Estimating age at onset distributions: a review of methods and issues

TLDR: In this paper, the authors comprehensively review methods for estimating the age at onset distribution of a disease and make recommendations for use of current methods and suggestions for future investigations of the issue.

Abstract: Since many genetic diseases have a variable age at onset, knowing the age at onset distribution of a disease facilitates genetic analyses in several ways. Age at onset distributions are used to estimate the risk of illness among relatives of probands and can improve estimates of recurrence rates in genetic counselling. The age at onset distribution is also useful when we test genetic hypotheses in segregation and linkage analyses. Unfortunately, estimation of a disease's age at onset distribution is not straightforward. The distribution we observe in a series of cases is biased towards younger ages and the magnitude of the bias is not negligible. In this paper we comprehensively review methods for estimating the age at onset distribution. We classify these methods based on the type of data required for the analysis: (1) independently ascertained probands; and (2) pedigree data. In presenting these methods, we focus on their conceptual derivation, mathematical formulation and critical assumptions. We also examine factors that limit the applicability of these methods to psychiatric disorders. We conclude with recommendations for use of current methods and suggestions for future investigations of the issue.