Estimating the age at onset distribution of the asymptomatic stage of a genetic disease based on pedigree data

Abstract

Information on the age at onset distribution of the asymptomatic stage of a disease can be of paramount importance in early detection and timely management of that disease. However, accurately estimating this distribution is challenging, because the asymptomatic stage is difficult to recognize for the patient and is often detected as an incidental finding or in case of recommended screening; the age at onset is often interval-censored. In this paper, we propose a method for the estimation of the age at onset distribution of the asymptomatic stage of a genetic disease based on ascertained pedigree data that take into account the way the data are ascertained to overcome selection bias. Simulation studies show that the estimates seem to be asymptotically unbiased. Our work is motivated by the analysis of data on facioscapulohumeral muscular dystrophy, a genetic muscle disorder. In our application, carriers of the genetic causal variant are identified through genetic screening of the relatives of symptomatic carriers and their disease status is determined by a medical examination. The estimates reveal an early age at onset of the asymptomatic stage of facioscapulohumeral muscular dystrophy.