Calibration of credibility of agnostic genome-wide associations

Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 09/2008; 147B(6):964-72. DOI: 10.1002/ajmg.b.30721
Source: PubMed


Genome-wide testing platforms are increasingly used to promote "agnostic" approaches to the discovery of gene variants associated with the risk of many common diseases and quantitative traits. The early track record of genome-wide association (GWA) studies suggests that some proposed associations are replicated quite consistently with large-scale subsequent evidence from multiple studies, others have a more inconsistent replication record, some have failed to be replicated by independent investigators and many more early proposed associations await further replication. An important question is how to calibrate the credibility of these postulated associations. A simple Bayesian method is applied here to achieve such calibration. The variability of the estimated credibility is examined under different assumptions. Empirical examples are drawn from existing GWA studies. It is demonstrated that the credibility of different proposed associations can cover a very wide range. The credibility of specific associations usually remains relatively robust when different plausible assumptions are made (within a reasonable range) for the prior odds of an association being true, or the magnitude of the anticipated effect size for genetic associations. Heterogeneity and bias assumptions can have a more major impact on the credibility estimates and thus they need very careful consideration in each case. Credibility calibration may be used in conjunction with qualitative criteria for the appraisal of the cumulative evidence that take into consideration the amount, consistency, and protection from bias in the data.

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    • "Power would be only 20% for a minor allele frequency of 2% and odds ratio of 1.15, but it would be 78% for the same minor allele frequency of 2% and odds ratio of 1.3. Furthermore , for associations with uncorrected p < 0.05, we also expressed the strength of the putative associations by calculating the respective Bayes factor, assuming that average genetic effects for PD susceptibility with common variants may reflect odds ratios of 1.30 and using a lump-and-smear prior, as described by Ioannidis (Ioannidis, 2008). Meta-analyses were performed using Review Manager 4.2.7 and STATA 10.0 (Stata Corp., College Station, TX, USA). "
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    American journal of epidemiology 08/2008; DOI:10.1093/aje/kwn152 · 5.23 Impact Factor
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