Assessing the Use of GEE Methods for Analyzing Continuous Outcomes from Family Studies: Strong Heart Family Study

Background: Because of its convenience and robustness, the generalized estimating equations (GEE) method has been commonly used to fit marginal models of continuous outcomes in family studies. However, unbalanced family sizes and complex pedigree structures within each family may challenge the GEE method, which treats families as clusters with the same correlation structure. The appropriateness of using the GEE method to analyze continuous outcomes in family studies remains unclear. In this paper, we performed simulation studies to evaluate the performance of GEE in the analysis of family study data. Methods: In simulation studies, we generated data from a linear mixed effects model with individual random effects. The random effects covariance matrix is specified as twice that of the pedigree matrix from the Strong Heart Family Study (SHFS) and other hypothetical pedigree structures. A Bayesian approach that utilizes the pedigree matrix was also conducted as a benchmark to compare with GEE methods with either independent or exchangeable correlation structures. Finally, analysis with a real data example was included. Results: Our simulation results showed that GEE with independent correlation structure worked well for family data with continuous outcomes. Real data analysis revealed that all GEE and Bayesian approaches produced similar results. Conclusion: GEE model performs well on continuous outcome in family studies, and it yields estimated coefficients similar to a Bayesian model, which takes genetic relationship into account. Overall, GEE is robust to misspecification of genetic relationships among family members.