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Assessing the Probability that a Finding Is Genuine for Large-Scale Genetic Association Studies

机译:评估大规模遗传关联研究的发现是真实的可能性

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摘要

Genetic association studies routinely involve massive numbers of statistical tests accompanied by P-values. Whole genome sequencing technologies increased the potential number of tested variants to tens of millions. The more tests are performed, the smaller P-value is required to be deemed significant. However, a small P-value is not equivalent to small chances of a spurious finding and significance thresholds may fail to serve as efficient filters against false results. While the Bayesian approach can provide a direct assessment of the probability that a finding is spurious, its adoption in association studies has been slow, due in part to the ubiquity of P-values and the automated way they are, as a rule, produced by software packages. Attempts to design simple ways to convert an association P-value into the probability that a finding is spurious have been met with difficulties. The False Positive Report Probability (FPRP) method has gained increasing popularity. However, FPRP is not designed to estimate the probability for a particular finding, because it is defined for an entire region of hypothetical findings with P-values at least as small as the one observed for that finding. Here we propose a method that lets researchers extract probability that a finding is spurious directly from a P-value. Considering the counterpart of that probability, we term this method POFIG: the Probability that a Finding is Genuine. Our approach shares FPRP's simplicity, but gives a valid probability that a finding is spurious given a P-value. In addition to straightforward interpretation, POFIG has desirable statistical properties. The POFIG average across a set of tentative associations provides an estimated proportion of false discoveries in that set. POFIGs are easily combined across studies and are immune to multiple testing and selection bias. We illustrate an application of POFIG method via analysis of GWAS associations with Crohn's disease.
机译:遗传关联研究通常涉及大量伴随P值的统计检验。全基因组测序技术将受测变体的潜在数量增加到数千万。执行的测试越多,则需要将较小的P值视为有意义的。但是,较小的P值不等于出现虚假发现的机会很小,并且显着性阈值可能无法充当针对错误结果的有效过滤器。尽管贝叶斯方法可以直接评估发现是伪造的可能性,但是其在关联研究中的采用速度很慢,部分原因是P值的普遍存在以及通常由P值自动产生的方式。软件包。尝试设计简单的方法将关联P值转换为发现是伪造的可能性的尝试遇到了困难。误报报告概率(FPRP)方法越来越受欢迎。但是,FPRP并非旨在估计特定发现的可能性,因为FPRP是为假设发现的整个区域定义的,P值至少与该发现所观察到的P值一样小。在这里,我们提出一种方法,使研究人员可以直接从P值中提取发现是虚假的概率。考虑到该概率的对应物,我们称此方法为POFIG:发现是真实的概率。我们的方法具有FPRP的简单性,但在给定P值的情况下给出了伪造发现的有效概率。除了简单的解释外,POFIG还具有所需的统计属性。一组临时关联中的POFIG平均值提供了该组中错误发现的估计比例。 POFIGs在研究中很容易合并,并且不受多重测试和选择偏见的影响。我们通过分析GWAS与克罗恩病的关联来说明POFIG方法的应用。

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