  In the search for genetic factors that are associated with complex heritable
human traits, considerable attention is now being focused on rare variants that
individually have small effects. In response, numerous recent papers have
proposed testing strategies to assess association between a group of rare
variants and a trait, with competing claims about the performance of various
tests. The power of a given test in fact depends on the nature of any
association and on the rareness of the variants in question. We review such
tests within a general framework that covers a wide range of genetic models and
types of data. We study the performance of specific tests through exact or
asymptotic power formulas and through novel simulation studies of over 10,000
different models. The tests considered are also applied to real sequence data
from the 1000 Genomes project and provided by the GAW17. We recommend a testing
strategy, but our results show that power to detect association in plausible
genetic scenarios is low for studies of medium size unless a high proportion of
the chosen variants are causal. Consequently, considerable attention must be
given to relevant biological information that can guide the selection of
variants for testing.
