Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Mar;50(3):189-200.
doi: 10.1080/10408444.2020.1727410. Epub 2020 Mar 12.

Smoking, air pollution, and lung cancer risk in the Nurses' Health Study cohort: time-dependent confounding and effect modification

Affiliations
Review

Smoking, air pollution, and lung cancer risk in the Nurses' Health Study cohort: time-dependent confounding and effect modification

Ellen T Chang et al. Crit Rev Toxicol. 2020 Mar.

Abstract

The proportional hazards (PH) model is commonly used in epidemiology despite the stringent assumption of proportionality of hazards over time. We previously showed, using detailed simulation data, that the impact of a modest risk factor cannot be estimated reliably using the PH model in the presence of confounding by a strong, time-dependent risk factor. Here, we examine the same and related issues using a real dataset. Among 97,303 women in the prospective Nurses' Health Study cohort from 1994 through 2010, we used PH regression to investigate how effect estimates for cigarette smoking are affected by increasingly detailed specification of time-dependent exposure characteristics. We also examined how effect estimates for fine particulate matter (PM2.5), a modest risk factor, are affected by finer control for time-dependent confounding by smoking. The objective of this analysis is not to present a credible estimate of the impact of PM2.5 on lung cancer risk, but to show that estimates based on the PH model are inherently unreliable. The best-fitting model for cigarette smoking and lung cancer included pack-years, duration, time since cessation, and an age-by-pack-years interaction, indicating that the hazard ratio (HR) for pack-years was significantly modified by age. In the fully adjusted best-fitting model for smoking including pack-years, the HR per 10-µg/m3 increase in PM2.5 was 1.06 (95% confidence interval (CI) = 0.90, 1.25); the HR for PM2.5 in the full cohort ranged between 1.02 and 1.10 in models with other smoking adjustments, indicating a residual confounding effect of smoking. The HR for PM2.5 was statistically significant only among former smokers when adjusting for smoking pack-years (HR = 1.35, 95% CI = 1.00, 1.82 in the best-fitting smoking model), but not in models adjusting for smoking duration and average packs (pack-years divided by duration). The association between cumulative smoking and lung cancer is modified by age, and improved model fit is obtained by including multiple time-varying components of smoking history. The association with PM2.5 is residually confounded by smoking and modified by smoking status. These findings underscore limitations of the PH model and emphasize the advantages of directly estimating hazard functions to characterize time-varying exposure and risk. The hazard function, not the relative hazard, is the fundamental measure of risk in a population. As a consequence, the use of time-dependent PH models does not address crucial issues introduced by temporal factors in epidemiological data.

Keywords: Air pollution; Cox proportional hazards regression; confounding; effect modification; epidemiology; lung cancer; particulate matter; smoking.

PubMed Disclaimer

Figures

Figures 1A–C.
Figures 1A–C.
Age-related modification of cumulative pack-years in (A) the full cohort, (B) former smokers, and (C) current smokers, using fully adjusted models. Lines illustrate the hazard ratio per 10 pack-years of smoking, and shading illustrates 95% confidence intervals around the hazard ratio. Red denotes models including PM2.5 and cumulative pack-years only (with age interactions), and blue denotes models including PM2.5, cumulative pack-years (with age interactions), years of smoking, and months since cessation.
Figures 1A–C.
Figures 1A–C.
Age-related modification of cumulative pack-years in (A) the full cohort, (B) former smokers, and (C) current smokers, using fully adjusted models. Lines illustrate the hazard ratio per 10 pack-years of smoking, and shading illustrates 95% confidence intervals around the hazard ratio. Red denotes models including PM2.5 and cumulative pack-years only (with age interactions), and blue denotes models including PM2.5, cumulative pack-years (with age interactions), years of smoking, and months since cessation.
Figures 1A–C.
Figures 1A–C.
Age-related modification of cumulative pack-years in (A) the full cohort, (B) former smokers, and (C) current smokers, using fully adjusted models. Lines illustrate the hazard ratio per 10 pack-years of smoking, and shading illustrates 95% confidence intervals around the hazard ratio. Red denotes models including PM2.5 and cumulative pack-years only (with age interactions), and blue denotes models including PM2.5, cumulative pack-years (with age interactions), years of smoking, and months since cessation.

Similar articles

Cited by

References

    1. Akaike H A new look at the statistical model identification. IEEE Transactions on Automatic Control 1974;19(6):716–723.
    1. Beelen R, Raaschou-Nielsen O, Stafoggia M, et al. Effects of long-term exposure to air pollution on natural-cause mortality: an analysis of 22 European cohorts within the multicentre ESCAPE project. Lancet 2014;383(9919):785–795. - PubMed
    1. Boffetta P, La Vecchia C, Moolgavkar S. Chronic Effects of Air Pollution are Probably Overestimated. Risk Anal 2015;35(5):766–769. - PubMed
    1. Brown CC, Chu KC. Implications of the multistage theory of carcinogenesis applied to occupational arsenic exposure. J Natl Cancer Inst 1983;70(3):455–463. - PubMed
    1. Burns DM, Shanks TG, Choi W, Thun MJ, Heath CW Jr., Garfinkel L, 1997. Chapter 3. The American Cancer Society Cancer Prevention Study I: 12-year followup of 1 million men and women in: Burns DM, Garfinkel L, Samet JM (Eds.), Monograph 8: Changes in Cigarette-Related Disease Risks and Their Implications for Prevention and Control. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, MD, p. 602.

Publication types