We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

In some applications, researchers using the synthetic control method (SCM) to evaluate the effect of a policy may struggle to determine whether they have identified a “good match” between the control group and treated group. In this paper, we demonstrate the utility of the mean and maximum Absolute Standardized Mean Difference (ASMD) as a test of balance between a synthetic control unit and treated unit, and provide guidance on what constitutes a poor fit when using a synthetic control. We explore (...) and compare other potential metrics using a simulation study. We provide an application of our proposed balance metric to the 2013 Los Angeles (LA) Firearm Study [9]. Using Uniform Crime Report data, we apply the SCM to obtain a counterfactual for the LA firearm-related crime rate based on a weighted combination of control units in a donor pool of cities. We use this counterfactual to estimate the effect of the LA Firearm Study intervention and explore the impact of changing the donor pool and pre-intervention duration period on resulting matches and estimated effects. We demonstrate how decision-making about the quality of a synthetic control can be improved by using ASMD. The mean and max ASMD clearly differentiate between poor matches and good matches. Researchers need better guidance on what is a meaningful imbalance between synthetic control and treated groups. In addition to the use of gap plots, the proposed balance metric can provide an objective way of determining fit. (shrink)