New insights into the dementia epidemic.

2275 quiring hospitalization in the pharmacogenetic group, whereas three such events occurred in the control group. These trends, which are consistent across studies, suggest that uncommon but clinically meaningful outcomes should be considered in addition to intermediate end points (e.g., percentage of time in the therapeutic range) in a totality-of-evidence approach to assessing the usefulness of pharmacogenetic approaches. The public’s expectations for pharmacogenetics may arguably be declining. Logistic and evidentiary challenges have converged to create disillusionment regarding the relevance of pharmacogenetics. Many observers have called for randomized, controlled trials to address the translation lag. Methodologic rigor is critical in evidence assessment, and it is equally important to design experiments to definitively clarify issues of public health relevance. Randomization, in and of itself, does not accomplish this end. Rather, the choice of control, the treatment setting, characteristics of the population tested, the analytic approach, and end-point definition are likely to be the key considerations that determine the public health relevance of pharmacogenetic trials in the future. Future trials should use various methods to assess the clinical usefulness of pharmacogenetic interventions; these may include designs focused on assessing efficacy (emphasis on internal validity), effectiveness (emphasis on generalizability), and implementation effectiveness (emphasis on adoption and uptake).2 These approaches are not mutually exclusive and, if combined, may expedite assessment of the effects of pharmacogenetic interventions on patients, providers, and health systems.3,4 Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.