Modeling the age-of-onset function in segregation analysis: a causal scheme for leprosy.

Several methods have been proposed to take into account the variable age of onset of a disease in genetic analysis. A different approach is presented from an etiological point of view. To illustrate the method, we used leprosy, an infectious disease with a variable age of onset depending on both the time of contamination with the bacillus and the latency of the disease; the role of a major gene in the susceptibility to this disease has been recently detected. The age-of-onset function was modeled to account for the two temporal processes: contamination event and incubation period. For genetic analysis, this function was combined with the probability of being susceptible to the disease, which was expressed by the use of regressive models. To test this new approach, ten sets of 500 nuclear families were simulated considering different hypotheses of contamination risks, which were either constant or dependent on contacts with contagious leprosy patients, and varying the extent to which the disease is heritable. Analyses of these data using two versions of the model indicate that the model can detect familial correlations in variable age of onset and discriminate between the different simulated effects.