BACKGROUND: Increased lung cancer risks for low socioeconomic status (SES) groups are only partially attributable to smoking habits. Little effort has been made to investigate the persistent risks related to low SES by quantification of potential biases. METHODS: Based on 12 case-control studies, including 18 centers of the international SYNERGY project (16,550 cases, 20,147 controls), we estimated controlled direct effects (CDE) of SES on lung cancer via multiple logistic regression, adjusted for age, study center, and smoking habits and stratified by sex. We conducted mediation analysis by inverse odds ratio weighting to estimate natural direct effects and natural indirect effects via smoking habits. We considered misclassification of smoking status, selection bias, and unmeasured mediator-outcome confounding by genetic risk, both separately and by multiple quantitative bias analyses, using bootstrap to create 95% simulation intervals (SI). RESULTS: Mediation analysis of lung cancer risks for SES estimated mean proportions of 43% in men and 33% in women attributable to smoking. Bias analyses decreased the direct effects of SES on lung cancer, with selection bias showing the strongest reduction in lung cancer risk in the multiple bias analysis. Lung cancer risks remained increased for lower SES groups, with higher risks in men (fourth vs. first [highest] SES quartile: CDE, 1.50 [SI, 1.32, 1.69]) than women (CDE: 1.20 [SI: 1.01, 1.45]). Natural direct effects were similar to CDE, particularly in men. CONCLUSIONS: Bias adjustment lowered direct lung cancer risk estimates of lower SES groups. However, risks for low SES remained elevated, likely attributable to occupational hazards or other environmental exposures.

Boston College Chestnut Hill MA

Cancer Epidemiology Unit Department of Medical Sciences University of Turin Turin Italy

Center for Research in Epidemiology and Population Health Team Exposome and Heredity U1018 Inserm University Paris Saclay University Paris Cité Villejuif France

Dalla Lana School of Public Health University of Toronto Toronto Canada

Department of Cancer Epidemiology and Prevention Maria Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Department of Cardiovascular Sciences and Public Health University of Padova Padova Italy

Department of Epidemiology and Prevention N N Blokhin National Medical Research Centre of Oncology Moscow Russia

Department of Family Population and Preventive Medicine Renaissance School of Medicine Stony Brook University Stony Brook NY

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Environmental Research Group School of Public Health Imperial College London United Kingdom

Epidemiology and Biostatistics Unit Centre Armand Frappier Santé Biotechnologie Institut national de la recherche scientifique Laval Quebec Canada

Epidemiology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Faculty of Medicine Palacky University Olomouc Czech Republic

From the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance Institute of the Ruhr University Bochum Bochum Germany

Health Research Institute of Asturias University of Oviedo ISPA and CIBERESP Spain

Institute and Clinic for Occupational Social and Environmental Medicine University Hospital LMU Munich; Comprehensive Pneumology Center Munich Munich Germany

Institute for Medical Informatics Biometry and Epidemiology University of Duisburg Essen Essen Germany

Institute for Risk Assessment Sciences Utrecht University Utrecht The Netherlands

Institute of Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Hygiene and Epidemiology 1 Faculty of Medicine Charles University Prague Czech Republic

International Agency for Research on Cancer Lyon France

ISGlobal Barcelona Spain

Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany

Masaryk Memorial Cancer Institute Brno Czech Republic

National Cancer Institute Bethesda MD

National Institute of Public Health Bucharest Romania

National Public Health Center Budapest Hungary

National Research Council Palermo Italy

Occupational Cancer Research Centre Ontario Health Toronto Canada

Regional Authority of Public Health Banska Bystrica Slovakia

Roy Castle Lung Cancer Research Programme Department of Molecular and Clinical Cancer Medicine The University of Liverpool Liverpool United Kingdom

Stony Brook Cancer Center Stony Brook University Stony Brook NY

The Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

The Nofer Institute of Occupational Medicine Lodz Poland

Université Rennes Inserm EHESP Irset UMR_S 1085 Pointe à Pitre France

University of Montreal Hospital Research Center Montreal Canada

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