Familial associations of lipid profiles: a generalized estimating equations approach

Elevated plasma levels of apolipoproteins A1 (apoA1) and B (apoB) are impor tant protective factors and risk factors, respectively, for atherosclerosis and coronary heart disease. It is well known that both apoA1 and apoB reve al strong familial aggregation. Our goal was to investigate whether exogeno us variables influence these associations. We used marginal regression mode ls for the mean and association structure (generalized estimating equations 2; GEE2) to analyse data from 1435 family members within 469 families of d ifferent sizes included in the Donolo-Tel Aviv Three-Generation Offspring S tudy. The usual robust variance matrix was approximated by extensions of ja ck-knife estimators of variance to GEE2 models. Estimation of standard erro rs in models with quite complex correlation structures was possible using t his approach. All analyses were easily carried out using a menu-driven stan d-alone software tool for marginal regression modelling. We demonstrate tha t 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-offspring pairs increased with decreasing age diff erence and that pairs with individuals of the same gender had more similar apoA1 levels than individuals of different gender. Associations between dif ferent relative pairs did not all agree with those expected from difference s in kinship coefficients. The analysis using GEE2 models revealed structur es that would not have been detected by other models and should therefore b e used in addition to traditional approaches of analysing family data. GEE2 should be considered a standard method for the investigation of familial a ggregation. Copyright (C) 2000 John Wiley & Sons, Ltd.