, ovary, and uterus with a fucus on the joint effect of multiple product exposure. METHODS: Sister Study participants (n=49 899) self-reported frequency of use in the year before enrollment (2003-2009) for 41 PCPs. Using five-level frequency categories based on questionnaire options, hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the associations between multiple PCP use and incident breast, ovarian, and uterine cancer using quantile-based g-computation with Cox proportional hazards regression as the underlying model. Multiple PCP use was examined using groupings (beauty, hygiene, and skincare products) determined by both a priori knowledge and Spearman correlation coefficients for co-occurring product use. Associations between individual PCPs and the three cancers were also examined using Cox proportional hazards models coupling with Benjamini-Hochberg procedure for multiple comparisons. RESULTS: Over an average of 11.6 years, 4 226 breast, 277 ovarian, and 403 uterine cancer cases were identified. Positive associations were observed between the hygiene mixture and ovarian cancer (HR=1.35, 95%CI=1.00, 1.83) and the beauty mixture with postmenopausal breast cancer (HR=1.08, 95%CI=1.01, 1.16). Additionally, we observed an inverse association between the skincare mixture and breast cancer (HR=0.91, 95%CI=0.83, 0.99). No significant associations were observed for individual products after corrected for multiple comparison. CONCLUSIONS: Findings from this multi-product, joint-effect approach contribute to the growing body of evidence for associations between PCPs and breast cancer and provides novel information on ovarian and uterine cancer.

Prenatal Exposure to Toxic Metals and Neural Tube Defects: A Systematic Review of the Epidemiologic Evidence.

BACKGROUND: Neural tube defects (NTDs) affect >300,000 pregnancies worldwide annually. Few nongenetic factors, other than folate deficiency, have been identified that may provide intervenable solutions to reduce the burden of NTDs. Prenatal exposure to toxic metals [arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn) and lead (Pb)] may increase the risk of NTDs. Although a growing epidemiologic literature has examined associations, to our knowledge no systematic review has been conducted to date. OBJECTIVE: Through adaptation of the Navigation Guide systematic review methodology, we aimed to answer the question "does exposure to As, Cd, Hg, Mn, or Pb during gestation increase the risk of NTDs?" and to assess challenges to evaluating this question given the current evidence. METHODS: We selected available evidence on prenatal As, Cd, Hg, Mn, or Pb exposure and risk of specific NTDs (e.g., spina bifida, anencephaly) or all NTDs via a comprehensive search across MEDLINE, Embase, Web of Science, and TOXLINE databases and applied inclusion/exclusion criteria. We rated the quality and strength of the evidence for each metal. We applied a customized risk of bias protocol and evaluated the sufficiency of evidence of an effect of each metal on NTDs. RESULTS: We identified 30 studies that met our criteria. Risk of bias for confounding and selection was high in most studies, but low for missing data. We determined that, although the evidence was limited, the literature supported an association between prenatal exposure to Hg or Mn and increased risk of NTDs. For the remaining metals, the evidence was inadequate to establish or rule out an effect. CONCLUSION: The role of gestational As, Cd, or Pb exposure in the etiology of NTDs remains unclear and warrants further investigation in high-quality studies, with a particular focus on controlling confounding, mitigating selection bias, and improving exposure assessment. https://doi.org/10.1289/EHP11872.

Volatile Hydrocarbon Exposures and Incident Coronary Heart Disease Events: Up to Ten Years of Follow-up among Deepwater Horizon Oil Spill Workers.

