Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation

The number of diagnosed cases of Autism Spectrum Disorders (ASD) has increased dramatically over the last four decades; however, there is still considerable debate regarding the underlying pathophysiology of ASD. This lack of biological knowledge restricts diagnoses to be made based on behavioral observations and psychometric tools. However, physiological measurements should support these behavioral diagnoses in the future in order to enable earlier and more accurate diagnoses. Stepping towards this goal of incorporating biochemical data into ASD diagnosis, this paper analyzes measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enables multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares is used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as severity prediction far exceeds any other approach in this field and is a strong indicator that the metabolites under consideration are strongly correlated with an ASD diagnosis but also that the statistical analysis used here offers tremendous potential for extracting important information from complex biochemical data sets.
Author summary Autism spectrum disorder (ASD) encompasses a family of neurological disorders characterized by limited social interaction and restricted repetitive behaviors. The number of children diagnosed with ASD has grown exponentially over the last four decades and is now estimated to affect ∼1.5% of children. Although ASD is currently diagnosed and treated based solely on psychometric tools, a biochemical view applicable to at least a subset of ASD cases is emerging. Abnormalities in folate-dependent one carbon metabolism and transsulfuration pathways can summarize a large number of observations of genetic and environmental effects that increase ASD predisposition. However, these complex, highly interconnected pathways require more advanced statistical models than the typical univariate models presented in the literature. Therefore, we developed multivariate statistical models that classify participants based on their neurological status and predict adaptive behavior in ASD. We emphasize that these models are cross-validated, helping to ensure that the results will generalize to new samples. The models developed herein have much stronger predictability than any existing approaches from the scientific literature.