Nature Genetics29, 306 - 309 (2001)
Published online: 15 October 2001; | doi:10.1038/ng749
Replication validity of genetic association studies
John P.A. Ioannidis1, 2, 3, Evangelia E. Ntzani1, Thomas A. Trikalinos1
& Despina G. Contopoulos-Ioannidis1, 4
1
Clinical and Molecular Epidemiology Unit and Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.
2
Ioannina Biomedical Research Institute, Ioannina 45110, Greece.
3
Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
4
Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington DC 20010, USA.
Correspondence should be addressed to John P.A. Ioannidis jioannid@cc.uoi.gr
The rapid growth of human genetics creates countless opportunities for studies of disease association. Given the number of potentially identifiable genetic markers and the multitude of clinical outcomes to which these may be linked, the testing and validation of statistical hypotheses in genetic epidemiology is a task of unprecedented scale1,
2. Meta-analysis provides a quantitative approach for combining the results of various studies on the same topic, and for estimating and explaining their diversity3,
4. Here, we have evaluated by meta-analysis 370 studies addressing 36 genetic associations for various outcomes of disease. We show that significant between-study heterogeneity (diversity) is frequent, and that the results of the first study correlate only modestly with subsequent research on the same association. The first study often suggests a stronger genetic effect than is found by subsequent studies. Both bias and genuine population diversity might explain why early association studies tend to overestimate the disease protection or predisposition conferred by a genetic polymorphism. We conclude that a systematic meta-analytic approach may assist in estimating population-wide effects of genetic risk factors in human disease.
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