Figure 1

Expected and observed Social Responsiveness Scale (SRS) scores in multiplex AGRE families. Children in multiplex families are assumed to have inherited a high degree of ASD risk. Under a threshold model, a quantitative measure of ASD severity, such as the SRS, would be expected to follow a normal distribution with unaffected individuals at the lower end. (A) The observed SRS scores for 927 male children (95 unaffected in blue, 832 affected in red) with each bar showing the sum of the number of unaffected and affected males. The black line shows the kernel density of the data, which approximates a normal distribution. (B) The corresponding plot is shown for 394 female children (151 unaffected, 243 affected). The SRS scores produce a bimodal distribution, as noted previously [22,23]. (C) To assess the expected distribution under quantitative trait model, we estimated the mean and standard deviation of the male observed data ‘A’ and used these characteristics to simulate a normal distribution for the same number of individuals. The scores were sorted, and a threshold for affected status was chosen to give the same number of affected and unaffected males as in ‘A’. Each bar shows the sum of the number of unaffected and affected simulated males, while the black line shows the kernel density. (D) The expected distribution under quantitative trait model is shown using the same method as in ‘C’ but for 394 females based on the female data in ‘B’. The expected distribution differs markedly from the observed in females, but not in males. (E) If multiple factors contribute to the presence of the FPE, then their combined effect is likely to produce a unimodal distribution. (F) As the number of factors contributing to the presence of the FPE decreases, the unimodal distribution in ‘E’ develops distinct distributions based on the number of factors present. (G) If only one factor contributes, then a bimodal distribution should be observed. (H) Finally, if there are no factors and the FPE is universally present in females, a unimodal distribution will arise based on the distribution of risk rather than protection.