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Biostatistics. 2014 Jan;15(1):117-28. doi: 10.1093/biostatistics/kxt041. Epub 2013 Oct 22.

A general regression framework for a secondary outcome in case-control studies.

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Department of Biostatistics, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.


Modern case-control studies typically involve the collection of data on a large number of outcomes, often at considerable logistical and monetary expense. These data are of potentially great value to subsequent researchers, who, although not necessarily concerned with the disease that defined the case series in the original study, may want to use the available information for a regression analysis involving a secondary outcome. Because cases and controls are selected with unequal probability, regression analysis involving a secondary outcome generally must acknowledge the sampling design. In this paper, the author presents a new framework for the analysis of secondary outcomes in case-control studies. The approach is based on a careful re-parameterization of the conditional model for the secondary outcome given the case-control outcome and regression covariates, in terms of (a) the population regression of interest of the secondary outcome given covariates and (b) the population regression of the case-control outcome on covariates. The error distribution for the secondary outcome given covariates and case-control status is otherwise unrestricted. For a continuous outcome, the approach sometimes reduces to extending model (a) by including a residual of (b) as a covariate. However, the framework is general in the sense that models (a) and (b) can take any functional form, and the methodology allows for an identity, log or logit link function for model (a).


Case–control studies; Generalized linear models; Secondary outcomes; Statistical genetics

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