title: A unified model for estimating and testing familial aggregation.
abstract: Investigations of familial aggregation of disease can provide important clues for genetic mechanisms, and many such studies have been published in the epidemiological literature using various statistical methods. We developed a unified model for familial risk by extending a Cox regression model to enable estimation of the detailed effects of kinship. By appropriate parameterisation of the model, we show how the risks to all specific first-degree kinships can be estimated and formally compared using simple interaction terms and how the model can be extended to accommodate higher-degree relatives. The correlation due to observations from family members and from the potential for repeated observations is accommodated by a robust sandwich variance estimator or a bootstrap estimate. Hazard ratios for different kinships are formally compared using a robust Wald test. We illustrate the method with applications to studies of adult leukemia and non-Hodgkin's lymphoma in the Swedish population and display our results on a pedigree diagram. Our estimates are consistent with published work that used simpler stratified methods, and our model enabled the detection of a number of statistically significant effects of kinship. The recognition of such kindred-specific disease risk could be a first step in the design of more informative genetic biomarker studies.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177, Stockholm, Sweden.
authors.forename: Myeongjee
authors.initials: M
authors.lastname: Lee
authors.forename: Paola
authors.initials: P
authors.lastname: Rebora
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Valsecchi
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Marie
authors.initials: M
authors.lastname: Reilly
mesh_terms: D000328:Adult; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007938:Leukemia / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D008297:Male; D010375:Pedigree; D016016:Proportional Hazards Models; D012306:Risk; D013548:Sweden
keywords: bootstrap; kindred-specific risk; leukemia; non-Hodgkin's lymphoma; robust sandwich variance; survival analysis