Estimating penetrance from family data using a retrospective likelihood when ascertainment depends on genotype and age of onset.: Estimating penetrance from family dataReportar como inadecuado




Estimating penetrance from family data using a retrospective likelihood when ascertainment depends on genotype and age of onset.: Estimating penetrance from family data - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 Génétique épidémiologique et structures des populations humaines

Abstract : In diseases caused by deleterious gene mutations, knowledge of age-specific cumulative risks is necessary for medical management of mutation carriers. When pedigrees are ascertained through several affected persons, ascertainment bias can be corrected by using a retrospective likelihood. This likelihood is a function of the genotypes of pedigree members given their phenotypes and provides unbiased estimates of penetrance without modeling the selection process, provided that selection is independent of genotypes. However, since mutation testing is offered only to relatives of mutation carriers, the genotypes of family members are available only in mutated families and selection does depend on genotype. In the present study, we quantified the bias due to selection on genotype using simulations. We found that this bias depended on the true penetrance value: the lower the penetrance, the higher the bias risk by age 80 estimated to be 46% for a true penetrance value of 20%. When age of onset is added to the selection criteria, as usually done, we showed that the bias was even higher. We modified the conditioning in the retrospective likelihood, what we call -genotype restricted likelihood- GRL. Using simulations, we show that this method provided unbiased parameter estimates under all the selection designs considered.

Keywords : Ascertainment retrospective likelihood genotype restricted likelihood GRL penetrance pedigree analysis





Autor: Jérôme Carayol - Catherine Bonaïti-Pellié -

Fuente: https://hal.archives-ouvertes.fr/



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