Other obvious issues with the current assessments of the power and other properties of rare variant analysis methods concern the simple fact that not enough time has elapsed since their introduction for someone to compare them all in a large study. In addition, some methods are clearly nuanced and are unlikely to work in situations other than those for which they were designed. For example, some methods do not take into account the possible direction of a rare variant effect, such as the methods described by Li and Leal28 and Madsen and Browning34 whereas other methods are designed to handle these situations40. Finally, although many such published power studies simulate data assuming a population genetics model for the propagation of rare variants, the appropriateness of the assumptions of these models is unclear. We believe that the best approach will be to take real sequence data obtained from many individuals (e.g., the 1000 Genomes Project data) and simulate phenotypes based on variants in those sequences, making assumptions only about phenotypic effect sizes and interactions between variants.
