Multi-observational Study for the Early Identification of Autism Spectrum Disorder (ASD) and Other Neurodevelopmental Disorders (NDD) in At-risk Populations

NCT06915805 | Recruiting DMC

• 1 other identifier: PNRR-MAD-2022-12376472
• Study Type: observational
• Target: 296
• Locations: 1 country
• Sites: 5

Brief Summary

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects about 78 million people worldwide. Its prevalence and degree of impact on individuals and families place it among disorders of global importance. ASD resulted in 4.31 million (95% UI 2.82-6.23) global Disability-Adjusted Life Years (DALYs) in 2019, equivalent to 0.2% (0.1-0.2) of DALYs and contributed to 3.4% (2.7-4.3) of DALYs for the aggregate of mental disorders. Evidence shows that early and tailored intervention limits the impact of symptomatology and improves the quality of life of people with ASD and other NDDs and their families. Early identification of clinical signs (red flags) is the first step to facilitating prompt referral for an assessment and diagnosis. In many cases, features of ASD/NDDs manifest early in development (first 6-12 months), although the specificity of these signs is still unclear. Three infants' populations are at higher risk for developing ASD/NDDs compared to the general population: siblings of children diagnosed with ASD (18.7%), preterms, and Small for Gestational Age (SGA). In preterm infants, the prevalence of ASD has been estimated as 7% (95% IC, 4-9) and ADHD is diagnosed twice as often (OR: 1.6; 95% CI: 1.3-1.8). Moreover, the risk for developing ASD in SGA has been estimated as 1.17 (95% CI, 1.09-1.24). Setting up a system to monitor infant neurodevelopmental trajectories through a specific experimental and clinical protocol will enable strategic preventive actions. Early detection of ASD/NDDs requires the mainstreaming of child development monitoring into Child Psychiatry Units (CPUs) and Neonatal Intensive Care Units (NICUs) follow-up programs of at-risk infants. Since 2010, the ISS coordinates the Italian Network for early detection of Autism Spectrum Disorders (NIDA Network), actually involving 45 NICUs and 148 CPUs implicated in the diagnosis and treatment of infants at risk for ASD/NDDs in all Italian Regions. Within the NIDA Network, the ISS implemented a clinical protocol for monitoring at-risk infants for ASD/NDDs in the NICUs follow-up and CPUs. However, the implementation of the protocol in the clinical routine practice requires human resources with specific competences in child psychiatry test scoring and motor/vocal/social behavioral analysis. The BABY@NET project will add to 6-to-36 months well-established clinical NIDA protocol, the experimental data collection and analysis of behavioral and neurophysiological/biological features (vocal, motor, social, EEG, genetic/epigenetic, metabolomic, and secretome), in the first 12 months of age, found altered in ASD/NDDs children. The existing IT platform will be improved for collecting research data, audios/videos, tests and providing the telehealth support to those NICUs and CPUs that suffer from shortage of human resources and competences in testing and video scoring of high risk infants. Through statistical analysis of clinical, behavioral, and neurophysiological/biological endpoints, it is possible to identify early risk signals that can significantly anticipate ASD/NDDs diagnoses in at-risk and general populations. The clinical/experimental protocol combined with the digital infrastructure (e-health) will be implemented in NICUs and CPUs throughout the National Health Service (NHS) ensuring the population of at-risk newborns a specialized assessment, the neurodevelopmental surveillance and activation of personalized prevention interventions.

Conditions

Autism Spectrum Disorder (ASD); Neurodevelopmental Disorders

Keywords

Autism Spectrum Disorder; Developmental Disorders; Child; Preterm Births; Small for Gestational Age; Tele-health; Public Health Surveillance; Risk factors; Electroencephalography; Genetics; Epigenomic; Metabolomics; Secretome

Outcome Measures

Primary Outcomes (2)

• Stability and accuracy of the predictive value of each risk index identified at birth, 3-6-12 mo through the correlation with the diagnostic outcome and ASD/NDDs-related traits at 18, 24 and 36 mo.