BACKGROUND: During the 2010 Deepwater Horizon (DWH) disaster, response and cleanup workers were potentially exposed to toxic volatile components of crude oil. However, to our knowledge, no study has examined exposure to individual oil spill-related chemicals in relation to cardiovascular outcomes among oil spill workers. OBJECTIVES: Our aim was to investigate the association of several spill-related chemicals [benzene, toluene, ethylbenzene, xylene, n-hexane (BTEX-H)] and total hydrocarbons (THC) with incident coronary heart disease (CHD) events among workers enrolled in a prospective cohort. METHODS: Cumulative exposures to THC and BTEX-H across the cleanup period were estimated via a job-exposure matrix that linked air measurement data with self-reported DWH spill work histories. We ascertained CHD events following each worker's last day of cleanup work as the first self-reported physician-diagnosed myocardial infarction (MI) or a fatal CHD event. We estimated hazard ratios (HR) and 95% confidence intervals for the associations of exposure quintiles (Q) with risk of CHD. We applied inverse probability weights to account for bias due to confounding and loss to follow-up. We used quantile g-computation to assess the joint effect of the BTEX-H mixture. RESULTS: Among 22,655 workers with no previous MI diagnoses, 509 experienced an incident CHD event through December 2019. Workers in higher quintiles of each exposure agent had increased CHD risks in comparison with the referent group (Q1) of that agent, with the strongest associations observed in Q5 (range of HR=1.14-1.44). However, most associations were nonsignificant, and there was no evidence of exposure-response trends. We observed stronger associations among ever smokers, workers with ≤high school education, and workers with body mass index <30 kg/m2. No apparent positive association was observed for the BTEX-H mixture. CONCLUSIONS: Higher exposures to volatile components of crude oil were associated with modest increases in risk of CHD among oil spill workers, although we did not observe exposure-response trends. https://doi.org/10.1289/EHP11859.

Fine particulate matter and incident coronary heart disease events up to 10 years of follow-up among Deepwater Horizon oil spill workers.

BACKGROUND: During the 2010 Deepwater Horizon (DWH) disaster, in-situ burning and flaring were conducted to remove oil from the water. Workers near combustion sites were potentially exposed to burning-related fine particulate matter (PM2.5). Exposure to PM2.5 has been linked to increased risk of coronary heart disease (CHD), but no study has examined the relationship among oil spill workers. OBJECTIVES: To investigate the association between estimated PM2.5 from burning/flaring of oil/gas and CHD risk among the DWH oil spill workers. METHODS: We included workers who participated in response and cleanup activities on the water during the DWH disaster (N = 9091). PM2.5 exposures were estimated using a job-exposure matrix that linked modelled PM2.5 concentrations to detailed DWH spill work histories provided by participants. We ascertained CHD events as the first self-reported physician-diagnosed CHD or a fatal CHD event that occurred after each worker's last day of burning exposure. We estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for the associations between categories of average or cumulative daily maximum PM2.5 exposure (versus a referent category of water workers not near controlled burning) and subsequent CHD. We assessed exposure-response trends by examining continuous exposure parameters in models. RESULTS: We observed increased CHD hazard among workers with higher levels of average daily maximum exposure (low vs. referent: HR = 1.26, 95% CI: 0.93, 1.70; high vs. referent: HR = 2.11, 95% CI: 1.08, 4.12; per 10 µg/m3 increase: HR = 1.10, 95% CI: 1.02, 1.19). We also observed suggestively elevated HRs among workers with higher cumulative daily maximum exposure (low vs. referent: HR = 1.19, 95% CI: 0.68, 2.08; medium vs. referent: HR = 1.38, 95% CI: 0.88, 2.16; high vs. referent: HR = 1.44, 95% CI: 0.96, 2.14; per 100 µg/m3-d increase: HR = 1.03, 95% CI: 1.00, 1.05). CONCLUSIONS: Among oil spill workers, exposure to PM2.5 from flaring/burning of oil/gas was associated with increased risk of CHD.

Use of Straighteners and Other Hair Products and Incident Uterine Cancer.

BACKGROUND: Hair products may contain hazardous chemicals with endocrine-disrupting and carcinogenic properties. Previous studies have found hair product use to be associated with a higher risk of hormone-sensitive cancers including breast and ovarian cancer; however, to our knowledge, no previous study has investigated the relationship with uterine cancer. METHODS: We examined associations between hair product use and incident uterine cancer among 33 947 Sister Study participants aged 35-74 years who had a uterus at enrollment (2003-2009). In baseline questionnaires, participants in this large, racially and ethnically diverse prospective cohort self-reported their use of hair products in the prior 12 months, including hair dyes; straighteners, relaxers, or pressing products; and permanents or body waves. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations between hair product use and uterine cancer using Cox proportional hazard models. All statistical tests were 2-sided. RESULTS: Over an average of 10.9 years of follow-up, 378 uterine cancer cases were identified. Ever vs never use of straightening products in the previous 12 months was associated with higher incident uterine cancer rates (HR = 1.80, 95% CI = 1.12 to 2.88). The association was stronger when comparing frequent use (>4 times in the past 12 months) vs never use (HR = 2.55, 95% CI = 1.46 to 4.45; Ptrend = .002). Use of other hair products, including dyes and permanents or body waves, was not associated with incident uterine cancer. CONCLUSION: These findings are the first epidemiologic evidence of association between use of straightening products and uterine cancer. More research is warranted to replicate our findings in other settings and to identify specific chemicals driving this observed association.

