CAG-repeat length and the age of onset in Huntington Disease (HD): A review and validation study of statistical approaches

Douglas R. Langbehn, Michael R. Hayden, Jane S. Paulsen, Hans Johnson, Elizabeth Aylward, Kevin Biglan, Karl Kieburtz, David Oakes, Ira Shoulson, Mark Guttman, Bernhard G. Landwehrmeyer, Martha Nance, Christopher Ross, Julie Stout

Research output: Contribution to journalReview articlepeer-review


CAG-repeat lengthin the gene forHDis inversely correlated with age of onset (AOO). A number of statistical models elucidating the relationship between CAG length and AOO have recently been published. In the present article, we review the published formulae, summarize essential differences in participant sources, statistical methodologies, and predictive results. We argue that unrepresentative sampling and failure to use appropriate survival analysis methodology may have substantially biased much of the literature. We also explain why the survival analysis perspective is necessary if any such model is to undergo prospective validation. We use prospective diagnostic data from the PREDICT-HDlongitudinal study ofCAG-expanded participants to test conditional predictions derived from two survival models of AOO of HD. A prior model of the relationship of CAG and AOO originally published by Langbehn et al. yields reasonably accurate predictions, while a similar model by Gutierrez and MacDonald substantially overestimates diagnosis risk for all but the highest risk participants in this sample. The Langbehn et al. model appears accurate enough to have substantial utility in various research contexts.Wealso emphasize remaining caveats, many of which are relevant for any direct application to genetic counseling.

Original languageEnglish (US)
Pages (from-to)397-408
Number of pages12
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Issue number2
StatePublished - Mar 2010


  • Huntington disease
  • Polyglutamine expansion
  • Prognosis
  • Survival analysis

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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