Ripatti Samuli, Gatz Margaret, Pedersen Nancy L, Palmgren Juni
Rolf Nevanlinna Institute, University of Helsinki, Länsisatamankatu 14 B 26, 00180 Helsinki, Finland.
Genet Epidemiol. 2003 Feb;24(2):139-49. doi: 10.1002/gepi.10209.
We present a frailty model to estimate the relative importance of genetic and environmental factors on age at onset of dementia in a twin design. We use modern survival methodology to define a model that accounts simultaneously for longitudinal aspects, e.g., left truncation and right censoring in data, and the multivariate nature of twin data. Additionally, we present a novel three-state frailty model, with nondemented, demented, and dead states, describing variation in the onset of disease and mortality simultaneously in one model, while accounting for possible dependence for the two competing events. The frailty structure, i.e., the latent random effects structure, mimics the traditional twin model for continuous variables used in quantitative genetics, and as such describes within-pair dependence. This in turn leads to estimates for intrapair correlations, as well as for additive genetic, and shared and nonshared environmental components of variance. A hierarchical Bayesian model formulation and Gibbs sampling are used to estimate posterior distributions of the parameters. The models are applied to Swedish Twin Registry data on the onset of dementia in elderly twins. Based on the three-state frailty model, we estimate the intrapair correlations for dementia to be 0.87 [90% credible interval: 0.61,0.98] and 0.68[0.18,0.91] for MZ and DZ twins, respectively. Based on our model, we estimate that genetic effects account for about one third, and shared environmental effects for almost a half, of the variation in dementia hazards between individuals. More data, however, are needed to gain precision in these estimates.
我们提出了一个虚弱模型，用于在双胞胎设计中估计遗传和环境因素对痴呆症发病年龄的相对重要性。我们使用现代生存方法来定义一个模型，该模型同时考虑纵向因素，例如数据中的左截断和右删失，以及双胞胎数据的多变量性质。此外，我们提出了一种新颖的三状态虚弱模型，包括非痴呆、痴呆和死亡状态，在一个模型中同时描述疾病发病和死亡率的变化，同时考虑两个竞争事件之间可能的依赖性。虚弱结构，即潜在随机效应结构，模仿了数量遗传学中用于连续变量的传统双胞胎模型，因此描述了双胞胎对之间的依赖性。这反过来又导致了对内相关性的估计，以及对方差的加性遗传、共享和非共享环境成分的估计。使用分层贝叶斯模型公式和吉布斯采样来估计参数的后验分布。这些模型应用于瑞典双胞胎登记处关于老年双胞胎痴呆症发病的数据。基于三状态虚弱模型，我们估计同卵双胞胎和异卵双胞胎痴呆症的对内相关性分别为0.87 [90%可信区间：0.61,0.98] 和0.68[0.18,0.91]。基于我们的模型，我们估计遗传效应约占个体间痴呆症风险差异的三分之一，共享环境效应约占近一半。然而，需要更多数据来提高这些估计的精度。
