Using survival methods to estimate age-at-onset distributions for genetic diseases with an application to Huntington disease.

Two important considerations in genetic disease are the risk of inheriting the gene for a disease and the age-at-onset distribution among those inheriting it. This paper describes the use of survival data analytic methods to estimate these entities. When a sample consists of children and/or siblings of affected individuals, standard life-table methods such as Kaplan-Meier techniques can be applied. The desired estimators are functions of the Kaplan-Meier estimator and their properties are derived using the invariance principle and delta methods. A discussion of the underlying assumptions and estimators of standard errors and mean onset age are given. In an application to Huntington disease, the risk (+/- SE) of inheriting the gene for disease among children of a singly affected parent is estimated to be 0.499 +/- 0.020 and the estimated mean onset age (+/- SE) is 45.6 +/- 0.7.