Curses--winner's and otherwise--in genetic epidemiology.

The estimated effect of a marker allele from the initial study reporting the marker-allele association is often exaggerated relative to the estimated effect in follow-up studies (the "winner's curse" phenomenon). This is a particular concern for genome-wide association studies, where markers typically must pass very stringent significance thresholds to be selected for replication. A related problem is the overestimation of the predictive accuracy that occurs when the same data set is used to select a multilocus risk model from a wide range of possible models and then estimate the accuracy of the final model ("over-fitting"). Even in the absence of these quantitative biases, researchers can over-state the qualitative importance of their findings--for example, by focusing on relative risks in a context where sensitivity and specificity may be more appropriate measures. Epidemiologists need to be aware of these potential problems: as authors, to avoid or minimize them, and as readers, to detect them.