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Modeling multi-level survival data in multi-center epidemiological cohort studies: Applications from the ELAPSE project

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Evangelia Samoli, Sophia Rodopoulou, Ulla A. Hvidtfeldt, Kathrin Wolf, Massimo Stafoggia, Bert Brunekreef, Maciej Strak, Jie Chen, Zorana J. Andersen, Richard Atkinson, Mariska Bauwelinck, Tom Bellander, Jørgen Brandt, Giulia Cesaroni, Francesco Forastiere, Daniela Fecht, John Gulliver, Ole Hertel, Barbara Hoffmann, Kees de Hoogh & 18 more Nicole A.H. Janssen, Matthias Ketzel, Jochem O. Klompmaker, Shuo Liu, Petter Ljungman, Gabriele Nagel, Bente Oftedal, Göran Pershagen, Annette Peters, Ole Raaschou-Nielsen, Matteo Renzi, Doris T. Kristoffersen, Gianluca Severi, Torben Sigsgaard, Danielle Vienneau, Gudrun Weinmayr, Gerard Hoek, Klea Katsouyanni

Original languageEnglish
Article number106371
JournalEnvironment International
PublishedFeb 2021

Bibliographical note

Funding Information: This work was supported by Health Effects Institute (HEI) Research Agreement [grant number #4954-RFA14-3/16-5-3]. Funding Information: “Research described in this article was conducted under contract to the Health Effects Institute (HEI), an organization jointly funded by the United States Environmental Protection Agency (EPA) (Assistance Award No. R-82811201) and certain motor vehicle and engine manufacturers. The contents of this article do not necessarily reflect the views of HEI, or its sponsors, nor do they necessarily reflect the views and policies of the EPA or motor vehicle and engine manufacturers.” Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Background: We evaluated methods for the analysis of multi-level survival data using a pooled dataset of 14 cohorts participating in the ELAPSE project investigating associations between residential exposure to low levels of air pollution (PM2.5 and NO2) and health (natural-cause mortality and cerebrovascular, coronary and lung cancer incidence). Methods: We applied five approaches in a multivariable Cox model to account for the first level of clustering corresponding to cohort specification: (1) not accounting for the cohort or using (2) indicator variables, (3) strata, (4) a frailty term in frailty Cox models, (5) a random intercept under a mixed Cox, for cohort identification. We accounted for the second level of clustering due to common characteristics in the residential area by (1) a random intercept per small area or (2) applying variance correction. We assessed the stratified, frailty and mixed Cox approach through simulations under different scenarios for heterogeneity in the underlying hazards and the air pollution effects. Results: Effect estimates were stable under approaches used to adjust for cohort but substantially differed when no adjustment was applied. Further adjustment for the small area grouping increased the effect estimates’ standard errors. Simulations confirmed identical results between the stratified and frailty models. In ELAPSE we selected a stratified multivariable Cox model to account for between-cohort heterogeneity without adjustment for small area level, due to the small number of subjects and events in the latter. Conclusions: Our study supports the need to account for between-cohort heterogeneity in multi-center collaborations using pooled individual level data.

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