'Location, Location, Location': a spatial approach for rare variant analysis and an application to a study on non-syndromic cleft lip with or without cleft palate.
'Location, Location, Location': a spatial approach for rare variant analysis and an application to a study on non-syndromic cleft lip with or without cleft palate.
复制标题
DOI：
10.1093/bioinformatics/bts568
复制
发表时间：
2012-12-01
期刊：
影响因子：
--
通讯作者：
Lange C
中科院分区：
文献类型：
--
作者：
Fier H;Won S;Prokopenko D;AlChawa T;Ludwig KU;Fimmers R;Silverman EK;Pagano M;Mangold E;Lange C
动机：为了分析序列数据中的罕见变异，人们提出了多种方法。固定和灵活的阈值方法将基因组区域的罕见变异信息折叠成降维的检验统计量。或者，可以将罕见变异信息组合在基于合适的回归模型、机器学习等的统计框架中。尽管现有方法提供了强大的测试，可以合并等位基因频率和先验生物学知识的信息，但无法合并病例和对照之间罕见变异的空间聚类差异。基于有害变异和保护性变异聚集或发生在感兴趣的基因组区域的不同部分的假设，我们提出了一种基于空间聚类方法的罕见变异测试策略，并指导该区域的生物相关片段的识别。我们的方法不需要对遗传效应的方向进行任何假设。结果：在模拟研究中，我们评估了聚类方法的功效并将其与现有方法进行比较。我们的模拟结果表明，即使在适合标准方法的情况下，稀有变体的聚类方法也具有良好的功能。我们的空间聚类方法的效率不受具有相反效应大小方向的罕见变异的存在的影响。在伴或不伴腭裂的非综合征性唇裂 (NSCL/P) 测序研究中的应用证明了其实际意义。所提出的测试策略应用于染色体 15q13.3 上的基因组区域，该区域在之前的全基因组关联研究中与 NSCL/P 病因学有关，并将其结果与标准方法进行了比较。可用性：R 实现的源代码和文档将在线提供。目前，R 实现仅支持基因型数据。我们目前正在开发 VCF 文件的扩展。联系方式：heide.fier@googlemail.com
Motivation: For the analysis of rare variants in sequence data, numerous approaches have been suggested. Fixed and flexible threshold approaches collapse the rare variant information of a genomic region into a test statistic with reduced dimensionality. Alternatively, the rare variant information can be combined in statistical frameworks that are based on suitable regression models, machine learning, etc. Although the existing approaches provide powerful tests that can incorporate information on allele frequencies and prior biological knowledge, differences in the spatial clustering of rare variants between cases and controls cannot be incorporated. Based on the assumption that deleterious variants and protective variants cluster or occur in different parts of the genomic region of interest, we propose a testing strategy for rare variants that builds on spatial cluster methodology and that guides the identification of the biological relevant segments of the region. Our approach does not require any assumption about the directions of the genetic effects. Results: In simulation studies, we assess the power of the clustering approach and compare it with existing methodology. Our simulation results suggest that the clustering approach for rare variants is well powered, even in situations that are ideal for standard methods. The efficiency of our spatial clustering approach is not affected by the presence of rare variants that have opposite effect size directions. An application to a sequencing study for non-syndromic cleft lip with or without cleft palate (NSCL/P) demonstrates its practical relevance. The proposed testing strategy is applied to a genomic region on chromosome 15q13.3 that was implicated in NSCL/P etiology in a previous genome-wide association study, and its results are compared with standard approaches. Availability: Source code and documentation for the implementation in R will be provided online. Currently, the R-implementation only supports genotype data. We currently are working on an extension for VCF files. Contact: heide.fier@googlemail.com
登录
查看更多内容
DOI：
10.1056/nejmra0808700
发表时间：
2009-04-23
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hardy J;Singleton A
通讯作者：
Singleton A
影响因子：
9.8
作者：
Li, Bingshan;Leal, Suzanne M.
通讯作者：
Leal, Suzanne M.
影响因子：
4.5
作者：
Neale BM;Rivas MA;Voight BF;Altshuler D;Devlin B;Orho-Melander M;Kathiresan S;Purcell SM;Roeder K;Daly MJ
通讯作者：
Daly MJ
影响因子：
30.8
作者：
Mathieson, Iain;McVean, Gil
通讯作者：
McVean, Gil
影响因子：
30.8
作者：
Mangold, Elisabeth;Ludwig, Kerstin U.;Noethen, Markus M.
通讯作者：
Noethen, Markus M.