  1. Study-specific and structured parent interview collected at the time of recruitment regarding gestational and family history, childbirth, socio-demographic variables, and environmental factors. 2. Experimental data collection at birth, 3, 6, and 12 months: a. auxological and head circumference measurements; b. developmental trajectories of spontaneous and intentional motor movements, vocal/language/communication performances; c. early audio-visual sensory processing and social skills measured by an innovative integrated electrophysiological + eye tracking approach at 12 months. 3. Clinical/diagnostic assessment for investigating longitudinal cognitive, motor, language, and adaptive profiles and determining the presence/absence of ASD/NDD diagnosis using standardized tools/tests and structured parental interviews at 6, 12, 18, 24 and 36 months.

  From month 3 to month 29 of the study period

• Building of a new predictive model and evaluation of its accuracy in terms of positive predictive value of ASD/NDD risk.

  A predictive model will be implemented to forecast the ASD/NDD risk based on the clinical, experimental (vocal, motor, sensory and social measures) and genetic/epigenetic, metabolomic and secretome parameters collected. Both classic statistical approaches and machine learning algorithms will be applied.

  From month 24 to month 30 of the study period

Secondary Outcomes (6)

• Genetic/environmental/inflammatory-related markers linking early life exposures to the neurodevelopmental outcome.

  From month 3 to month 29 of the study period

• Increase of at least 25% in the number of Child Psychiatry Units (CPUs)/Neonatal Intensive Care Units (NICUs) in the NIDA Network performing the clinical/experimental surveillance protocol.

  From month 3 to month 30 of the study period

• Increase of at least 25% in the number of High-risk (HR) infants enrolled/monitored compared with the current NIDA surveillance protocol.

  From month 3 to month 30 of the study period

• Update the developmental surveillance implemented by the NIDA Network within the well-child care visits between 0-36 months of infant age.

  From month 3 to month 30 of the study period

• Develop evidence-based practices and/or guidelines for the early detection of ASD/NDDs in the NICU-follow-up services.

  From month 18 to month 30 of the study period

Study Arms (4)

Siblings of children diagnosed with ASD

The sibling population has a 10-fold higher risk than the general population of developing ASD.

Preterms

Infants of preterm birth (born between 26 and 31 gestational weeks) are considered at heightened risk for ASD/NDDs than the general population.

Small for Gestational Age (SGA)

SGA (weight below the 3rd percentile) are considered at heightened risk for ASD/NDDs than the general population.

Low-risk (LR) infants

LR infants are at term and appropriate for gestational age infants.

Eligibility Criteria

• Age: 0 Months - 36 Months
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

The study population consists of three infant groups at higher risk of developing ASD/NDDs compared to the general population: siblings of children diagnosed with ASD, preterm infants, and those born Small for Gestational Age (SGA). The clinical and experimental protocol is implemented in NICUs and CPUs across the National Health Service (NHS), ensuring specialized assessment, neurodevelopmental surveillance, and the activation of personalized prevention interventions for at-risk newborns.

You may qualify if:

• Low-risk (LR) infants: born after 37 GW and with birth weight \>= 2500 g;
• High-risk (HR) infants: siblings of children already diagnosed with ASD; SGA: birth weight below the 3rd percentile; Preterm: born between 26+0 and 31+6 GW;
• Apgar index over 7 at 5th minute.

You may not qualify if:

• Infants born before 26 GW;
• Presence of major acquired perinatal brain lesions, severe cardiovascular, organ and system diseases, known genetic syndromes related to ASD, and medical conditions affecting brain development or infant's ability to participate in the study.

