Evaluating the Validity of an Eye Gaze Paradigm in Predicting Autism Spectrum Disorder

The current study will occur in four phases: pilot testing, development, validation, and
re-test. In each phase, participants will view a visual attention stimulus with social
elements (social attention paradigm) while eye tracking measurements are remotely acquired.
The visual attention paradigm will be refined in the pilot testing but will remain the same
for development, validation, and re-test phases. The entire process, including calibration
and viewing of the visual paradigm, will take about 15 minutes. The text below describes
each phase in detail and the reviews specific methodology for the social attention paradigm
and eye tracking procedures.

1. Pilot Phase. Pilot testing of the social attention paradigm used to elicit eye gaze
measurements to ensure they are sufficiently engaging across the ages of children
participating. The visual attention paradigm during this phase is expected to be 10-12
minutes. This phase will also be used to determine optimal strategies for maintaining
attention throughout the testing period. Initial data may also provide some insights
into the most discriminating stimulus elements to include in future phases.
Investigators anticipate recruiting approximately 10 ASD and 10 non-ASD participants in
this phase. The pilot phase is expected to require 2.5 months of recruitment and 0.5
months of data reduction and analysis.

2. Development Phase. Once pilot testing is completed, 30 ASD-affected and 30 non-ASD
children ages 1.5 to 18 will be recruited. Each child will complete the social
attention paradigm while their eye gaze is remotely tracked. Eye gaze data is then
scored for more than 100 parameters and these scores are entered into a database that
includes diagnostic and cognitive information about each participant. The eye tracking
data is then analyzed to create the diagnostic and prognostic algorithms that will
refine the system's diagnostic sensitivity and specificity in the ASD population. The
development period will require 6 months of data collection, followed by 3 months of
scoring and algorithm computation.

3. Validation Phase. Collection of the validation sample will include 60 ASD-affected and
60 non-ASD affected children ages 1.5-18. The validation phase will use the same visual
social attention paradigm and methods used in the development sample. The validation
period will overlap algorithm development and require 8 months of data collection and 1
month of analysis.

4. Re-Test Phase. Participants in the re-test phase will include 30 ASD and 30 non-ASD
children recruited in the first half of the validation phase. These participants will
be explained in the validation phase that investigators will be re-recruiting them for
the re-test phase approximately 3-6 months following their initial testing during the
validation phase.

The target sample size varies depending on the phase of the study. Below are the target
sample sizes for each phase:

Pilot Phase = 10 ASD and 10 Non-ASD Development Phase = 30 ASD and 30 Non-ASD Validation
Phase = 60 ASD and 60 Non-ASD Re-Test Phase = 30 ASD and 30 Non-ASD (from the validation
phase) The study population is individuals with autism spectrum disorder, or a clinical
diagnosis of another developmental or psychiatric disorder (developmental/psychiatric
controls), or have no specific developmental or psychiatric diagnosis (healthy controls),
ages 1.5 (18 months) to 18 (120 months) at time of consent.

Eye gaze data will be collected using a remote eye tracker from Sensori-motoric instruments
(SMI). Remote eye tracking offers minimal invasiveness to the viewer's field of view and
collects time-stamped, 3D eye position, and binocular gaze and pupil data at a sampling rate
of 120 Hz. Eye gaze capture is automatically calibrated to 2/5/9 points and provides
position accuracy to 0.5° at a 60cm viewing distance. Gaze tracking data, screen recordings,
user events, and gaze position will be recorded simultaneously. Data will be analyzed with
emphasis on areas-of- interest and dwell time on specific targets on a second-by-second
basis. Examples of the types of measures captured include: dwell time to any area of the
stimulus, dwell time to the face and non-face regions of a human form on the video, fixation
shifts between stimuli.

Additional tests and demographic data will be collected from standard of care autism
diagnostic and behavioral health diagnostic appointments that can be found in the medical
record.

Pilot Analyses. In the pilot phase, investigators will compute the effect size (Cohen's d)
between ASD and non-ASD participants for each of the eye gaze parameters acquired for each
of the individual stimuli in the social attention paradigm. Stimulus elements eliciting the
largest discrimination between ASD and non-ASD patients will be retained in the development
phase.

ASD Diagnostic Algorithm Analyses. In the development phase, all of the eye gaze
measurements acquired from the social attention paradigm will be included as predictor
variables in a random forest analysis. This analysis permits evaluation of the
discriminative ability of a large number of variables in data sets with a modest number of
cases. The variables with highest importance scores, indicating good diagnostic
discrimination, will be entered into a logistic regression analysis with ASD diagnostic
status (ASD vs. non-ASD) as the dichotomous dependent variable. Significant predictors will
be retained and coefficients from the retained predictors will serve as the diagnostic
algorithm.

The diagnostic algorithm scores will then be submitted to Receiver Operating Characteristic
(ROC) curve analyses to provide detailed evaluation of sensitivity and specificity of the
algorithm in the detection of ASD. Areas under the curve of >.90 are expected, indicating
strong diagnostic validity.

Prognostic Algorithm Analyses. To identify a prognostic algorithm, a similar process will be
conducted with all the available eye tracking measurements as predictors and non-verbal
cognitive ability scores (dichotomized at <70 and 70 and above) as the dependent variable in
random forest analyses. Non-verbal cognitive ability scores will be dichotomized based on
previous data suggesting that individuals with ASD and intellectual disability show worse
outcome. The predictor variables with highest importance, indicating good diagnostic
discrimination, will then be entered into a logistic regression analysis with non-verbal
cognitive ability (<70, >=70) as the dichotomous dependent variable. Significant predictors
will be retained and coefficients from the retained predictors will serve as the prognostic
algorithm. The prognostic algorithm scores will then be submitted to Receiver Operating
Characteristic (ROC) curve analyses to provide detailed evaluation of sensitivity and
specificity of the algorithm in the detection of non-verbal cognitive disability. Areas
under the curve of >.80 are expected, indicating good validity in predicting cognitive
disability. Non-verbal cognitive ability will be the primary focus of these analyses because
of its documented relationship with outcome in individuals with autism. However, similar
analyses will be computed for verbal cognitive ability and adaptive function scores.
Investigators will also conduct the above analyses using continuous measurements as
dichotomization may unnecessarily deflate validity.

Treatment Tracking Algorithm Analyses. To identify a treatment tracking algorithm,
investigators will simply combine the eye tracking measurements identified in the diagnostic
and prognostic algorithm into a single treatment tracking algorithm. To evaluate test
re-test reliability of these measurements investigators will use intra-class correlation
coefficients (model 2 - absolute agreement).

Inclusion Criteria:

- Clinical diagnosis of Autism Spectrum Disorder (299.0) following evaluation in
Cleveland Clinic Center for Autism Diagnostic Clinic, or a clinical diagnosis of
another developmental or psychiatric disorder, or have no specific developmental or
psychiatric diagnosis.

- Age 1.5 to 18 years at time of consent.

Exclusion Criteria:

- Individuals whom, with corrective lenses are still legally blind.

- Individuals whom, it is determined at the discretion of hte Primary Investigator,
after consultation with the evaluating psychologist in the Center for Autism
Diagnostic Clinic, are not able to sufficiently attend to the stimulus presentation
or have substantial challenging behaviors that would prohibit participation.