Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.

Fig. 1. Correct classification of 6-month-old infants at high familial risk for ASD using functional connectivity MRI

Functional connections were selected as those that showed a correlation with at least one of the 24-month ASD-related behaviors, which included measures of social behavior, language, motor development, and repetitive behavior. The top two principal components of the functional connections that showed a correlation with these behaviors are shown for both ASD (blue) and non-ASD (red) 6-month-old infants. The two participants that were incorrectly classified in the leave-one-out nested cross-validation analysis are circled; these two participants were diagnosed with ASD but were classified as non-ASD. Classification was correct for 96.6% of 6-month-old high-risk infants.

Fig. 2. Differences in functional connectivity in ASD infants versus non-ASD infants

Each panel represents the functional connections that show a relationship to scores on each of the behavioral assessments (see Table 1): CSBS (top), MSEL (middle), and RBS-R (bottom). For each assessment, the functional connections associated with individual measures were combined and projected onto a Talairach brain, with the right hemisphere marked (R). The color and thickness of each connection signify the sign and strength of the t value it represents. Unpaired two-sample t tests were used to test the difference between group means (ASD versus non-ASD) for each functional connection. Red signifies a connection that shows more negative connectivity in the ASD infant group on average, whereas blue signifies more positive connectivity. t values were set to a threshold of P < 0.005 (uncorrected), and the thickness of each bar represents its strength. Coordinates for each sphere are listed in table S1. These calculations are only for visualization and should not be interpreted as differences directly contributing to any individual's classification.