Modelling disease progression in terms of exposure history

We consider the relationship between accumulating exposure to a putative ag ent and the associated change in physiologic function. This type of problem is common to prospective studies of cognitive, pulmonary and cardiovascula r function. A general model is proposed for data from prospective, observat ional studies with concurrent measures of exposures and continuous outcome measures. This model permits non-linearity in the relationship between expo sure and outcome and is designed to describe outcome in terms of one's enti re exposure history. As exposure data are often severely right-skewed, we u se regression spline estimation methods which localize the influence of ext reme points. We illustrate our methodology using data from a longitudinal e pidemiologic investigation of the effects of amateur boxing on neuropsychol ogic function. Copyright (C) 1999 John Wiley & Sons, Ltd.