Comparing Trial and Real-world Adjuvant Oxaliplatin Delivery in Patients With Stage III Colon Cancer Using a Longitudinal Cumulative Dose.

Importance: Delivery of adjuvant chemotherapy can differ substantially between trial and real-world populations. Adherence metrics like relative dose intensity (RDI) cannot capture the timing of modifications and mask differences in the total amount of chemotherapy received. Objective: To compare oxaliplatin delivery between MOSAIC trial participants and patients treated in the US Oncology Network with stage III colon cancer using a longitudinal cumulative dose (LCD). Design, Setting, and Participants: This cohort study used secondary data from the MOSAIC trial, an international randomized clinical trial (concluded in 2004), and electronic health records from US Oncology (2009-2018), a network of community oncology practices in the US. It included participants in MOSAIC with stage III colon cancer who were randomized to receive treatment with oxaliplatin and fluorouracil/leucovorin (n = 663) and US Oncology patients with stage III colon cancer who were treated with a modified FOLFOX-6 regimen (n = 2523). Exposures: Oxaliplatin and fluorouracil/leucovorin. Outcomes and Measures: We evaluated RDI and LCD over time and at the end of treatment in the MOSAIC and US Oncology populations. We used bootstrapping to estimate 95% confidence bands for LCD differences between the populations. Results: The 663 MOSAIC participants (296 women [44.7%]) and 2523 US Oncology patients (1245 women [49.4%]) were generally similar with respect to demographic characteristics. Median RDI was lower in US Oncology (80% in MOSAIC vs 70% in US Oncology). The LCD also suggested differences in the total amount of oxaliplatin received between populations; the final median LCD in US Oncology was 10.2% lower than in MOSAIC, equivalent to receiving 1.2 fewer treatment cycles less of oxaliplatin. This difference only began 133 days into treatment and persisted after accounting for covariates, likely in terms of more frequent oxaliplatin treatment discontinuation in US Oncology patients than their MOSAIC counterparts. Conclusions and Relevance: The study results suggest that real-world patients in community practice in the US treated with modified FOLFOX 6 received less oxaliplatin than their historical counterparts in the MOSAIC trial, with differences manifesting late in the treatment course. The LCD allowed us to identify the amount and extent of these differences, the timing of which was unclear when using RDI alone. Trial Registration: ClinicalTrials.gov identifier: NCT00275210.

Light at night and the risk of breast cancer: Findings from the Sister study.

BACKGROUND: Light at night (LAN) may alter estrogen regulation through circadian disruption. High levels of outdoor LAN may increase breast cancer risk, but studies have largely not considered possible residual confounding from correlated environmental exposures. We evaluated the association between indoor and outdoor LAN and incident breast cancer. METHODS: In 47,145 participants in the prospective Sister Study cohort living in the contiguous U.S., exposure to outdoor LAN was determined using satellite-measured residential data and indoor LAN was self-reported (light/TV on, light from outside the room, nightlight, no light). We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between outdoor and indoor LAN and breast cancer risk. Models were adjusted for age, race/ethnicity, educational attainment, annual household income, neighborhood disadvantage, latitude, and population density as a proxy for urbanicity. To evaluate the potential for residual confounding of the outdoor LAN and breast cancer relationship by factors associated with urbanicity, we considered further adjustment for exposures correlated with outdoor LAN including NO2 [Spearman correlation coefficient, rho (ρ) = 0.78], PM2.5 (ρ = 0.36), green space (ρ =  - 0.41), and noise (ρ = 0.81). RESULTS: During 11 years of follow-up, 3,734 breast cancer cases were identified. Outdoor LAN was modestly, but non-monotonically, associated with a higher risk of breast cancer (Quintile 4 vs 1: HR = 1.10, 95% CI: 0.99-1.22; Quintile 5 vs 1: HR = 1.04, 95% CI: 0.93-1.16); however, no association was evident after adjustment for correlated ambient exposures (Quintile 4 vs 1: HR = 0.99, 95% CI: 0.86-1.14; Quintile 5 vs 1: HR = 0.89, 95% CI: 0.74-1.06). Compared to those with no indoor LAN exposure, sleeping with a light or TV on was associated with a HR = 1.09 (95% CI: 0.97-1.23) in the adjusted model. CONCLUSIONS: Outdoor LAN does not appear to increase the risk of breast cancer after adjustment for correlated environmental exposures.

