Although the distinction between the liability-index and mediational models for EP is conceptually important, it is devilishly difficult in humans to design experiments to discriminate powerfully between them. Rarely can we directly intervene on EP and determine whether risk for PD is altered. Longitudinal and twin models can potentially discriminate between causal and noncausal relationships between an EP and a PD,7,8 but sample sizes sufficient to allow for powerful discrimination may be hard to achieve, especially with relatively rare PDs and/or expensive EPs.9 Developmental studies in which interventions directly on EP in unaffected individuals can be tested to see whether they reduce disease risk would be another way to test the mediational model.
