Recently, Price et al.35 implemented a method for testing rare coding variants that considers optimal or variable weighting of the variants in a procedure resembling Madsen and Browning’s.34 Price et al.35 showed that their method is more powerful than approaches that consider fixed weights. In addition, they argued that the use of the predicted functional impact of each individual non-synonymous coding variant could be leveraged in their model. Finally, Han and Pan40 recently devised a method that cleverly considers the direction of the effect of the implicated variants (e.g., protective or deleterious) which can be implemented in a regression model framework (see below). Other summary statistic methods essentially ignore direction of effect and hence may be problematic in settings in which rare variants are not necessarily more frequent in disease or certain a priori defined phenotypic states.