Associations between airborne crude oil chemicals and symptom-based asthma.

RATIONALE: The 2010 Deepwater Horizon (DWH) oil spill response and cleanup (OSRC) workers were exposed to airborne total hydrocarbons (THC), benzene, toluene, ethylbenzene, o-, m-, and p-xylenes and n-hexane (BTEX-H) from crude oil and PM2.5 from burning/flaring oil and natural gas. Little is known about asthma risk among oil spill cleanup workers. OBJECTIVES: We assessed the relationship between asthma and several oil spill-related exposures including job classes, THC, individual BTEX-H chemicals, the BTEX-H mixture, and PM2.5 using data from the Gulf Long-Term Follow-up (GuLF) Study, a prospective cohort of 24,937 cleanup workers and 7,671 nonworkers following the DWH disaster. METHODS: Our analysis largely focused on the 19,018 workers without asthma before the spill who had complete exposure, outcome, and covariate information. We defined incident asthma 1-3 years following exposure using both self-reported wheeze and self-reported physician diagnosis of asthma. THC and BTEX-H were assigned to participants based on measurement data and work histories, while PM2.5 used modeled estimates. We used modified Poisson regression to estimate risk ratios (RR) and 95% confidence intervals (CIs) for associations between spill-related exposures and asthma and a quantile-based g-computation approach to explore the joint effect of the BTEX-H mixture on asthma risk. RESULTS: OSRC workers had greater asthma risk than nonworkers (RR: 1.60, 95% CI: 1.38, 1.85). Higher estimated THC exposure levels were associated with increased risk in an exposure-dependent manner (linear trend test p < 0.0001). Asthma risk also increased with increasing exposure to individual BTEX-H chemicals and the chemical mixture: A simultaneous quartile increase in the BTEX-H mixture was associated with an increased asthma risk of 1.45 (95% CI: 1.35,1.55). With fewer cases, associations were less apparent for physician-diagnosed asthma alone. CONCLUSIONS: THC and BTEX-H were associated with increased asthma risk defined using wheeze symptoms as well as a physician diagnosis.

Real and Illusory Precision Gains in Meta-Analysis to Speed Action on Carcinogens.

One should avoid benzene exposure, all other things being equal. Risk assessment can help inform human health outcomes when all other things are not equal, as when competing legal or economic interests arise. In sparse literatures where exposures may be highly deleterious and yet understudied, there is a dire need for evidence synthesis, such as meta-analysis, to maximally inform risk assessment. Here, using the analysis and approach of Scholten and colleagues from the current issue as a touch point, I describe how meta-analysis could ideally meet this aim and how it often fails to do so. Some of the current literature on transportability of causal effects is illustrative, and I describe how some of the lessons from this literature could be applied within the innovative framework of Scholten and colleagues to leverage meta-analysis within the broader decision-making framework of risk-assessment. See related article by Scholten et al., p. 751.

Comparison of Approaches for Measuring Adherence and Persistence to Oral Oncologic Therapies in Patients Diagnosed with Metastatic Renal Cell Carcinoma.

BACKGROUND: Adherence and persistence studies face several methodologic difficulties, including short-term mortality. We compared approaches to quantify adherence and persistence to first line (1L) oral targeted therapy (TT) in patients diagnosed with metastatic renal cell carcinoma (mRCC). METHODS: Patients with mRCC ages 66 years or more who initiated TTs within 4 months of diagnosis were identified in the Surveillance, Epidemiology, and End Results Medicare-linked database (2007-2015). Adherence [proportion of days covered (PDC) >80%] was calculated using (i) PDC with a fixed 6-month denominator including then excluding patients who died within the 6 months and (ii) PDC with a denominator measuring time on treatment. Risk of nonpersistence was obtained by censoring death or treating death as a competing risk using cumulative incidence functions. RESULTS: Among 485 patients with mRCC initiating a 1L oral TT (sunitinib, 64%; pazopanib, 25%; other, 11%), 40% died within 6 months. Adherence was higher after restricting to patients who survived (60%) compared with including those patients and assigning zero days covered after death (47%). Risk of nonpersistence was higher when censoring patients at death, 0.91 [95% confidence interval (CI), 0.88-0.94], compared with treating death as a competing risk, 0.75 (95% CI, 0.71-0.79). CONCLUSIONS: Different approaches to handling death resulted in different adherence and persistence estimates in the metastatic setting. Future studies should explicitly report the proportion of patient deaths over time and explore appropriate methods to account for death as competing risk. IMPACT: Use of several approaches can provide a more comprehensive picture of medication-taking behavior in the metastatic setting where death is a major competing risk.

