Prospective Validation of Molecular Subtype Diagnostics for Autism Spectrum Disorders and Neurodevelopmental Disorders

Background:

Autism is a complex neurodevelopment disorder with underlying genetic, metabolic, and environmental factors leading to individual differences in clinical presentation and response to therapies. Earlier diagnosis of children with autism spectrum disorder (ASD) improves outcomes through the early initiation of therapeutic interventions. Based on previous metabolic profiling of ASD in three clinical studies involving more than 500 subjects, we postulated that metabolites can define subpopulations or metabolic subtypes of ASD. These subtypes could then be used to stratify the ASD population based on metabolic differences. Initial analysis of metabolomic data were used to design the Children’s Autism Metabolome Project (CAMP, ClinicalTrials.gov Identifier NCT02548442); the largest metabolomics study of autism conducted to date. CAMP has enrolled over 1,000 pediatric subjects, carried out metabolomic analyses of donated, fasting blood samples and is validating subtypes prospectively providing potentially actionable results. Metabolic subtypes have the potential to identify subjects that may benefit from specific dietary and pharmacological interventions.

Objectives:

The objective of this study is to prospectively validate metabolite-based diagnostics for neurodevelopmental disorders (ND), ASD and developmental delay (DD) where each subtype diagnostic identifies a subpopulation with high specificity. Evaluate the clinical performance of each diagnostic by testing plasma samples from subjects in the CAMP study consisting of ASD, DD and typically developing (TD) subjects.

Methods:

The CAMP study is being conducted at 8 locations. Diagnosis is based on Diagnostic and Statistical Manual of Mental Disorders (DSM-5) confirmed by research reliable Autism Diagnostic Observation Schedule (ADOS) for ASD and the Mullen scales of early learning for DD. Samples from 368 subjects (242 ASD, 40 DD, 87 TD) aged from 18 to 48 months were selected to set thresholds for each subtype diagnostic. Plasma from these subjects was analyzed using a quantitative assay for a panel of amine containing metabolites and these measurements were used to set thresholds for each subtype diagnostic. A second set of approximately 350 subjects that had not been previously measured were analyzed using the same quantitative method to determine the clinical performance of each subtype diagnostic.

Results:

Thresholds were set for five molecular subtype diagnostics for ASD or DD. Thresholds were also set for a subtype diagnostic for the diagnosis of ASD. A prospective analysis of 368 children aged from 18 to 48 months is underway and will be completed at the time of this presentation. We expect to validate several molecular subtypes of ND with a combined sensitivity exceeding 20% and a specificity of greater than 90%.

Conclusions:

The CAMP study provides the largest set of samples collected under procedures designed for the investigation of metabolic differences associated with NDs such as ASD and developmental delay (DD). This report focuses on the validation of a collection of molecular subtype diagnostics which reliably identify ASD and DD children in a prospective analysis. Each molecular subtype suggests altered levels of metabolites or an imbalance of metabolites which suggests possible interventions to improve outcomes.