Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.
Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.
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DOI：
10.1002/humu.20896
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发表时间：
2008-11
期刊：
影响因子：
3.9
通讯作者：
Thomas, Alun
中科院分区：
文献类型：
--
作者：
Tavtigian, Sean V.;Byrnes, Graham B.;Goldgar, David E.;Thomas, Alun
关键词：
在对候选易感基因进行深度测序和对已知易感基因进行临床突变筛查的过程中，会遇到许多个别罕见的错义替换。BRCA 1和BRCA 2是所有基因中重测序最多的，这些基因的临床突变筛查为分析罕见的错义置换提供了广泛的数据集。Align-GVGD是一种数学上简单的错义替换分析算法，基于Grantham差异，该算法已经对BRCA 1，BRCA 2和CHEK 2中的错义替换分类做出了贡献。然而，作为Align-GVGD的输出变量格兰瑟姆变异（GV）和格兰瑟姆偏差（GD）的函数的遗传风险的分布还没有得到很好的表征。在这里，我们使用了来自Myriad Genetic Laboratories数据库的近70，000个全序列测试的数据，加上两个风险估计，一个近似比值比，另一个反映选择的强度，以显示GV-GD平面中的风险分布作为一系列表面。我们从表面提取轮廓，并使用轮廓来定义从最大风险到最小风险排序的错义替换等级序列。这些等级是使用第三种基于个人和家族史的风险衡量标准进行内部验证的。这里定义的Align-GVGD等级既适用于对已知易感基因中观察到的罕见错义置换进行分类的遗传流行病学问题，也适用于分析候选易感基因病例对照突变筛查研究期间观察到的罕见错义置换的分子流行病学问题。
Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes. BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions. Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2. However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized. Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces. We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk. The grades were validated internally using a third, personal and family history-based, measure of risk. The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes.
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影响因子：
9.8
作者：
Easton, Douglas F.;Deffenbaugh, Amie M.;Goldgar, David E.
通讯作者：
Goldgar, David E.
DOI：
10.1093/jnci/dji176
发表时间：
2005-07-06
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Landi, MT;Kanetsky, PA;Pfeiffer, RM
通讯作者：
Pfeiffer, RM
影响因子：
7
作者：
Ng, PC;Henikoff, S
通讯作者：
Henikoff, S
影响因子：
9.8
作者：
Goldgar, DE;Easton, DF;Couch, FJ
通讯作者：
Couch, FJ
影响因子：
7
作者：
Stone, EA;Sidow, A
通讯作者：
Sidow, A