Sponsors & Collaborators

• Istituto Superiore di Sanità: lead
• Associazione La Nostra Famiglia, Como, Italy: collaborator
• Federico II University: collaborator
• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: collaborator
• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: collaborator

Study Sites (5)

IRCCS MEDEA - Associazione La Nostra Famiglia

Como, 22037, Italy

RECRUITING

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

RECRUITING

Azienda Ospedaliera Universitaria Federico II

Naples, 80131, Italy

RECRUITING

Istituto Superiore di Sanità

Rome, 00161, Italy

ACTIVE NOT RECRUITING

Ospedale Isola Tiberina-Gemelli Isola

Rome, 00186, Italy

RECRUITING

Related Publications (15)

• Caruso A, Micai M, Gila L, Fulceri F, Scattoni ML. The Italian Network for Early Detection of Autism Spectrum Disorder: Research Activities and National Policies. Psychiatr Danub. 2021 Dec;33(Suppl 11):65-68.

  PMID: 34862895 BACKGROUND

• Fontana C, Marasca F, Provitera L, Mancinelli S, Pesenti N, Sinha S, Passera S, Abrignani S, Mosca F, Lodato S, Bodega B, Fumagalli M. Early maternal care restores LINE-1 methylation and enhances neurodevelopment in preterm infants. BMC Med. 2021 Feb 5;19(1):42. doi: 10.1186/s12916-020-01896-0.

  PMID: 33541338 BACKGROUND

• Riva V, Cantiani C, Mornati G, Gallo M, Villa L, Mani E, Saviozzi I, Marino C, Molteni M. Distinct ERP profiles for auditory processing in infants at-risk for autism and language impairment. Sci Rep. 2018 Jan 15;8(1):715. doi: 10.1038/s41598-017-19009-y.

  PMID: 29335488 BACKGROUND

• Marchi V, Hakala A, Knight A, D'Acunto F, Scattoni ML, Guzzetta A, Vanhatalo S. Automated pose estimation captures key aspects of General Movements at eight to 17 weeks from conventional videos. Acta Paediatr. 2019 Oct;108(10):1817-1824. doi: 10.1111/apa.14781. Epub 2019 Apr 1.

  PMID: 30883894 BACKGROUND

• Caruso A, Gila L, Fulceri F, Salvitti T, Micai M, Baccinelli W, Bulgheroni M, Scattoni ML. Early Motor Development Predicts Clinical Outcomes of Siblings at High-Risk for Autism: Insight from an Innovative Motion-Tracking Technology. Brain Sci. 2020 Jun 16;10(6):379. doi: 10.3390/brainsci10060379.

  PMID: 32560198 BACKGROUND

• Purpura G, Costanzo V, Chericoni N, Puopolo M, Scattoni ML, Muratori F, Apicella F. Bilateral Patterns of Repetitive Movements in 6- to 12-Month-Old Infants with Autism Spectrum Disorders. Front Psychol. 2017 Jul 11;8:1168. doi: 10.3389/fpsyg.2017.01168. eCollection 2017.

  PMID: 28744250 BACKGROUND

• Loke YJ, Hannan AJ, Craig JM. The Role of Epigenetic Change in Autism Spectrum Disorders. Front Neurol. 2015 May 26;6:107. doi: 10.3389/fneur.2015.00107. eCollection 2015.

  PMID: 26074864 BACKGROUND

• Needham BD, Adame MD, Serena G, Rose DR, Preston GM, Conrad MC, Campbell AS, Donabedian DH, Fasano A, Ashwood P, Mazmanian SK. Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder. Biol Psychiatry. 2021 Mar 1;89(5):451-462. doi: 10.1016/j.biopsych.2020.09.025. Epub 2020 Oct 10.

  PMID: 33342544 BACKGROUND

• Baccinelli W, Bulgheroni M, Simonetti V, Fulceri F, Caruso A, Gila L, Scattoni ML. Movidea: A Software Package for Automatic Video Analysis of Movements in Infants at Risk for Neurodevelopmental Disorders. Brain Sci. 2020 Mar 31;10(4):203. doi: 10.3390/brainsci10040203.

