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Am J Epidemiol. 2008 Jul 15;168(2):212-24. doi: 10.1093/aje/kwn104. Epub 2008 May 28.

On the estimation of additive interaction by use of the four-by-two table and beyond.

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  • 1Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.


A four-by-two table with its four rows representing the presence and absence of gene and environmental factors has been suggested as the fundamental unit in the assessment of gene-environment interaction. For such a table to be more meaningful from a public health perspective, it is important to estimate additive interaction. A confidence interval procedure proposed by Hosmer and Lemeshow has become widespread. This article first reveals that the Hosmer-Lemeshow procedure makes an assumption that confidence intervals for risk ratios are symmetric and then presents an alternative that uses the conventional asymmetric intervals for risk ratios to set confidence limits for measures of additive interaction. For the four-by-two table, the calculation involved requires no statistical programs but only elementary calculations. Simulation results demonstrate that this new approach can perform almost as well as the bootstrap. Corresponding calculations in more complicated situations can be simplified by use of routine output from multiple regression programs. The approach is illustrated with three examples. A Microsoft Excel spreadsheet and SAS codes for the calculations are available from the author and the Journal's website, respectively.

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