Statistical Genetics Methods for Mixed Pathologies

描述（由申请人提供）：这项指导职业发展资助申请提出了一个培训计划，将Fardo博士之前在生物统计学和统计遗传学方面的研究整合到包括高度流行的神经退行性疾病在内的衰老疾病的研究中。他的长期职业目标是发展一个独立的研究项目，专注于统计方法的进步，以了解复杂疾病的遗传学基础，重点是大脑衰老疾病。这将通过通过正式课程和指导经验获得老年脑疾病领域的知识来实现；对相关研究数据的管理、分析和解释进行培训；对衰老研究中使用的大规模遗传数据进行全面检查，并在新的尖端生物统计方法可以改进分析的领域进行全面检查；统计遗传学方法在大规模遗传数据分析中的应用、改进和发展；以及继续进行负责任的研究培训。法尔多博士的研究培训将涉及一个充满热情的跨学科研究人员团队，他们拥有强大的研究记录。K25应用程序的总体目标是利用来自大型多中心衍生数据库的临床和神经病理学数据来识别与特定神经病理内表型相关的单核苷酸多态性（snp）。大多数调查与年龄有关的复杂疾病的遗传易感性的研究都是用一个直接比较患有或不患有疾病的模型来概念化的，例如，患有或不患有阿尔茨海默病（AD）。然而，这种疾病/非疾病的方法效率低下，不适合调查所谓的混合病理的遗传风险因素，这是老年人的常态。拟议的研究计划将询问与大量尸检大脑的神经病理特征的遗传联系。这将通过利用数据来完成

DESCRIPTION (provided by applicant): This mentored career development grant application proposes a training program to integrate Dr. Fardo's previous research in biostatistics and statistical genetics into investigations of aging disorders including highly prevalent neurodegenerative diseases. His long-term career goal is to develop an independent research program focusing on the advancement of statistical methodologies to understand the genetics underlying complex diseases, with an emphasis on diseases of brain aging. This will be achieved through acquiring knowledge in the area of brain diseases of aging through formal coursework and mentored experiences; training in the management, analysis and interpretation of associated research data; comprehensive examination of the large-scale genetic data used in aging studies and the areas where novel, cutting-edge biostatistical methodologies could improve analyses; application, refinement and development of statistical genetic approaches to the analysis of this large-scale genetic data; and the continuation of training in the responsible conduct of research. Dr. Fardo's research training will involve an enthusiastic team of cross- disciplinary researchers with a strong research track record. An overall goal of this K25 application is to capitalize on the clinical and neuropathologic data available from large, multicenter-derived databases to identify single nucleotide polymorphisms (SNPs) associated with specific neuropathologic endophenotypes. Most research investigating the genetic predisposition of age-related complex diseases has been conceptualized with a model directly comparing those with or without a disease, for example, with or without Alzheimer's disease (AD). However, this disease/non-disease approach is inefficient and not appropriate for investigating the genetic risk factors for so-called mixed pathologies which are the norm in advanced age. The proposed research program will interrogate genetic associations with neuropathologic features of a large cohort of autopsied brains. This will be done by utilizing data collected from large, NIH-funded resources. Neuropathology data and genome-wide genetic data will be merged from these resources, and genetic associations for mixed-pathology dementias and neuropathologic features will be comprehensively tested. This work will result in new methods to analyze mixed-pathology dementias and neuropathologic features as well as the exploration of associated genetic risk factors and gene-environment interactions.