Statistical tools for phenotype definition in genetic studies

表型定义是在遗传学研究中建立可靠的基因-表型关系的必要前提。为了确定复杂疾病的候选感兴趣区域，“明确定义的”表型应具有以下特征：1)高度可遗传；2)遗传同质性；3)结合收集的与疾病相关的各种项目的信息。这项提议的目标是建立一套统计工具，用于在收集了大量关于患者的项目和/或当遗传相关疾病定义不明确时，在基因研究中定义表型，例如精神障碍。在前人工作的基础上，我将着力抓好以下三个目标： 1)基于遗传力的表型选择(在家系研究中)。我计划扩展基于遗传力的主成分方法来结合表型信息(Ott，1999)。这一方法将扩展到考虑到任何类型的家庭结构。 2)基于因子分析的表型构建(在家族性研究中)。该项目是我们为家庭/谱系数据开发的潜在类别模型的直接扩展(Labbe等人，2009年；Tayeb等人，2009年)。拟议的项目包括将这项工作扩展到连续病例，即疾病由未观察到的潜在连续因素控制，而不是由分类类别控制。 3)次级表型关联研究(病例对照研究)。该项目将侧重于用于分析次级表型的统计方法，即在病例对照研究中除了疾病特征之外还收集到的表型(特征)。由于病例和对照之间的选择概率不相等，这些次级表型不是从人群的随机样本中收集的，标准方法分析这种类型的表型可能会导致误导结果(Lin&Zeng，2009)。我计划提出一个疾病状态和次级表型的联合模型，该模型将考虑疾病和次级性状之间的关联，以及次级性状和给定的SNP之间的关联。

Phenotype definition is a necessary prerequisite to establish reliable genotype-phenotype relationships in genetic studies. In order to identify candidate regions of interest for complex diseases, a "well defined" phenotype should have the following characteristics: i) be highly heritable; ii) be genetically homogeneous; iii) combine the information collected on a variety of items related to the disease. The goal of this proposal is to establish a set of statistical tools for defining the phenotype in genetic studies, when a large number of items are collected on the patients and/or when a genetically relevant disease definition is unclear, as is the case in psychiatric disorders for example. Based on previous work, I will try to focus on the three following objectives: 1) Selection of the phenotype based on its heritability (in family studies). I am planning to extend the principal component approach based on heritability for combining phenotype information (Ott, 1999). This approach will be extended to account for any type of family structure. 2) Construction of phenotypes based on a factorial analysis of the items collected (in family studies). This project is a direct extension of the latent class model we developed for familial/pedigree data (Labbe et al., 2009; Tayeb et al., 2009). The proposed project consists of extending this work to the continuous cases, i.e. where the disease is controlled by unobserved latent continuous factors instead of categorical classes. 3) Association study for secondary phenotypes (case-control studies). This project will focus on the statistical approach used to analyze secondary phenotypes, i.e. phenotypes (traits) that have been collected in addition to the disease trait in case-control studies. Because of unequal selection probabilities between cases and controls, these secondary phenotypes are not collected from a random sample of the population, and standard methods analyzing this type of phenotypes can lead to misleading results (Lin & Zeng, 2009). I am planning to propose a joint model for the disease status and the secondary phenotype, which will account for the association between the disease and secondary trait, and between the secondary trait and a given SNP.