The Autism Biomarkers Consortium for Clinical Trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials

Abstract

Background Eye tracking (ET) is a powerful methodology for studying attentional processes through quantification of eye movements. The precision, usability, and cost-effectiveness of ET render it a promising platform for developing biomarkers for use in clinical trials for autism spectrum disorder (ASD). Methods The autism biomarkers consortium for clinical trials conducted a multisite, observational study of 6–11-year-old children with ASD (n = 280) and typical development (TD, n = 119). The ET battery included: Activity Monitoring, Social Interactive, Static Social Scenes, Biological Motion Preference, and Pupillary Light Reflex tasks. A priori, gaze to faces in Activity Monitoring, Social Interactive, and Static Social Scenes tasks were aggregated into an Oculomotor Index of Gaze to Human Faces (OMI) as the primary outcome measure. This work reports on fundamental biomarker properties (data acquisition rates, construct validity, six-week stability, group discrimination, and clinical relationships) derived from these assays that serve as a base for subsequent development of clinical trial biomarker applications. Results All tasks exhibited excellent acquisition rates, met expectations for construct validity, had moderate or high six-week stabilities, and highlighted subsets of the ASD group with distinct biomarker performance. Within ASD, higher OMI was associated with increased memory for faces, decreased autism symptom severity, and higher verbal IQ and pragmatic communication skills. Limitations No specific interventions were administered in this study, limiting information about how ET biomarkers track or predict outcomes in response to treatment. This study did not consider co-occurrence of psychiatric conditions nor specificity in comparison with non-ASD special populations, therefore limiting our understanding of the applicability of outcomes to specific clinical contexts-of-use. Research-grade protocols and equipment were used; further studies are needed to explore deployment in less standardized contexts. Conclusions All ET tasks met expectations regarding biomarker properties, with strongest performance for tasks associated with attention to human faces and weakest performance associated with biological motion preference. Based on these data, the OMI has been accepted to the FDA’s Biomarker Qualification program, providing a path for advancing efforts to develop biomarkers for use in clinical trials.

Treatment biomarkers for ADHD: Taking stock and moving forward

“…The field needs to move towards systematic replication and out-of-sample validation of promising biomarker findings in larger samples, which will be essential to guarantee that the validity of biomarkers will generalize to individuals in clinical settings in the future. This is likely to require collaborative, multi-site recruitment efforts, following examples set by biomarker research on other neurodevelopmental and psychiatric disorders [ 127 , 128 ].…”

Modern Biomarkers for Autism Spectrum Disorder: Future Directions

“…Other studies suggest this abnormality may be related to social skills and facial memory when comparing upright versus inverted stimuli [63] and may be specific to attending to the eyes as opposed to the nose or mouth [64]. Promising results from the Autism Biomarker Consortium for Clinical Trials (ABC-CT), a large multi-site study led by the Yale Child Study Center has leading to the acceptance of N170 latency to upright human faces as an identifier of biological subgroups of ASD into the US Food and Drug Administration's Biomarker Qualification Program [65].…”

Heterogeneity thwarts autism explanatory power: A proposal for endophenotypes

“…Introduction: Heterogeneity thwarts autism explanatory power: Can transdiagnostic behavioral endophenotypes help? patterns, comorbidities, and biomarkers (3)(4)(5)(6)(7). Casanova et al (8) asserted that, "The diagnostic boundaries of the behavioral phenotype that define ASD are fairly broad due to the large variability that is observed in symptom types, onset, and severity.…”

“…The efforts for reducing autism heterogeneity-creating prototypical autism, excluding moderate-to-severe autism symptoms, creating subgroups, and increasing sample sizes-have not yet been effective in reducing heterogeneity. Thus, heterogeneity remains an unresolved problem (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Moreover, as discussed previously, establishing the unitary DSM-5 ASD diagnosis has not reduced autism heterogeneity.…”

“…However, because autism heterogeneity is so extensive, if the Lancet Commission Report's goal is finding behavioral treatments for each of the heterogenous “manifestations of autism” then hundreds of studies will be needed to discover unique behavioral treatments for each manifestation of autism. Moreover, Shic et al ( 4 ) noted that “Progress in developing interventions for ASD has been hindered by a lack of measures that can, within this heterogeneity, provide objective quantification of intrinsic features of ASD with sensitivity, reliability, and mechanistic relationship to core symptoms” (p. 2).…”