Statistical modeling of Huntington disease onset

Huntington disease (HD) is caused by a CAG trinucleotide expansion in the huntingtin gene. We now have the power to predict age-at-onset from subject-specific features like motor and neuroimaging measures. In clinical trials, properly modeling onset age is important, because it improves power calculations and directs clinicians to recruit subjects with certain features. The history of modeling onset, from simple linear and logistic regression to advanced survival models, is discussed. We highlight their advantages and disadvantages, emphasizing the methodological challenges when genetic mutation status is unavailable. We also discuss the potential bias and higher variability incurred from the uncertainty associated with subjective definitions for onset. Methods to adjust for the uncertainty in survival models are still in their infancy, but would be beneficial for HD and neurodegenerative diseases with long prodromal periods like Alzheimer's and Parkinson's disease.