In Search of Biomarkers for Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) lacks validated measures of core social functions across development stages suitable for clinical trials. We assessed the concurrent validity between ASD clinical measures and putative biomarkers of core deficits, and their feasibility of implementation in human studies. Datasets from two adult ASD studies were combined (observational study [n = 19] and interventional study baseline data [n = 19]). Potential biomarkers included eye‐tracking, olfaction, and auditory and visual emotion recognition assessed via the Affective Speech Recognition test (ASR) and Reading‐the‐Mind‐in‐the‐Eyes Test (RMET). Current functioning was assessed with intelligence quotient (IQ), adaptive skill testing, and behavioral ratings. Autism severity was determined by the Autism Diagnostic Observation Scale‐2 and Social Communication Interaction Test (SCIT). Exploratory measures showed varying significant associations across ASD severity, adaptive skills, and behavior. Eye tracking endpoints showed little relationship to adaptive ability but correlated with severity and behavior. ASR scores significantly correlated with most adaptive behavior domains, as well as severity. Olfaction predicted visual and auditory emotion recognition. SCIT scores related moderately to multiple severity domains, and was the only measure not related with IQ. RMET accuracy was less related to ASD features. Eye tracking, SCIT, and ASR showed high test–retest reliability. We documented associations of proximal biomarkers of social functioning with multiple ASD dimensions. With the exception of SCIT, most correlations were modest, limiting utility as proxy measures of social communication. Feasibility and reliability were high for eye‐tracking, ASR, and SCIT. Overall, several novel experimental paradigms showed potential as social biomarkers or surrogate markers in ASD. Autism Research 2018, 11: 1567–1579. © 2018 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc.Lay SummaryMore accurate measurements of treatment effects are needed to help the development of new drug treatments for autism spectrum disorders (ASD). This study evaluates the relationship between assessments designed to measure behaviors associated with social communication and cognition in ASD with clinical and diagnostic assessments of symptom severity as well as their implementation. The assessments including eye‐tracking, auditory and visual social stimuli recognition, and olfaction identification showed potential for use in the evaluation of treatments for social difficulties in ASD.

Exploring Social Biomarkers in High-Functioning Adults with Autism and Asperger’s Versus Healthy Controls: A Cross-Sectional Analysis

“…This contrasts with results of many previous studies in younger subjects which showed that the best predictor of autism was reduced eye region fixation time Klin et al 2002). Moreover, despite the association found between looking at the mouth and social communication skills (Del Valle Rubido et al 2018), there was no difference in fixation in the mouth between groups.…”

“…In the assessment of concurrent validity of this study, we observed that reduced olfaction was associated with worse emotion recognition ability on both RMET (r = 0.54) and ASR (r = 0.40), possibly indicating greater impairments in their TOM capacity, as well as communication deficits in the ADOS communication domain (r = − 0.34) and in the inappropriate speech subscale of the ABC (r = − 0.32). Olfaction identification also correlated with the VIQ (r = 0.47) and FSIQ (r = 0.40) (Del Valle Rubido et al 2018 ). These subanalyses did not control for differences in IQ, thus, the contribution of IQ differences to these associations is unknown.…”

“…In our correlation analysis of these measures, pupillometry was mostly unrelated to ASD severity and core social deficits, except for the biomotion task that correlated with the ADOS total score (r = − 0.33) and the communication subdomain of the Vineland (r = 0.36). However, larger pupil size was consistently related to lower behavioral ratings of hyperactivity on the ABC (r values ranging from − 0.36 to − 0.43) and higher FSIQ (ranging from 0.38 to 0.45) and PIQ scores (ranging from 0.36 to 0.44) while the VIQ remained unrelated (Del Valle Rubido et al 2018 ). Thus, in ASD, better functioning is associated with larger pupil sizes.…”

“…A companion manuscript describing the assessment of the concurrent validity of these exploratory assessments and the feasibility of implementation in a clinical study has recently been published (Del Valle Rubido et al 2018 ) and helps to contextualize the findings of the present work. These exploratory measures showed varying associations across ASD severity, adaptive skills, and behavior, suggesting that each of the exploratory measures examined have the sensitivity to capture information that individually informs aspects of social functioning, but they appear to largely tap into functional differences that are at least partially independent.…”

Biomarker Acquisition and Quality Control for Multi-Site Studies: The Autism Biomarkers Consortium for Clinical Trials

“…The ABC-CT ET included nine paradigms in Feasibility, reduced to five in the Main Study: (1) activity monitoring, which includes both static images and dynamic videos of two adult actors playing with children's toys while gazing at each other or at their shared activity (Shic et al, 2011;Umbricht et al, 2017;Del Valle Rubido et al, 2018). (2) Biological motion preference, where two point-light displays are shown on either side of the screen, one displaying biological motion and one displaying a control condition of rotating or scrambled dots (Annaz et al, 2011;Umbricht et al, 2017;Del Valle Rubido et al, 2018). (3) Pupillary light reflex, in which a dark screen with a small fixation animation at the center is shown, then replaced briefly by a white screen, followed by the same dark screen with animation (Nyström et al, 2015).…”