Statistical methods for the time-to-event analysis of individual participant data from multiple epidemiological studies

Simon Thompson, Stephen Kaptoge, Ian White, Angela Wood, Philip Perry, John Danesh, Emerging Risk Factors Collaboration The Emerging Risk Factors Collaboration, S. G. Thompson, S. Kaptoge, I. R. White, A. M. Wood, P. L. Perry, J. Danesh, R. W. Tipping, C. E. Ford, L. M. Simpson, G. Walldius, I. Jungner, L. E. Chambless, D. B. PanagiotakosC. Pitsavos, C. Chrysohoou, C. Stefanadis, M. Knuiman, U. Goldbourt, M. Benderly, D. Tanne, P. H. Whincup, S. G. Wannamethee, R. W. Morris, J. Willeit, S. Kiechl, P. Santer, A. Mayr, D. A. Lawlor, J. W G Yarnell, J. Gallacher, E. Casiglia, V. Tikhonoff, P. J. Nietert, S. E. Sutherland, D. L. Bachman, J. E. Keil, M. Cushman, R. P. Tracy, A. Tybjærg-Hansen, B. G. Nordestgaard, M. Benn, R. Frikke- Schmidt, S. Giampaoli, L. Palmieri, S. Panico, D. Vanuzzo, A. Gómez de la Cámara, J. A. Gómez- Gerique, L. Simons, J. McCallum, Y. Friedlander, F. G R Fowkes, A. J. Lee, J. Taylor, J. M. Guralnik, R. Wallace, J. Guralnik, D. G. Blazer, J. M. Guralnik, J. M. Guralnik, K. T. Khaw, H. Brenner, E. Raum, H. Müller, D. Rothenbacher, J. H. Jansson, P. Wennberg, A. Nissinen, C. Donfrancesco, S. Giampaoli, V. Salomaa, K. Harald, P. Jousilahti, E. Vartiainen, M. Woodward, R. B. D'Agostino, R. S. Vasan, M. J. Pencina, E. M. Bladbjerg, T. Jørgensen, L. Møller, J. Jespersen, R. Dankner, A. Chetrit, F. Lubin, A. Rosengren, G. Lappas, C. Björkelund, L. Lissner, C. Bengtsson, P. Cremer, D. Nagel, R. S. Tilvis, T. E. Strandberg, Y. Kiyohara, H. Arima, Y. Doi, T. Ninomiya, B. Rodriguez, J. M. Dekker, G. Nijpels, C. D A Stehouwer, E. Rimm, J. K. Pai, S. Sato, H. Iso, A. Kitamura, H. Noda, U. Goldbourt, V. Salomaa, K. Harald, P. Jousilahti, E. Vartiainen, J. T. Salonen, T. P. Tuomainen, D. J H Deeg, J. L. Poppelaars, T. W. Meade, J. A. Cooper, B. Hedblad, G. Berglund, G. Engstrom, W. M M Verschuren, A. Blokstra, M. Cushman, S. Shea, A. Döring, W. Koenig, C. Meisinger, W. Mraz, W. M M Verschuren, A. Blokstra, H. Bas Bueno-de-Mesquita, A. Rosengren, G. Lappas, L. H. Kuller, G. Grandits, R. Selmer, A. Tverdal, W. Nystad, R. Gillum, M. Mussolino, E. Rimm, S. Hankinson, J. E. Manson, J. K. Pai, T. W. Meade, J. A. Cooper, C. Knottenbelt, J. A. Cooper, K. A. Bauer, S. Sato, A. Kitamura, Y. Naito, H. Iso, I. Holme, R. Selmer, A. Tverdal, W. Nystad, H. Nakagawa, K. Miura, P. Ducimetiere, X. Jouven, C. J. Crespo, M. R. Garcia Palmieri, P. Amouyel, D. Arveiler, A. Evans, J. Ferrieres, H. Schulte, G. Assmann, J. Shepherd, C. J. Packard, N. Sattar, I. Ford, B. Cantin, J. P. Després, G. R. Dagenais, E. Barrett-Connor, D. L. Wingard, R. Bettencourt, V. Gudnason, T. Aspelund, G. Sigurdsson, B. Thorsson, M. Trevisan, J. Witteman, I. Kardys, M. Breteler, A. Hofman, H. Tunstall-Pedoe, R. Tavendale, G. D O Lowe, M. Woodward, Y. Ben-Shlomo, G. Davey-Smith, B. V. Howard, Y. Zhang, J. Umans, A. Onat, T. W. Meade, T. Wilsgaard, E. Ingelsson, L. Lind, V. Giedraitis, L. Lannfelt, J. M. Gaziano, P. Ridker, J. M. Gaziano, P. Ridker, H. Ulmer, G. Diem, H. Concin, A. Tosetto, F. Rodeghiero, S. Wassertheil-Smoller, J. E. Manson, M. Marmot, R. Clarke, R. Collins, E. Brunner, M. Shipley, P. Ridker, J. Buring, J. Shepherd, S. M. Cobbe, I. Ford, M. Robertson, Y. He, A. Marín Ibañez, E. J M Feskens, D. Kromhout, R. Collins, E. Di Angelantonio, S. Erqou, S. Kaptoge, S. Lewington, L. Orfei, L. Pennells, P. L. Perry, K. K. Ray, N. Sarwar, M. Alexander, A. Thompson, S. G. Thompson, M. Walker, S. Watson, F. Wensley, I. R. White, A. M. Wood, J. Danesh

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Background Meta-analysis of individual participant time-to-event data from multiple prospective epidemiological studies enables detailed investigation of exposure-risk relationships, but involves a number of analytical challenges. Methods This article describes statistical approaches adopted in the Emerging Risk Factors Collaboration, in which primary data from more than 1 million participants in more than 100 prospective studies have been collated to enable detailed analyses of various risk markers in relation to incident cardiovascular disease outcomes. Results Analyses have been principally based on Cox proportional hazards regression models stratified by sex, undertaken in each study separately. Estimates of exposure-risk relationships, initially unadjusted and then adjusted for several confounders, have been combined over studies using meta-analysis. Methods for assessing the shape of exposure-risk associations and the proportional hazards assumption have been developed. Estimates of interactions have also been combined using meta-analysis, keeping separate within-and between-study information. Regression dilution bias caused by measurement error and within-person variation in exposures and confounders has been addressed through the analysis of repeat measurements to estimate corrected regression coefficients. These methods are exemplified by analysis of plasma fibrinogen and risk of coronary heart disease, and Stata code is made available. Conclusion Increasing numbers of meta-analyses of individual participant data from observational data are being conducted to enhance the statistical power and detail of epidemiological studies. The statistical methods developed here can be used to address the needs of such analyses.

Original languageEnglish (US)
Pages (from-to)1345-1359
Number of pages15
JournalInternational journal of epidemiology
Issue number5
StatePublished - 2010

Bibliographical note

Funding Information:
Methodological work in the ERFC has been supported by specific grants from the UK Medical Research Council. The ERFC Coordinating Centre is underpinned by a programme grant from the British Heart Foundation and supported by the BUPA Foundation and unrestricted educational grants from GlaxoSmithKline. Various sources have supported recruitment, follow-up and laboratory measurements in the cohorts contributing to the ERFC. Investigators of several of these studies have contributed to a list naming some of these funding sources, which can be found at

Publisher Copyright:
© The Author 2010; all rights reserved.


  • Epidemiological studies
  • Individual participant data
  • Meta-analysis
  • Statistical methods
  • Survival analysis

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