  PMID: 32244544 BACKGROUND

• Malatesta G, Marzoli D, Apicella F, Abiuso C, Muratori F, Forrester GS, Vallortigara G, Scattoni ML, Tommasi L. Received Cradling Bias During the First Year of Life: A Retrospective Study on Children With Typical and Atypical Development. Front Psychiatry. 2020 Feb 27;11:91. doi: 10.3389/fpsyt.2020.00091. eCollection 2020.

  PMID: 32174855 BACKGROUND

• Chericoni N, Balboni G, Costanzo V, Mancini A, Prosperi M, Lasala R, Tancredi R, Scattoni ML; NIDA Network; Muratori F, Apicella F. A Combined Study on the Use of the Child Behavior Checklist 1(1/2)-5 for Identifying Autism Spectrum Disorders at 18 Months. J Autism Dev Disord. 2021 Nov;51(11):3829-3842. doi: 10.1007/s10803-020-04838-0. Epub 2021 Jan 4.

  PMID: 33394248 BACKGROUND

• Frye RE, Vassall S, Kaur G, Lewis C, Karim M, Rossignol D. Emerging biomarkers in autism spectrum disorder: a systematic review. Ann Transl Med. 2019 Dec;7(23):792. doi: 10.21037/atm.2019.11.53.

  PMID: 32042808 BACKGROUND

• Micai M, Fulceri F, Caruso A, Guzzetta A, Gila L, Scattoni ML. Early behavioral markers for neurodevelopmental disorders in the first 3 years of life: An overview of systematic reviews. Neurosci Biobehav Rev. 2020 Sep;116:183-201. doi: 10.1016/j.neubiorev.2020.06.027. Epub 2020 Jun 28.

  PMID: 32610179 BACKGROUND

• Di Giorgio E, Rosa-Salva O, Frasnelli E, Calcagni A, Lunghi M, Scattoni ML, Simion F, Vallortigara G. Abnormal visual attention to simple social stimuli in 4-month-old infants at high risk for Autism. Sci Rep. 2021 Aug 4;11(1):15785. doi: 10.1038/s41598-021-95418-4.

  PMID: 34349200 BACKGROUND

• Zeidan J, Fombonne E, Scorah J, Ibrahim A, Durkin MS, Saxena S, Yusuf A, Shih A, Elsabbagh M. Global prevalence of autism: A systematic review update. Autism Res. 2022 May;15(5):778-790. doi: 10.1002/aur.2696. Epub 2022 Mar 3.

  PMID: 35238171 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

At birth, cord blood samples (200-500 µl) will be collected and subjected to: a. Measurement of LINE1 promoter methylation. Genomic DNA extraction, LINE1 methylation and bioinformatic analysis as in Fontana et al. 2021. The first meconium will be collected into a sterile tube and suspended in phosphate-buffered saline at a concentration of 100 g/L. Samples will be filtered and stored at -80°C until use: b1. Stool metabolomic analysis will be performed as described in Roggero et al. 2020. Two-microlitre of samples will be processed through the gas chromatography-mass spectrometry system. b2. Secretome analysis: a large number of soluble molecules (cytokines/chemokines, growth factors, and other inflammation-related molecules) will be measured using xMAP technology on the Luminex platform. Commercial kits (Bio-Rad Laboratories and/or R\&D Systems) will be used. Results will be confirmed with ELISA or other immunometric analyses.

MeSH Terms

Conditions

Autism Spectrum Disorder; Neurodevelopmental Disorders; Developmental Disabilities; Premature Birth

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Mental Disorders; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Study Officials

• Maria Luisa Scattoni, Ph.D.

  Istituto Superiore di Sanità

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria Luisa Scattoni, Ph.D.

CONTACT

+39 0649903104; marialuisa.scattoni@iss.it

Patrizio Pezzotti, MSc

CONTACT

+39 3394438833; patrizio.pezzotti@iss.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2025
• First Posted: April 8, 2025
• Study Start: April 1, 2023
• Primary Completion: November 1, 2025
• Study Completion: November 1, 2025
• Last Updated: April 8, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (5)