Combination of Predictive Biomarkers to Increase Diagnostics Efficiency of Autism Spectrum Disorder

Study Overview
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Brief Summary
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Early identification and diagnosis of autism spectrum disorder (ASD) is necessary to promote access to early treatment. Despite the high incidence, in Italy it is estimated that 1 in 77 children (age 7-9 years) (Narzisi et al., 2018), the diagnosis and the choice of rehabilitation treatment for patients with Autism Spectrum Disorder (ASD) are still based on clinical observation. In the absence of targeted pharmacological therapies, early surveillance and evaluation aimed at timely intervention represent the only successful strategy to reduce the severity of symptoms (Palomo R et al., 2006) and improve the quality of life of children affected by ASD and their families, thus also leading to a reduction in costs for the National Health Service (Ganz ML. 2007). However, compared to the great advances in neuroscience, the clinical management of autistic individuals is seriously lagging behind, and the disorder is often diagnosed after 3-4 years of age despite the presence of deficits starting from the very first months of life (Zwaigenbaum L et al. al., 2013). The aim of this project is to bridge the gap between research and clinic, thanks to the convergence of multiple biological and clinical data.

Detailed Description
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The purpose of this project is to combine multiple biological levels of information and their matching with the clinical phenotype and personal/family anamnesis of the single individual. In fact, by stratifying multiple levels of biomarkers, including behavioral (eye tracking), clinical and neuropsychological variables, parameters taken from transcriptomics (RNAseq), the goal is to identify a panel of intermediate biomarkers capable of (a) distinguishing autistic subjects from typically developing brothers/sisters, (b) to distinguish autistic subjects from typically developing subjects, (c) to stratify autistic patients into a limited number of homogeneous subgroups by physiopathology, in order to allow personalized pharmacology and improve their management clinic.

Official Title
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Mind the Gap: a Bridge Between Research and Clinic for the Prevention and Diagnosis of Autism Spectrum Disorders

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Diagnostic Test: Salivary collection
* Diagnostic Test: eye-tracking recorder
* Diagnostic Test: neuropsychological assessment


Participation Criteria
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Eligibility Criteria
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Autistic Spectrum Disorder patients, Inclusion Criteria: aged between 4 and 17years; Autism Spectrum Disorder diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria; healthy brothers/sisters, aged 4 to 17 years; adequate ocular vision, i.e. absence of objective eye problems such as double vision, cataracts, etc.; ability to maintain position in front of the monitor, i.e. knowing how to maintain or regain posture independently or with the help of postural aids; cognitive skills appropriate to the task such as being able to recognize images. ASD siblings and Typical Developmental children, Inclusion Criteria aged between 4 and 17years; typical development, absence of known pathologies; adequate ocular vision, i.e. absence of objective eye problems such as double vision, cataracts, etc.; ability to maintain position in front of the monitor, i.e. knowing how to maintain or regain posture independently or with the help of postural aids; cognitive skills appropriate to the task such as being able to recognize images. Autistic Spectrum Disorder patients, Exclusion Criteria: age not between 4 years and 17 years; difficulty in controlling ocular motility and visual hookup; unavailability of at least one sibling to participate in the diagnostic process; subjects with a syndromic phenotype or for which the presence of a known genetic syndrome has already been ascertained (e.g. Syndrome Rett, Xfra, Tuberous Sclerosis, etc.). ASD siblings and Typical Developmental children, Exclusion Criteria: age not between 4 years and 17 years; subjects diagnosed with moderate/severe intellectual disability, or affected by known neurological pathologies (infantile cerebral palsy, epilepsy, sensory deficits) or with a history of preterm birth (≤32w) or underweight (≤10°ile for gestational age); subjects with a syndromic phenotype or for which the presence of a known genetic syndrome has already been ascertained (e.g. Syndrome Rett, Xfra, Tuberous Sclerosis, etc.); difficulty in controlling ocular motility and visual hookup; subjects suffering from neurodevelopmental disorders or family history for ASD for the control group.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Autism Spectrum Disorder Patients<br>This group is comprised of 3-17 years children with an expert clinical diagnosis of autism spectrum disorders. | Diagnostic Test: Salivary collection<br>* Collection of saliva via swab for miRNA processing<br>Diagnostic Test: eye-tracking recorder<br>* Administration of eye-tracking session recording Saccadic Eye Movements, fixation duration and pupillary response.<br>Diagnostic Test: neuropsychological assessment<br>* Administration of neuropsychological tests and collected patient medical history<br>|
| Siblings of children with Autism Spectrum Disorders<br>This group is comprised of 3-17 years old siblings, with typical development, of a child with an expert clinical diagnosis of autism spectrum disorders. | Diagnostic Test: Salivary collection<br>* Collection of saliva via swab for miRNA processing<br>Diagnostic Test: eye-tracking recorder<br>* Administration of eye-tracking session recording Saccadic Eye Movements, fixation duration and pupillary response.<br>|
| Typical Development children<br>This group is comprised of 3-17 years children with typical development. | Diagnostic Test: Salivary collection<br>* Collection of saliva via swab for miRNA processing<br>Diagnostic Test: eye-tracking recorder<br>* Administration of eye-tracking session recording Saccadic Eye Movements, fixation duration and pupillary response.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Salivary miRNA profile | Measures of salivary miRNA profile - identify the microRNAs differentially expressed in patients with autism spectrum disorder compared to sibling and healthy controls. | At time of enrollment | 
| eye-gaze path characteristics - Saccadic Eye Movements | Saccadic eye movement assessments measure the speed and accuracy of a participant's saccadic eye movements in response to various stimuli. | At time of enrollment | 
| eye-gaze path characteristics - fixation time | Total fixation duration measurements in pre-selected areas (areas of interest) | At time of enrollment | 
| eye-gaze path characteristics - pupillary response | pupillary response measurements assess the changes of mean pupil diameters for the left and right eyes after exposition to pre-selected immages (areas of interest) | At time of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Autism Diagnostic Observation Schedule 2 (ASD patients only) | Ados2 is a semi-structured, standardised assessment to measure autistic behaviors. | At time of enrollment | 
| Vineland Adaptive Behavior Scales (VABS) II (ASD patients only) | The VABS II is a standardized semi-structured interview to measure adaptive behavior. | At time of enrollment | 
| Intellectual Quotient (ASD patients only) | Intellectual quotient measured using one cognitive test per subject, chosen depending on age and language development (either Griffiths Developmental Rating Scales, Wechsler Intelligence Scale for Children - Fourth Edition, or Leiter III). | At time of enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism, miRNA, Eye Tracker, biomarkers