The PUREMIND OS1/OS2 study is a multinational, prospective, longitudinal observational study designed to identify early neurophysiological, biological, environmental, and psychosocial markers associated with neurodevelopmental and mental health conditions from infancy through young adulthood. Observational Study 1 (OS1) follows infants and toddlers at high risk for Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) to discover biomarkers predictive of later clinical diagnosis, using EEG, fNIRS, psychometric assessments, and biological samples. Observational Study 2 (OS2) includes children, adolescents, and young adults with ASD, ADHD, or Developmental Coordination Disorder (DCD) to identify environmental and biological factors causally linked to anxiety and depression symptoms, and to support the development of personalised criteria for evidence-based interventions. Approximately 800 participants will be recruited across 10 international clinical sites. The study aims to generate multi-domain data to support predictive modelling and inform future personalised mental-health prevention strategies across childhood and young adulthood.
The PUREMIND study is part of a 4-year Horizon Europe consortium aiming to develop the first Integrated Mental Healthcare Ecosystem (IMHE) for preventing mental health conditions across the life course. The protocol describes two complementary observational components (OS1 and OS2) whose data will underpin predictive modelling of neurodevelopmental and mental-health trajectories. Observational Study 1 (OS1) OS1 is a 42-month prospective longitudinal cohort study of infants at elevated risk for ASD or ADHD due to prematurity, hypoxic-ischaemic encephalopathy, or perinatal asphyxia, along with a term-born comparison group. The aim is to identify early neurophysiological and behavioural biomarkers detectable before 18 months of age and predictive of later ASD/ADHD diagnoses. Participants complete five study visits at 6, 12, 18, 24, and 42 months, including: Demographic and clinical data collection Psychometric and developmental assessments EEG and fNIRS neurophysiology paradigms Stool and urine sampling for metabolomics and microbiome analyses Dietary intake questionnaires A clinical diagnosis of ASD/ADHD is established at 42 months. OS1 data will enable the extraction of multilayer Effective Brain Connectivity Networks (EBCNs) and the identification of causal neural features using graph-theoretical and machine-learning models. Observational Study 2 (OS2) OS2 is a 9-month longitudinal study with repeated assessments every 3 months in children (5-10), adolescents (11-18), and young adults (19-25) with clinical diagnoses of ASD, ADHD, or DCD-populations at high risk for anxiety and depression. The aim is to model the dynamic interaction between personal natural environmental (PNE) factors, gene-gut-brain (GGB) mechanisms, and mental-health outcomes (the PNE-GGB-MH process). Data collection includes: Demographic, clinical, and psychosocial measures Physical assessments Psychometric testing of anxiety, depression, executive function, and related constructs Stool, urine, and buccal swab samples for metabolomics, microbiome, and DNA-methylation analyses At-home monitoring via the MindMe app (behavioural, environmental, contextual data) Food frequency and dietary questionnaires relevant to epigenetic assays OS2 uses machine learning and system-identification modelling to identify causal environmental factors contributing to symptom severity and progression, ultimately supporting the development of personalised selection criteria for evidence-based mental-health interventions. Overall Study Design \& Setting The study is conducted across 10 clinical and academic sites in the UK, Ireland, Italy, Spain, Germany, Romania, Ethiopia, and Bangladesh. A total sample of \~800 participants is planned (400 infants/toddlers; 400 youths/young adults). Data are stored in the secure PUREMIND Central Server Platform, compliant with GDPR and HL7/FHIR standards. The combined OS1 and OS2 datasets will support predictive models integrating neurophysiology, genetics, epigenetics, metabolomics, microbiome profiles, environmental exposures, and psychosocial factors. While no intervention is delivered within this protocol, findings are intended to guide future personalised, evidence-based prevention and mental-health support strategies.
Study Type
OBSERVATIONAL
Enrollment
800
University of Exeter
Exeter, United Kingdom
EEG-Based Effective Brain Connectivity Network (EBCN) Features for ASD/ADHD Prediction - OS1
Quantitative features extracted from single-layer and multi-layer effective brain connectivity networks using electroencephalography (EEG). These features characterize directional, causal interactions between brain regions using Granger Causality and Dynamic Causal Modelling, generating dimensionless connectivity indices (ranging 0-1) to identify early neurophysiological markers predictive of Autism Spectrum Disorder (ASD) and/or Attention-Deficit/Hyperactivity Disorder (ADHD) diagnosis at 42 months of age.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, and 24 months
Effective Brain Connectivity Networks (EBCN) Features for ASD/ADHD Prediction - OS1
Composite score derived from quantitative graph-theoretical features extracted from multilayer effective brain connectivity networks constructed using simultaneous electroencephalography (EEG, 32-channel) and functional near-infrared spectroscopy (fNIRS, 24-channel). Features quantify directional causal interactions between brain regions using Granger Causality and/or Dynamic Causal Modelling methods. Machine learning algorithms will integrate multiple EBCN features to generate a single predictive probability score (range 0-1, where higher values indicate greater likelihood of ASD/ADHD diagnosis) indicating likelihood of Autism Spectrum Disorder (ASD) and/or Attention-Deficit/Hyperactivity Disorder (ADHD) diagnosis at 42 months of age.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, and 24 months
Clinical Diagnosis of ASD and/or ADHD - OS1
Clinical diagnosis of Autism Spectrum Disorder (ASD) and/or Attention-Deficit/Hyperactivity Disorder (ADHD) established using ICD-11 and DSM-5-TR diagnostic criteria administered by qualified clinicians.
