A correction for ascertainment bias in estimating rates of onset of highly penetrant genetic disorders

Carolina Espinosa, Angus S. Macdonald

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3 Citations (Scopus)


Estimation of rates of onset of rare, late-onset dominantly inherited genetic disorders is complicated by: (a) probable ascertainment bias resulting from the 'recruitment' of strongly affected families into studies; and (b) inability to identify the true 'at risk' population of mutation carriers. To deal with the latter, Gui & Macdonald (2002a) proposed a non-parametric (Nelson-Aalen) estimate ?(x) of a simple function ?(x) of the rate of onset at age x. The function ?(x) had a finite bound, which was an increasing function of the probability p that a child of an affected parent inherits the mutation and s the life-time penetrance. However if ?(x) exceeds this bound, it explodes to infinity, and this can happen at quite low ages. We show that such 'failure' may in fact be a useful measure of ascertainment bias. Gui & Macdonald assumed that p = 1/2 and s = 1, but ascertainment bias means that p > 1/2 and s ? 1 in the sample. The maximum attained by ?(x) allows us to estimate a range for the product ps, and therefore the degree of ascertainment bias that may be present, leading to bias-corrected estimates of rates of onset. However, we find that even classical independent censoring, prior to ascertainment, can introduce new bias. We apply these results to early-onset Alzheimer's disease associated with mutations in the Presenilin-1 gene. © 2007 by Astin Bulletin. All rights reserved.

Original languageEnglish
Pages (from-to)429-452
Number of pages24
JournalASTIN Bulletin: The Journal of the IAA
Issue number2
Publication statusPublished - Nov 2007


  • Ascertainment bias
  • Early-onset Alzheimer's disease
  • Nelson-Aalen estimate
  • Presenilin-1 gene
  • Rate of onset


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