Observational Study

. 2022 Mar 21;13(1):15.

doi: 10.1186/s13229-021-00482-2.

The autism biomarkers consortium for clinical trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials

Frederick Shic^{1

2}, Adam J Naples³, Erin C Barney^{4

3}, Shou An Chang⁵, Beibin Li^{4

6}, Takumi McAllister³, Minah Kim⁷, Kelsey J Dommer⁴, Simone Hasselmo³, Adham Atyabi^{4

8

9}, Quan Wang³, Gerhard Helleman¹⁰, April R Levin^{11

12}, Helen Seow³, Raphael Bernier¹³, Katarzyna Charwaska³, Geraldine Dawson¹⁴, James Dziura¹⁵, Susan Faja^{12

16}, Shafali Spurling Jeste¹⁷, Scott P Johnson¹⁸, Michael Murias¹⁹, Charles A Nelson^{12

16

20}, Maura Sabatos-DeVito¹⁴, Damla Senturk²¹, Catherine A Sugar^{21

17}, Sara J Webb^{4

13}, James C McPartland²²

Affiliations

¹ Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, 1920 Terry Ave, Seattle, WA, 98101, USA. fshic@uw.edu.
² Department of General Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. fshic@uw.edu.
³ Yale Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA.
⁴ Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, 1920 Terry Ave, Seattle, WA, 98101, USA.
⁵ Department of Psychology, Yale University, 2 Hillhouse Ave, New Haven, CT, 06520, USA.
⁶ Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA.
⁷ Department of Psychology, University of Virginia, 102 Gilmer Hall, P.O. Box 400400, Charlottesville, VA, 22904, USA.
⁸ Department of General Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
⁹ Department of Computer Science, University of Colorado - Colorado Springs, Colorado Springs, CO, USA.
¹⁰ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
¹¹ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
¹² Harvard Medical School, Boston, MA, USA.
¹³ Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, USA.
¹⁴ Duke Center for Autism and Brain Development, Duke University, Durham, NC, USA.
¹⁵ Emergency Medicine, Yale University School of Medicine, New Haven, CT, USA.
¹⁶ Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
¹⁷ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹⁸ Department of Psychology, University of California Los Angeles, Los Angeles, CA, USA.
¹⁹ Institute for Innovations in Developmental Sciences, Northwestern University, Chicago, IL, USA.
²⁰ Graduate School of Education, Harvard University, Boston, MA, USA.
²¹ Department of Biostatistics, University of California Los Angeles, Los Angeles, CA, USA.
²² Yale Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA. james.mcpartland@yale.edu.

PMID: 35313957
PMCID: PMC10124777
DOI: 10.1186/s13229-021-00482-2

Observational Study

The autism biomarkers consortium for clinical trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials

Frederick Shic et al. Mol Autism. 2022.

. 2022 Mar 21;13(1):15.

doi: 10.1186/s13229-021-00482-2.

Authors

Affiliations

¹ Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, 1920 Terry Ave, Seattle, WA, 98101, USA. fshic@uw.edu.
² Department of General Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. fshic@uw.edu.
³ Yale Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA.
⁴ Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, 1920 Terry Ave, Seattle, WA, 98101, USA.
⁵ Department of Psychology, Yale University, 2 Hillhouse Ave, New Haven, CT, 06520, USA.
⁶ Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA.
⁷ Department of Psychology, University of Virginia, 102 Gilmer Hall, P.O. Box 400400, Charlottesville, VA, 22904, USA.
⁸ Department of General Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
⁹ Department of Computer Science, University of Colorado - Colorado Springs, Colorado Springs, CO, USA.
¹⁰ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
¹¹ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
¹² Harvard Medical School, Boston, MA, USA.
¹³ Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, USA.
¹⁴ Duke Center for Autism and Brain Development, Duke University, Durham, NC, USA.
¹⁵ Emergency Medicine, Yale University School of Medicine, New Haven, CT, USA.
¹⁶ Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
¹⁷ Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹⁸ Department of Psychology, University of California Los Angeles, Los Angeles, CA, USA.
¹⁹ Institute for Innovations in Developmental Sciences, Northwestern University, Chicago, IL, USA.
²⁰ Graduate School of Education, Harvard University, Boston, MA, USA.
²¹ Department of Biostatistics, University of California Los Angeles, Los Angeles, CA, USA.
²² Yale Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA. james.mcpartland@yale.edu.

