Comparison of methods for competitive tests of pathway analysis.
Comparison of methods for competitive tests of pathway analysis.
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DOI：
10.1371/journal.pone.0041018
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Dudbridge F
中科院分区：
文献类型：
--
作者：
Evangelou M;Rendon A;Ouwehand WH;Wernisch L;Dudbridge F
有人建议，在探索全基因组关联数据时，通路分析可以补充单 SNP 分析。通路分析结合了基因和 SNP 的可用生物学知识，有望提高揭示复杂性状的潜在遗传结构的机会。根据测试的假设，路径分析方法可以分为竞争性（富集）或独立（关联）。尽管关联测试在统计上比富集测试更强大，但它们可能难以校准，因为分析中的偏差会在多个 SNP 或基因中累积。此外，富集测试比关联测试在科学上更相关，因为它们检测到的路径比其余基因具有相对更多的关联证据。在这里，我们展示了如何简单地调整一些众所周知的关联测试来测试丰富性，并将其性能与一些已建立的丰富性测试进行比较。我们提出了自适应排名截断乘积 (ARTP)、尾部强度测量和 Fisher 的 p 值组合的版本，用于测试富集零假设。我们将这些提出的方法的行为与已建立的超几何测试和基因集富集分析（GSEA）进行比较。模拟研究的结果表明，ARTP 方法的修改版本在所考虑的情况下通常具有最佳性能。该方法还用于寻找体重指数（BMI）和血小板功能表型的富集途径。 BMI 的通路分析发现血管活性肠肽通路与 BMI 显着相关。此前已有报道称该途径与体重指数和肥胖风险相关。 ARTP 方法是在所有测试的通路数据库和表型中鉴定出最多数量的富集通路的方法。模拟和数据应用结果与关联测试的先前工作一致，并表明 ARTP 应优先用于富集和关联测试。
It has been suggested that pathway analysis can complement single-SNP analysis in exploring genomewide association data. Pathway analysis incorporates the available biological knowledge of genes and SNPs and is expected to improve the chances of revealing the underlying genetic architecture of complex traits. Methods for pathway analysis can be classified as competitive (enrichment) or self-contained (association) according to the hypothesis tested. Although association tests are statistically more powerful than enrichment tests they can be difficult to calibrate because biases in analysis accumulate across multiple SNPs or genes. Furthermore, enrichment tests can be more scientifically relevant than association tests, as they detect pathways with relatively more evidence for association than the remaining genes. Here we show how some well known association tests can be simply adapted to test for enrichment, and compare their performance to some established enrichment tests. We propose versions of the Adaptive Rank Truncated Product (ARTP), Tail Strength Measure and Fisher’s combination of p-values for testing the enrichment null hypothesis. We compare the behaviour of these proposed methods with the established Hypergeometric Test and Gene-Set Enrichment Analysis (GSEA). The results of the simulation study show that the modified version of the ARTP method has generally the best performance across the situations considered. The methods were also applied for finding enriched pathways for body mass index (BMI) and platelet function phenotypes. The pathway analysis of BMI identified the Vasoactive Intestinal Peptide pathway as significantly associated with BMI. This pathway has been previously reported as associated with BMI and the risk of obesity. The ARTP method was the method that identified the largest number of enriched pathways across all tested pathway databases and phenotypes. The simulation and data application results are in agreement with previous work on association tests and suggests that the ARTP should be preferred for both enrichment and association testing.
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