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Pré-Publication, Document De Travail Année : 2024

Estimation of penetrance in age-dependent genetic disease with sporadic cases from pedigree data

Estimation de pénétrance de maladies génétiques dépendantes de l'âge et présentant des cas sporadiques à partir de données de pédigrées

Résumé

In the context of genetic disease with low allele frequency in the general population and high penetrance (i.e. Mendelian disease), family-based approach is convenient as patients are often refered to geneticists due to their strongly affected pedigree. In this context, the estimation of survival in age-dependent genetic disease has direct applications in the medical protocol of patient care. The main issue in these estimations is that genotypes are mostly unknown and must be treated as a latent variable. In the specific case where the disease does not present sporadic cases, the problem is easier as an affected individual is therefore a mutation carrier, the genotype incertainty leans on the unaffected population. In that simple case, methods already exist based on Expectation-Maximisation and sum-produt algorithm. However, most diseases affect both people with and without known deleterious mutations at different rates. The few existing methods in this case generally assume that the incidence of the disease is known in the general population as well as the proportion of mutation carriers. They also assume that the incidence for non-carriers is equal to the incidence for the general population. This is close to reality for mutations with very low allele frequency and very penetrance but falls down in more moderate scenarios. The proposed method aims to generalize previous estimation methods of genetic disease survival. It relies on two hypothesis: the hazard rate of general population is piecewise constant and known, the hazard ratio between carriers and non-carriers is also piecewise constant. The model is a survival mixture parameterized by the hazard ratio and the proportion of carriers. At fixed parameters, the hazard rates (incidences) of carriers and non-carriers can be computed under the constrained hazard rate of general population through a fixed point method. With the pedigree data, the likelihood of the model can be computed with a sum-product algorithm and, therefore, the maximum likelihood parameters are estimated using a BFGS optimization algorithm. The method is tested on 2000 simulated datasets of 744 people (28 families). Standard simulations followed the model with a proportion of carriers at 0.0975, hazard ratio is (RH1=20, RH2=10) with a cut-off at age 50. A robustness analysis is also performed where the dataset are generated with Weibull function as hazard ratio.
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Dates et versions

hal-04529575 , version 1 (02-04-2024)

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Paternité

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  • HAL Id : hal-04529575 , version 1

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Lucas Ducrot, G. Nuel. Estimation of penetrance in age-dependent genetic disease with sporadic cases from pedigree data. 2024. ⟨hal-04529575⟩
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