The fact that the family-based design used in our study played a key role in allowing us to identify association presents an important contrast to the prevailing wisdom with regard to genome-wide association studies of common variants, in which there is a tendency to rely on unrelated case-control designs, given the relative ease of generating very large sample sizes. It is notable that the statistical power afforded by the low probability of observing multiple recurrent rare de novo events by chance more than compensated for the comparatively small sample reported here. This is particularly striking with respect to 16p11.2. Based on a traditional case-control comparison, the most significant finding in this sample, 14 events in probands and 0 in siblings (p=0.001, Fisher's exact test), did not provide evidence sufficient to withstand correction for multiple comparisons, while the analysis based on the null expectation for de novo recurrence clearly detected association. It is certain that the SSC sample ascertainment process enhanced certain findings and attenuated others. There is little question that restricting the comparison group to matched siblings limited power to
