Abstract
Some diseases are due to germline mutations in predisposing genes, such as cancer family syndromes. Precise estimation of the age-specific cumulative risk (penetrance) for mutation carriers is essential for defining prevention strategies. The genotype-restricted likelihood (GRL) method is aimed at estimating penetrance from multiple case families with such a mutation. In this paper, we proposed an extension of the GRL to account for multiple trait disease and to allow for a parent-of-origin effect. Using simulations of pedigrees, we studied the properties of this method and the effect of departures from underlying hypotheses, misspecification of disease incidence in the general population or misspecification of the index case, and penetrance heterogeneity. In contrast with the previous version of the GRL, accounting for multiple trait disease allowed unbiased estimation of penetrance. We also showed that accounting for a parent-of-origin effect allowed a powerful test for detecting this effect. We found that the GRL method was robust to misspecification of disease incidence in the population, but that misspecification of the index case induced a bias in some situations for which we proposed efficient corrections. When ignoring heterogeneity, the penetrance estimate was biased toward that of the highest risk individuals. A homogeneity test performed by stratifying the families according to the number of affected members was shown to have low power and seems useless for detecting such heterogeneity. These extensions are essential to better estimate the risk of diseases and to provide valid recommendations for the management of patients.
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APPENDIX
APPENDIX
Example of misspecification of the index case
In 2005, a woman was affected by colorectal cancer at age 52 years and died 2 years later from ovarian cancer (case 1). Nobody suspected Lynch syndrome at that time although one of her uncle, currently aged 70 years, was affected at age 45 years by colorectal cancer (case 2). In 2009, the brother of the latter, aged 71 years, also developed colorectal cancer (case 3). The sister of case 1 suspected a hereditary syndrome and asked for genetic counselling. As case 1 was not available any more and case 3 could be a sporadic case because of late-onset diagnosis, the geneticist proposed genetic testing of case 2. Therefore, case 2 was designed as the index case although case 3 was obviously the incident case that would have been the ‘natural’ index.
Why should this choice induce a bias in the analysis? As the GRL is conditioned not only on the phenotypes of family members, but also on the genotype of the index case, the choice of case 2 as the index case ‘cancels’ his contribution to the likelihood and replaces it by the contribution of case 3. As case 3 was affected at an older age than case 2, this tends to overestimate age of onset and to decrease the penetrance estimate.
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Bonaïti, B., Bonadona, V., Perdry, H. et al. Estimating penetrance from multiple case families with predisposing mutations: extension of the ‘genotype-restricted likelihood’ (GRL) method. Eur J Hum Genet 19, 173–179 (2011). https://doi.org/10.1038/ejhg.2010.158
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DOI: https://doi.org/10.1038/ejhg.2010.158
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