Vitamin D Supplement Use and Risk of Breast Cancer by Race-Ethnicity.

BACKGROUND: Vitamin D has anticarcinogenic properties, but a relationship between vitamin D supplement use and breast cancer is not established. Few studies have accounted for changes in supplement use over time or evaluated racial-ethnic differences. METHODS: The Sister Study is a prospective cohort of 50,884 women with 35-74 years of age who had a sister with breast cancer, but no breast cancer themselves at enrollment (2003-2009). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D supplement use and incident breast cancer (3,502 cases; median follow-up 10.5 years). RESULTS: Vitamin D supplement use was common, with 64% reporting ever use (at least once per month) in the year before enrollment. Considering supplement use over time, ever use of vitamin D supplements was not meaningfully associated with breast cancer (HR = 0.96, 95% CI = 0.88, 1.0), relative to never use. However, after adjusting for prior use, recent use of vitamin D supplements ≥1/month was inversely associated with breast cancer (HR = 0.88, 95% CI = 0.78, 1.0), relative to nonrecent use. The inverse association was stronger for ductal carcinoma in situ (HR = 0.67, 95% CI = 0.52, 0.87) than invasive breast cancer (HR = 0.94, 95% CI = 0.72, 1.1, p-for-heterogeneity = 0.02). Supplement use was less common among African American/Black (56%) and non-Black Hispanic/Latina (50%) women than non-Hispanic White women (66%), but there was limited evidence of racial-ethnic differences in HRs (p-for-heterogeneity = 0.16 for ever use, P = 0.55 for recent). CONCLUSIONS: Our findings are consistent with the hypothesis that recent vitamin D use is inversely associated with breast cancer risk.

Life expectancy in older adults with advanced cancer: Evaluation of a geriatric assessment-based prognostic model.

OBJECTIVES: Oncologists estimate patients' prognosis to guide care. Evidence suggests oncologists tend to overestimate life expectancy, which can lead to care with questionable benefits. Information obtained from geriatric assessment may improve prognostication for older adults. In this study, we created a geriatric assessment-based prognostic model for older adults with advanced cancer and compared its performance to alternative models. MATERIALS AND METHODS: We conducted a secondary analysis of a trial (URCC 13070; PI: Mohile) capturing geriatric assessment and vital status up to one year for adults age ≥ 70 years with advanced cancer. Oncologists estimated life expectancy as 0-6 months, 7-12 months, and > 1 year. Three statistical models were developed: (1) a model including age, sex, cancer type, and stage (basic model), (2) basic model + Karnofsky Performance Status (≤50, 60-70, and 80+) (KPS model), and (3) basic model +16 binary indicators of geriatric assessment impairments (GA model). Cox regression was used to model one-year survival; c-indices and time-dependent c-statistics assessed model discrimination and stratified survival curves assessed model calibration. RESULTS: We included 484 participants; mean age was 75; 48% had gastrointestinal or lung cancer. Overall, 43% of patients died within one year. Oncologists classified prognosis accurately for 55% of patients, overestimated for 35%, and underestimated for 10%. C-indices were 0.61 (basic model), 0.62 (KPS model), and 0.63 (GA model). The GA model was well-calibrated. CONCLUSIONS: The GA model showed moderate discrimination for survival, similar to alternative models, but calibration was improved. Further research is needed to optimize geriatric assessment-based prognostic models for use in older adults with advanced cancer.

Metals and Breast Cancer Risk: A Prospective Study Using Toenail Biomarkers.

