American Journal of Epidemiology Advance Access originally published online on September 8, 2008
American Journal of Epidemiology 2008 168(8):855-865; doi:10.1093/aje/kwn206
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Evaluation of the Potential Excess of Statistically Significant Findings in Published Genetic Association Studies: Application to Alzheimer's Disease
Correspondence to Dr. John P. A. Ioannidis, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece (e-mail: jioannid{at}cc.uoi.gr).
Received for publication October 9, 2007. Accepted for publication June 12, 2008.
The authors evaluated whether there is an excess of statistically significant results in studies of genetic associations with Alzheimer's disease reflecting either between-study heterogeneity or bias. Among published articles on genetic associations entered into the comprehensive AlzGene database (www.alzgene.org) through January 31, 2007, 1,348 studies included in 175 meta-analyses with 3 or more studies each were analyzed. The number of observed studies (O) with statistically significant results (P = 0.05 threshold) was compared with the expected number (E) under different assumptions for the magnitude of the effect size. In the main analysis, the plausible effect size of each association was the summary effect presented in the respective meta-analysis. Overall, 19 meta-analyses (all with eventually nonsignificant summary effects) had a documented excess of O over E: Typically single studies had significant effects pointing in opposite directions and early summary effects were dissipated over time. Across the whole domain, O was 235 (17.4%), while E was 164.8 (12.2%) (P < 10–6). The excess showed a predilection for meta-analyses with nonsignificant summary effects and between-study heterogeneity. The excess was seen for all levels of statistical significance and also for studies with borderline P values (P = 0.05–0.10). The excess of significant findings may represent significance-chasing biases in a setting of massive testing.
Alzheimer disease; bias (epidemiology); genetic markers; genetics; meta-analysis; publication bias
Abbreviations: ABCA, ATP-binding cassette transporter A; ACE, angiotensin-converting enzyme; APBB, amyloid beta (A4) precursor protein-binding family B; APOE, apolipoprotein E; BDNF, brain-derived neurotrophic factor; CTSD, cathepsin D; IL6, interleukin-6
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