Standardizing the CAP Score in Huntington's Disease by Predicting Age-at-Onset

Background: Huntington's disease (HD) is an autosomal dominant, neurological disease caused by an expanded CAG repeat near the N-terminus of the huntingtin (HTT) gene. A leading theory concerning the etiology of HD is that both onset and progression are driven by cumulative exposure to the effects of mutant (or CAG expanded) huntingtin (mHTT). The CAG-Age-Product (CAP) score (i.e., the product of excess CAG length and age) is a commonly used measure of this cumulative exposure. CAP score has been widely used as a predictor of a variety of disease state variables in HD. The utility of the CAP score has been somewhat diminished, however, by a lack of agreement on its precise definition. The most commonly used forms of the CAP score are highly correlated so that, for purposes of prediction, it makes little difference which is used. However, reported values of CAP scores, based on commonly used definitions, differ substantially in magnitude when applied to the same data. This complicates the process of inter-study comparison. Objective: In this paper, we propose a standardized definition for the CAP score which will resolve this difficulty. Our standardization is chosen so that CAP = 100 at the expected age of diagnosis. Methods: Statistical methods include novel survival analysis methodology applied to the 13 disease landmarks taken from the Enroll-HD database (PDS 5) and comparisons with the existing, gold standard, onset model. Results: Useful by-products of our work include up-to-date, age-at-onset (AO) results and a refined AO model suitable for use in other contexts, a discussion of several useful properties of the CAP score that have not previously been noted in the literature and the introduction of the concept of a toxicity onset model. Conclusion: We suggest that taking L = 30 and K = 6.49 provides a useful standardization of the CAP score, suitable for use in the routine modeling of clinical data in HD.