title: Establishment of genetic associations for complex diseases is independent of early study findings.
abstract: Numerous genetic association studies for complex diseases are performed. Investigators place emphasis on formal statistical significance (P-values < 0.05), but the predictive ability of early statistically significant ('positive') findings is unclear. We scrutinized 55 cumulative meta-analyses of genetic associations (579 studies), in order to assess whether having statistical significance in the earliest (first) published study or in at least half among several (> or =3) early-published studies, or high statistical significance in early studies had any predictive ability for establishing or refuting the presence of the genetic association in subsequent research. In 35 associations, a first study was 'positive' and in 15 associations more than half of the early-published reports were 'positive'. The average publication rate of subsequent studies increased 1.71-fold with a 'positive' first report. When compared against the summary results of subsequent research, sensitivity and specificity were 0.65 and 0.38 for the first reports, and 0.40 and 0.73, respectively, when at least three early studies were considered. First studies also had poor predictive ability, when we considered the estimated attributable fraction and coverage of the 95% confidence interval thereof or higher levels of statistical significance. We conclude that although 'positive' findings in the very first reports provide strong incentive for conducting more studies on a putative genetic epidemiological association, the statistical significance or even the magnitude of the effect of early studies cannot adequately predict eventual establishment of an association. Conversely, many genuine epidemiological associations would be missed, if research were abandoned after early underpowered 'negative' studies.
authors.affiliation: 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, Greece.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Trikalinos
authors.forename: Evangelia E
authors.initials: EE
authors.lastname: Ntzani
authors.forename: Despina G
authors.initials: DG
authors.lastname: Contopoulos-Ioannidis
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
mesh_terms: D015984:Causality; D016208:Databases, Factual; D020022:Genetic Predisposition to Disease; D006801:Humans; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D017594:Publication Bias; D012680:Sensitivity and Specificity