Generalized estimating equations and regression diagnostics for longitudinal controlled clinical trials: A case study

Maren Vens, Andreas Ziegler*

*Corresponding author for this work
20 Citations (Scopus)


Generalized estimating equations (GEE) were proposed for the analysis of correlated data. They are popular because regression parameters can be consistently estimated even if only the mean structure is correctly specified. GEE have been extended in several ways, including regression diagnostics for outlier detection. However, GEE have rarely been used for analyzing controlled clinical trials. The SB-LOT trial, a double-blind placebo-controlled randomized multicenter trial in which the oedema-protective effect of a vasoactive drug was investigated in patients suffering from chronic insufficiency was re-analyzed using the GEE approach. It is demonstrated that the autoregressive working correlation structure is the most plausible working correlation structure in this study. The effect of the vasoactive drug is a difference in lower leg volume of 2.64 ml per week (p=0.0288, 95% confidence interval 0.274.99 ml per week), making a difference of 30 ml at the end of the study. Deletion diagnostics are used for identification of outliers and influential probands. After exclusion of the most influential patients from the analysis, the overall conclusion of the study is not altered. At the same time, the goodness of fit as assessed by half-normal plots increases substantially. In summary, the use of GEE in a longitudinal clinical trial is an alternative to the standard analysis which usually involves only the last follow-up. Both the GEE and the regression diagnostic techniques should accompany the GEE analysis to serve as sensitivity analysis.

Original languageEnglish
JournalComputational Statistics and Data Analysis
Issue number5
Pages (from-to)1232-1242
Number of pages11
Publication statusPublished - 01.05.2012


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