Risk prediction in multicentre studies when there is confounding by cluster or informative cluster size

Abstract

Background Clustered data arise in research when patients are clustered within larger units. Generalised Estimating Equations (GEE) and Generalised Linear Models (GLMM) can be used to provide marginal and cluster-specific inference and predictions, respectively. Methods Confounding by Cluster (CBC) and Informative cluster size (ICS) are two complications that may arise when modelling clustered data. CBC can arise when the distribution of a predictor variable (termed ‘exposure’), varies between clusters\xa0causing confounding of the exposure-outcome relationship. ICS means that the cluster size conditional on covariates is not independent of the outcome. In both situations, standard GEE and GLMM may provide biased or misleading inference, and modifications have been proposed. However, both CBC and ICS are routinely overlooked in the context of risk prediction, and their impact on the predictive ability of the models has been little explored. We study the effect of CBC and ICS on the predictive ability of risk models for binary outcomes when GEE and GLMM are used. We examine whether two simple approaches to handle CBC and ICS, which involve adjusting for the cluster mean of the exposure and the cluster size, respectively, can improve the accuracy of predictions. Results Both CBC and ICS can be viewed as violations of the assumptions in the standard GLMM; the random effects are correlated with exposure for CBC and cluster size for ICS. Based on these principles, we simulated data subject to CBC/ICS. The simulation studies suggested that the predictive ability of models derived from using standard GLMM and GEE ignoring CBC/ICS was affected. Marginal predictions were found to be mis-calibrated. Adjusting for the cluster-mean of the exposure or the cluster size improved calibration, discrimination and the overall predictive accuracy of marginal predictions, by explaining part of the between cluster variability. The presence of CBC/ICS did not affect the accuracy of conditional predictions. We illustrate these concepts using real data from a multicentre study with potential CBC. Conclusion Ignoring CBC and ICS when developing prediction models for clustered data can affect the accuracy of marginal predictions. Adjusting for the cluster mean of the exposure or the cluster size can improve the predictive accuracy of marginal predictions.