RISK ESTIMATION AND MODIFIER GENES IN INHERITED CANCER

描述(改编自调查人员摘要)：在过去的十年中， 在定位和识别特定基因方面取得了进展，例如 BRCA1和p16在改变时可显著增加易感性 相对常见的癌症。尽管这些基因的变异显然 在各种解剖部位增加癌症风险存在争议 这些风险的大小。基于人群的研究衍生的风险 对风险的估计低于从研究中估计的 单个大家庭或一系列多个高危家庭。不管是这些 差异反映了用于风险估计的方法的固有偏见或 代表了在高危家庭中修改基因座分离的效果 不是很明显。估计基因效应的统计方法相对来说 不发达。此外，还没有研究检查 在总的背景下对假设的修饰基因座进行定位的可行性 基因组搜索。该项目旨在检查相关的效率和偏差 用不同的抽样设计和统计方法估计癌症 由于这些基因而产生的风险。蒙特卡罗模拟和现有数据集 包含上述三种方法将用于 评价的方法有多种。A)测试效果的几种设计 关于特定候选基因座的风险修饰；b)检测是否存在 残留遗传效应；以及c)检查不同抽样的能力 用于定位修饰基因的全基因组屏幕的设计也将是 检查过了。

DESCRIPTION (Adapted from investigator's abstract): During the past decade, progress has been made in localizing and identifying specific genes such as BRCA1 and p16 which when altered can confer a markedly increased susceptibility to relatively common cancers. Although variations at these genes apparently increase risk of cancer at a variety of anatomical sites, there is controversy about the magnitude of these risks. Risks derived from population-based studies have produced lower estimates of risk than those estimated from studies of single large families or series of multiple high-risk families. Whether these differences reflect inherent biases in the methods used for risk estimation or represent the effects of modifying loci segregating in high-risk families is not obvious. Statistical methods for estimation of gene effects are relatively underdeveloped. Additionally, there have been no studies that examine the feasibility of mapping hypothesized modifier loci in the context of a total genome search. This project seeks to examine the efficiency and bias associated with various sampling designs and statistical methods for estimation of cancer risks due to such genes. Monte-Carlo simulation and existing datasets encompassing the three approaches described above will be used for the evaluation of a variety of methods. Several designs for a) testing the effect on risk modification of specific candidate loci; b) detecting the presence of residual genetic effects; and c) examining the power of different sampling designs for genome-wide screens to localize modifier loci also will be examined.