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A Parametric Model for Analyzing Anticipation in Genetically Predisposed Families

Author

Listed:
  • Larsen Klaus

    (Hvidovre Hospital)

  • Petersen Janne

    (Hvdiovre Hospital)

  • Bernstein Inge

    (Hvidovre Hospital)

  • Nilbert Mef

    (Hvidovre Hospital)

Abstract

Anticipation, i.e. a decreasing age-at-onset in subsequent generations has been observed in a number of genetically triggered diseases. The impact of anticipation is generally studied in affected parent-child pairs. These analyses are restricted to pairs in which both individuals have been affected and are sensitive to right truncation of the data. We propose a normal random effects model that allows for right-censored observations and includes covariates, and draw statistical inference based on the likelihood function.We applied the model to the hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome family cohort from the national Danish HNPCC register. Age-at-onset was analyzed in 824 individuals from 2-4 generations in 125 families with proved disease-predisposing mutations. A significant effect from anticipation was identified with a mean of 3 years earlier age-at-onset per generation. The suggested model corrects for incomplete observations and considers families rather than affected pairs and thereby allows for studies of large sample sets, facilitates subgroup analyses and provides generation effect estimates.

Suggested Citation

  • Larsen Klaus & Petersen Janne & Bernstein Inge & Nilbert Mef, 2009. "A Parametric Model for Analyzing Anticipation in Genetically Predisposed Families," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 8(1), pages 1-13, June.
    • Handle: RePEc:bpj:sagmbi:v:8:y:2009:i:1:n:26
    DOI: 10.2202/1544-6115.1424
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    References listed on IDEAS

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    1. Daniel Rabinowitz & Qiong Yang, 1999. "Testing for Age-at-Onset Anticipation with Affected Parent-Child Pairs," Biometrics, The International Biometric Society, vol. 55(3), pages 834-838, September.
    2. van der Laan, Mark J., 1996. "Nonparametric Estimation of the Bivariate Survival Function with Truncated Data," Journal of Multivariate Analysis, Elsevier, vol. 58(1), pages 107-131, July.
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    Cited by:

    1. Philip S. Boonstra & Bhramar Mukherjee & Jeremy M. G. Taylor & Mef Nilbert & Victor Moreno & Stephen B. Gruber, 2011. "Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome," Biometrics, The International Biometric Society, vol. 67(4), pages 1627-1637, December.

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