PMID: 35313957
PMCID: PMC10124777
DOI: 10.1186/s13229-021-00482-2

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.

Trial registration: ClinicalTrials.gov NCT02996669.

Keywords: Autism spectrum disorder; Biological motion; Biomarkers; Eye tracking; Face processing; Gaze pattern; Visual attention.

PubMed Disclaimer

Conflict of interest statement

The authors AJN, ECB, SAC, BL, TM, MK, KD, SH, AA, QW, GH, ARL, HS, RB, KC, JD, SF, SSJ, SPJ, MM, CAN, MS, DS, CAS, and SJW declare that they have no competing interests. James C. McPartland consults with Customer Value Partners, Bridgebio, Determined Health, and BlackThorn Therapeutics, has received research funding from Janssen Research and Development, serves on the Scientific Advisory Boards of Pastorus and Modern Clinics, and receives royalties from Guilford Press, Lambert, and Springer. He has stock interests in Modern Clinics. Dr. Dawson is on the Scientific Advisory Boards of Janssen Research and Development, Akili Interactive, Inc, LabCorp, Inc, Roche Pharmaceutical Company, and Tris Pharma, and is a consultant to Apple, Gerson Lehrman Group, Guidepoint Global, Inc, and is CEO of DASIO, LLC. Dr. Dawson has stock interests in Neuvana, Inc. Frederick Shic consults for Roche Pharmaceutical Company, Janssen Research and Development, BlackThorn Therapeutics, and BioStream Technologies. Sara J. Webb consults for Janssen Research and Development. No company contributed to funding of this study. A representative from Janssen served on the FNIH Biomarkers Consortium Project Team and provided in kind support in terms of sharing experiences and preliminary results of the JAKE study.

Figures

**Fig. 1**
Experimental Tasks. (*Top row*) Tasks comprising the Oculomotor Index of Gaze to Human Faces (OMI): ActivityMonitoring (AM, videos depicting two actors engaged in a shared activity), SocialInteractive Scenes (SI, videos depicting two children involved in interactive and parallel play activities), and StaticScenes (SS, Social Static Scene images showing everyday scenes involving social interactions). (*Bottom row*) Biomotion (BM, Biological Motion preferential looking videos with point-light displays of human actions paired with non-human control conditions. Lines in human figure added for illustrative purposes only), and Pupillary Light Reflex task (PLR, images depict frames in the video sequence including the bright screen flash)

**Fig. 2**
A Six-week stability (T1 to T2) in the ASD group; B T1 ASD vs. TD boxplots; and C T1 ASD versus TD histograms for Oculomotor Index of Gaze to Human Faces (OMI), Biomotion (BM) %Bio, and PLR Latency Biomarkers. Diagonal line in stability charts is identity (slope = 1). See Supplemental Figures S2-S3 for additional biomarkers

**Fig. 3**
Oculomotor Index of Gaze to Human Faces (OMI) relationships with child characteristics in the ASD group at T1. Spearman’s Correlation Coefficient and p value reported

See this image and copyright information in PMC

References

1. American Psychiatric Association . Diagnostic and statistical manual of mental disorders: DSM-5. Arlington: American Psychiatric Association; 2013.
1. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and Other Tools) Resource. Silver Spring (MD): Food and Drug Administration (US). Retrieved September 28, 2017 (2016). http://www.ncbi.nlm.nih.gov/books/NBK326791/ - PubMed
1. Insel TR. The NIMH research domain criteria (RDoC) project: precision medicine for psychiatry. Am J Psychiatry. 2014;171:395–397. - PubMed
1. Shen L, Zhao Y, Zhang H, Feng C, Gao Y, Zhao D, et al. Advances in biomarker studies in autism spectrum disorders. In: Guest PC, et al., editors. Reviews on biomarker studies in psychiatric and neurodegenerative disorders. Cham: Springer International Publishing; 2019. pp. 207–233. - PubMed
1. McPartland JC. Refining biomarker evaluation in ASD. Eur Neuropsychopharmacol. 2021;48:34–36. - PMC - PubMed

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The autism biomarkers consortium for clinical trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials

Affiliations

The autism biomarkers consortium for clinical trials: evaluation of a battery of candidate eye-tracking biomarkers for use in autism clinical trials

Authors

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Abstract

Conflict of interest statement

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