The role of metals in breast cancer is of interest because of their carcinogenic and endocrine-disrupting capabilities. Evidence from epidemiologic studies remains elusive, and prior studies have not investigated metal mixtures. In a case cohort nested within the Sister Study (enrolled in 2003-2009; followed through September 2017), we measured concentrations of 15 metals in toenails collected at enrollment in a race/ethnicity-stratified sample of 1,495 cases and a subcohort of 1,605 women. We estimated hazard ratios and 95% confidence intervals for each metal using Cox regression and robust variance. We used quantile g-computation to estimate the joint association between multiple metals and breast cancer risk. The average duration of follow-up was 7.5 years. There was little evidence supporting an association between individual metals and breast cancer. An exception was molybdenum, which was associated with reduced incidence of overall breast cancer risk (third tertile vs. first tertile: hazard ratio = 0.82, 95% confidence interval: 0.67, 1.00). An inverse association for antimony was observed among non-Hispanic Black women. Predefined groups of metals (all metals, nonessential metals, essential metals, and metalloestrogens) were not strongly associated with breast cancer. This study offers little support for metals, individually or as mixtures, as risk factors for breast cancer. Mechanisms for inverse associations with some metals warrant further study.

Lung Cancer Mortality and Styrene Exposure in the Reinforced-Plastics Boatbuilding Industry: Evaluation of Healthy Worker Survivor Bias.

The evidence for styrene's being a human lung carcinogen has been inconclusive. Occupational cohorts within the reinforced-plastics industry are an ideal population in which to study this association because of their relatively high levels of exposure to styrene and lack of concomitant exposures to other known carcinogens. However, healthy worker survivor bias (HWSB), where healthier workers stay employed longer and thus have higher exposure potential, is a likely source of confounding bias for exposure-response associations, in part due to styrene's acute effects. Through December 31, 2016, we studied a cohort of 5,163 boatbuilders exposed to styrene in Washington State who were employed between 1959 and 1978; prior regression analyses had demonstrated little evidence for an exposure-response relationship between styrene exposure and lung cancer mortality. Based on estimates of necessary components of HWSB, we found evidence for a potentially large HWSB. Using g-estimation of a structural nested model to account for HWSB, we estimated that 1 year of styrene exposure at more than 30 parts per million accelerated time to lung cancer death by 2.29 years (95% confidence interval: 1.53, 2.94). Our results suggest possibly strong HWSB in our small cohort and indicate that large, influential studies of styrene-exposed workers may suffer from similar biases, warranting a reassessment of the evidence of long-term health effects of styrene exposure.

Introducing longitudinal cumulative dose to describe chemotherapy patterns over time: Case study of a colon cancer trial.

Adjuvant chemotherapy regimens take months to complete. Despite this, studies evaluate chemotherapy adherence via measures assessed at the end of treatment (eg, number of patients missing any dose, relative dose intensity [RDI]). This approach ignores information like the timing of treatment delays. We propose longitudinal cumulative dose (LCD) to integrate impacts of dose reductions, missed doses and dose delays over time. We obtained data from the 2246 participants in the MOSAIC trial randomized to FOLFOX (all three agents) or 5-FU/LV (only 5-fluorouracil and leucovorin). We evaluated proportions of patients stopping treatment early and reducing, missing or delaying a dose in each arm for each chemotherapy agent at each cycle. We calculated LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each agent and compared it over time and at 24 weeks between treatment arms. Participants randomized to FOLFOX were more likely to stop treatment, reduce doses, miss doses or delay cycles; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. The LCD for 5-fluorouracil differed between arms (FOLFOX arm median: 81%; 5-FU/LV arm median: 96%). Visualizing LCD highlighted the timing of deviations from standard administration in a way RDI could not, with major differences in 5-fluorouracil LCD across treatment arms beginning after the sixth dose. Further evaluation of LCD and its impacts on clinical outcomes may clarify mechanisms for heterogeneous patient outcomes.

Outdoor air pollution and terminal duct lobular involution of the normal breast.

