Familial Associations of Lipid Pro les: A Generalised Estimating Equations Approach

Elevated plasma levels of apolipoproteins A1 (apoA1) and B (apoB) are important protective factors and risk factors, respectively, for atheroscle-rosis and coronary heart disease. It is well known that both apoA1 and apoB reveal strong familial aggregation. Our goal was to investigate whether exogenous variables innuence these associations. We used marginal regression models for the mean and association structure (Gen-eralised Estimating Equations 2; GEE2) to analyse data from 1435 family members within 469 families of diierent sizes included in the Donolo-Tel Aviv Three-Generation OOspring Study. The usual robust variance matrix was approximated by extensions of jackknife estimators of variance to GEE2 models. Upon use of this approach estimation of standard errors in models with quite complex correlation structures was possible. All analyses were easily carried out using a menu-driven stand-alone software tool for marginal regression modelling. We demonstrate that a variety of hypotheses can be tested using Wald statistics by modelling regression matrices for the association structure. We show that correlation for apoB between parent-oospring pairs increased with decreasing age diier-ence and that pairs with individuals of the same gender had more similar apoA1 levels than individuals of diierent gender. Associations between diierent relative pairs did not all agree with those expected from diier-ences in kinship coeecients. The analysis using GEE2 models revealed structures that would not have been detected by other models and should therefore be used in addition to traditional approaches of analysing family data. GEE2 should be considered a standard method for the investigation of familial aggregation.