Abstract
Clinical diagnosis of autism spectrum disorder (ASD) relies on time-consuming subjective assessments. The primary purpose of this study was to investigate the utility of salivary microRNAs for differentiating children with ASD from peers with typical development (TD) and non-autism developmental delay (DD). The secondary purpose was to explore microRNA patterns among ASD phenotypes. This multicenter, prospective, case-control study enrolled 443 children (2-6 years old). ASD diagnoses were based on DSM-5 criteria. Children with ASD or DD were assessed with the Autism Diagnostic Observation Schedule II and Vineland Adaptive Behavior Scales II. MicroRNAs were measured with high-throughput sequencing. Differential expression of microRNAs was compared among the ASD (n= 187), TD (n= 125), and DD (n= 69) groups in the training set (n= 381). Multivariate logistic regression defined a panel of microRNAs that differentiated children with ASD and those without ASD. The algorithm was tested in a prospectively collected naïve set of 62 samples (ASD, n= 37; TD, n= 8; DD, n= 17). Relations between microRNA levels and ASD phenotypes were explored. Fourteen microRNAs displayed differential expression (false discovery rate< 0.05) among ASD, TD, and DD groups. A panel of 4 microRNAs (controlling for medical/demographic covariates) best differentiated children with ASD from children without ASD in training (area under the curve= 0.725) and validation (area under the curve= 0.694) sets. Eight microRNAs were associated (R > 0.25, false discovery rate< 0.05) with social affect, and 10 microRNAs were associated with restricted/repetitive behavior. Salivary microRNAs are "altered" in children with ASD and associated with levels of ASD behaviors. Salivary microRNA collection is noninvasive, identifying ASD-status with moderate accuracy. A multi-"omic" approach using additional RNA families could improve accuracy, leading to clinical application. A Salivary miRNA Diagnostic Test for Autism; https://clinicaltrials.gov/; NCT02832557.
Highlights
Has been limited by several factors: no miRNA study has used more than 55 participants with autism spectrum disorder (ASD),[21] despite the broad, heterogeneous nature of the disorder; no miRNA study has enrolled children at the ages (2–6 years) when ASD diagnosis first occurs; no miRNA study has compared children with ASD to peers with nonautism developmental delay (DD)—a comparison required to develop a robust diagnostic toolset; and no study has examined the ability of miRNA signatures to differentiate ASD phenotypes, a priority for the autism community
Secondary analyses investigated the mRNA targets for 2 sets of miRNAs: the miRNAs “altered” between ASD, typical development (TD), and DD groups based on initial Kruskal-Wallis testing and the miRNAs associated with ASD features at ADOS testing
A panel of 4 miRNAs that controlled for sex, disordered sleep, attention-deficit/hyperactivity disorder (ADHD), family history (Hx) of ASD, gastrointestinal (GI) disturbance, and chronic medical conditions demonstrated an area under the curve (AUC) of 0.725 in the training set (n 1⁄4 381) using a 100-fold cross-validation (CV) approach
Summary
Clinical diagnosis of autism spectrum disorder (ASD) relies on time-consuming subjective assessments. The clinical applicability of miRNA studies in persons with ASD has been limited by several factors: no miRNA study has used more than 55 participants with ASD,[21] despite the broad, heterogeneous nature of the disorder; no miRNA study has enrolled children at the ages (2–6 years) when ASD diagnosis first occurs (ie, when a diagnostic biomarker panel would have the most clinical utility); no miRNA study has compared children with ASD to peers with nonautism developmental delay (DD)—a comparison required to develop a robust diagnostic toolset; and no study has examined the ability of miRNA signatures to differentiate ASD phenotypes, a priority for the autism community. We hypothesized that characterization of salivary miRNA concentrations in children with ASD, DD, and typical development (TD) would identify a panel of miRNAs with diagnostic potential We posited that these miRNAs would exhibit brain-related targets on functional pathway analyses and display associations with specific autism phenotypes (assessed through standard measures of communication, socialization, and repetitive behavior)
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