Ioannidis John P A, Trikalinos Thomas A, Ntzani Evangelia E, Contopoulos-Ioannidis Despina G
Department of Hygiene, University of Ioannina School of Medicine, Ioannina, Greece.
Lancet. 2003 Feb 15;361(9357):567-71. doi: 10.1016/S0140-6736(03)12516-0.
Advances in human genetics could help us to assess prognosis on an individual basis and to optimise the management of complex diseases. However, different studies on the same genetic association sometimes have discrepant results. Our aim was to assess how often large studies arrive at different conclusions than smaller studies, and whether this situation arises more frequently when findings of first published studies disagree with those of subsequent research.
We examined the results of 55 meta-analyses (579 study comparisons) of genetic associations and tested whether the magnitude of the genetic effect differs in large versus smaller studies.
We noted significant between-study heterogeneity in 26 (47%) meta-analyses. The magnitude of the genetic effect differed significantly in large versus smaller studies in ten (18%), 20 (36%), and 21 (38%) meta-analyses with tests of rank correlation, regression on SE, and regression on inverse of variance, respectively. The largest studies generally yielded more conservative results than the complete meta-analyses, which included all studies (p=0.005). In 14 (26%) meta-analyses the proposed association was significantly stronger in the first studies than in subsequent research. Only in nine (16%) meta-analyses was the genetic association significant and replicated without hints of heterogeneity or bias. There was little concordance in first versus subsequent discrepancies, and large versus small discrepancies.
Genuine heterogeneity and bias could affect the results of genetic association studies. Genetic risk factors for complex diseases should be assessed cautiously and, if possible, using large scale evidence.
人类遗传学的进展有助于我们基于个体情况评估预后，并优化复杂疾病的管理。然而，关于同一基因关联的不同研究有时会得出不一致的结果。我们的目的是评估大型研究与小型研究得出不同结论的频率，以及当首次发表的研究结果与后续研究结果不一致时，这种情况是否更频繁出现。
我们检查了55项基因关联的荟萃分析结果（579项研究比较），并测试了大型研究与小型研究中基因效应的大小是否不同。
我们注意到26项（47%）荟萃分析中存在显著的研究间异质性。在分别采用秩相关检验、标准误回归和方差倒数回归的10项（18%）、20项（36%）和21项（38%）荟萃分析中，大型研究与小型研究的基因效应大小存在显著差异。最大型的研究通常比纳入所有研究的完整荟萃分析得出更保守的结果（p=0.005）。在14项（26%）荟萃分析中，首次研究中提出的关联比后续研究显著更强。只有9项（16%）荟萃分析中的基因关联显著且得到重复，没有异质性或偏倚的迹象。首次研究与后续研究的差异、大型研究与小型研究的差异之间几乎没有一致性。
真正的异质性和偏倚可能会影响基因关联研究的结果。对于复杂疾病的遗传风险因素应谨慎评估，如有可能，应使用大规模证据。