BACKGROUND: Exposure to certain outdoor air pollutants may be associated with a higher risk of breast cancer, though potential underlying mechanisms are poorly understood. We examined whether outdoor air pollution was associated with involution of terminal duct lobular units (TDLUs), the histologic site where most cancers arise and an intermediate marker of breast cancer risk. METHODS: Pathologist-enumerated TDLUs were assessed in H&E (hematoxylin and eosin)-stained breast tissue sections from 1904 US women ages 18-75 who donated to the Susan G. Komen Tissue Bank (2009-2012). The 2009 annual fine particulate matter < 2.5 µm in diameter (PM2.5) total mass (µg/m3) at each woman's residential address was estimated from the Environmental Protection Agency's Downscaler Model combining Community Multiscale Air Quality (CMAQ) System modeling with air quality monitoring data. We secondarily considered CMAQ-modeled components of PM2.5 and gaseous pollutants. We used K-means clustering to identify groups of individuals with similar levels of PM2.5 components, selecting groups via cluster stability analysis. Relative rates (RRs) and 95% confidence intervals (95% CIs) for the association between air pollutants and TDLU counts were estimated from a zero-inflated negative binomial regression model adjusted for potential confounders. RESULTS: PM2.5 total mass was associated with higher TDLU counts among all women (interquartile range (IQR) increase, RR = 1.06; 95% CI: 1.01-1.11). This association was evident among both premenopausal and postmenopausal women (premenopausal RR = 1.05, 95% CI: 1.00-1.11; postmenopausal RR = 1.11, 95% CI: 1.00-1.23). We identified 3 groups corresponding to clusters that varied geographically and roughly represented high, medium, and low levels of PM2.5 components relative to population mean levels. Compared to the cluster with low levels, the clusters with both high (RR = 1.74; 95% CI: 1.08-2.80) and medium (RR = 1.82; 95% CI: 1.13-2.93) levels were associated with higher TDLU counts; although not significantly different, the magnitude of the associations was stronger among postmenopausal women. CONCLUSIONS: Higher PM2.5 levels were associated with reduced TDLU involution as measured by TDLU counts. Air pollution exposure may influence the histologic characteristics of normal tissue which could in turn affect breast cancer risk.

Toenail metal concentrations and age at menopause: A prospective study.

BACKGROUND: Menopause timing is related to cancer, cardiovascular disease, and mortality. Lead has been associated with an earlier age at menopause, but no study has considered exposure to other metals or multiple metals simultaneously. METHODS: At baseline, we measured toenail concentrations of 16 metals for 903 premenopausal women in the Sister Study (2003-2009). Age at menopause was ascertained through follow-up questionnaires. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between individual metals and age at menopause. We used quantile-g-computation to examine the association between age at menopause and the joint effect of a simultaneous increase in (1) all metals and for subgroups of metals categorized as (2) essential or (3) non-essential. RESULTS: For individual metals, we observed negligible associations except for an interquartile range increase in lead which was modestly associated with an earlier age at menopause (HR = 1.03, 95% CI = 1.01, 1.05). In the mixture analyses, a quartile increase in all metals was associated with a later age at menopause (HR = 0.81, 95% CI = 0.64, 1.02). The metals with the largest negative contributions (i.e., associated with a later age at menopause) were chromium and nickel. The joint effect for the essential metals remained inverse (HR = 0.83, 95% CI = 0.64, 1.07), but was attenuated for nonessential metals (HR = 0.98, 95% CI = 0.76, 1.24). CONCLUSIONS: Although no individual metal was strongly associated with age at menopause, our joint effect analysis suggests that having low levels of essential metals could be associated with an earlier age at menopause.

Meta-analysis of published excess relative risk estimates.

A meta-analytic summary effect estimate often is calculated as an inverse-variance-weighted average of study-specific estimates of association. The variances of published estimates of association often are derived from their associated confidence intervals under assumptions typical of Wald-type statistics, such as normality of the parameter. However, in some research areas, such as radiation epidemiology, epidemiological results typically are obtained by fitting linear relative risk models, and associated likelihood-based confidence intervals are often asymmetric; consequently, reasonable estimates of variances associated with study-specific estimates of association may be difficult to infer from the standard approach based on the assumption of a Wald-type interval. Here, a novel method is described for meta-analysis of published results from linear relative risk models that uses a parametric transformation of published results to improve on the normal approximation used to assess confidence intervals. Using simulations, it is illustrated that the meta-analytic summary obtained using the proposed approach yields less biased summary estimates, with better confidence interval coverage, than the summary obtained using the more classical approach to meta-analysis. The proposed approach is illustrated using a previously published example of meta-analysis of epidemiological findings regarding circulatory disease following exposure to low-level ionizing radiation.