RT Journal Article SR Electronic T1 New mutations, old statistical challenges JF bioRxiv FD Cold Spring Harbor Laboratory SP 115964 DO 10.1101/115964 A1 Jeffrey C. Barrett A1 Joseph D. Buxbaum A1 David J. Cutler A1 Mark J. Daly A1 Bernie Devlin A1 Jacob Gratten A1 Matthew E. Hurles A1 Jack A. Kosmicki A1 Eric S. Lander A1 Daniel G. MacArthur A1 Benjamin M. Neale A1 Kathryn Roeder A1 Peter M. Visscher A1 Naomi R. Wray YR 2017 UL http://biorxiv.org/content/early/2017/03/12/115964.abstract AB Based on targeted sequencing of 208 genes in 11,730 neurodevelopmental disorder cases, Stessman et al. report the identification of 91 genes associated (at a False Discovery Rate [FDR] of 0.1) with autism spectrum disorders (ASD), intellectual disability (ID), and developmental delay (DD)—including what they characterize as 38 novel genes, not previously reported as connected with these diseases1.If true, this would represent a substantial step forward. Unfortunately, each of the two discovery analyses (1. De novo mutation analysis and, 2. a comparison of private mutations with public control data) contain critical statistical flaws. When one accounts for these problems, fewer than half of the genes--and very few, if any, of the novel findings--survive. These errors have implications for how future analyses should be conducted, for understanding the genetic basis of these disorders, and for genomic medicine.We discuss the two main analyses in turn and provide more detailed treatment of the issues in a supplementary technical note.