Time frame: 42 months (corrected age)
DNA Methylation Profiles from Buccal Swabs - OS1 and OS2
Epigenetic DNA methylation profiles analyzed from buccal swab samples using standard microarray technique. Methylation levels are measured as beta values representing the proportion of methylated cytosines at specific CpG sites.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, and 24 months for OS1. Baseline, 3 months, 6 months and 9 months for OS2
Metabolomic Signatures from Stool and Urine - OS1 and OS2
Metabolomic analysis of stool and urine samples using nuclear magnetic resonance spectroscopy and mass spectrometry to identify metabolite concentrations and profiles relevant to neurodevelopmental outcomes.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, and 24 months for OS1. Baseline, 3 months, 6 months and 9 months for OS2
Shotgun Metagenomic Microbiome Profiles from Stool - OS1 and OS2
Comprehensive shotgun metagenomics analysis of stool samples characterizing the composition and potential function of bacteria, archaea, fungi, and viruses. Measured as relative abundance (percentage), taxonomic diversity, and alpha/beta diversity indices.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, and 24 months for OS1. Baseline, 3 months, 6 months and 9 months for OS2
General Cognitive Development - OS1
Assessment of general cognitive development using the Wechsler Preschool and Primary Scale of Intelligence \| Fourth Edition (WPPSI-IV) at 42 months and the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) at 12 and 24 months. The WPPSI-IV provides a Full Scale IQ with scores ranging from 40 to 160 (mean=100, SD=15), where higher scores indicate better cognitive abilities. The Bayley-4 provides composite scores ranging from 40 to 160 (mean=100, SD=15) for cognitive, language, and motor domains, with higher scores indicating better developmental functioning.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Attention Function - OS1
Assessment of attention function using age-appropriate subtests from the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) for ages 6-24 months and the Wechsler Preschool and Primary Scale of Intelligence \| Fourth Edition (WPPSI-IV) attention/executive function subtests at 42 months. Scaled scores range from 1 to 19 (mean=10, SD=3), with higher scores indicating better attention function.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Temperament Assessment - OS1
Assessment of infant temperament using the Infant Behavior Questionnaire-Revised, Short Version (IBQ-R Short) at 12 months, the Early Childhood Behavior Questionnaire (ECBQ) at 24 months, and the Child Behavior Questionnaire (CBQ) at 42 months, all completed by parents/caregivers. Scores are averaged across items for each temperament dimension, ranging from 1 to 7, with higher scores indicating greater intensity of the specific temperament characteristic being measured.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Anxiety Symptoms - OS1
Assessment of anxiety symptoms using the Infant-Toddler Social \& Emotional Assessment-Revised (ITSEA) at 12 and 24 months and the Child Behavior Checklist 1.5-5 (CBCL 1.5-5) at 42 months, completed by parents/caregivers. The ITSEA anxiety domain provides T-scores (mean=50, SD=10), and the CBCL provides T-scores for the anxiety problems subscale (mean=50, SD=10), with higher scores indicating greater anxiety symptoms.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Executive Functions - OS1
Assessment of executive functions using age-appropriate measures including the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) cognitive subtests at 6-24 months and the Wechsler Preschool and Primary Scale of Intelligence \| Fourth Edition (WPPSI-IV) executive function subtests at 42 months. Scaled scores range from 1 to 19 (mean=10, SD=3), with higher scores indicating better executive functioning.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Social-Communication Skills - OS1
Assessment of social-communication abilities using the Ages and Stages Questionnaire-3 (ASQ-3) communication and personal-social domains, the Infant-Toddler Social \& Emotional Assessment-Revised (ITSEA) social competence domains at 12 and 24 months, and the Child Behavior Checklist 1.5-5 (CBCL 1.5-5) social problems subscale at 42 months. ASQ-3 domain scores indicate whether development is on schedule, requires monitoring, or indicates concern. ITSEA and CBCL provide T-scores (mean=50, SD=10), with higher scores on competence domains indicating better social skills and higher scores on problem scales indicating greater difficulties.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Autism Traits - OS1
Assessment of autism traits using the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) Toddler Module at 12, 18, and 24 months and Module 1-3 at 42 months, administered by trained researchers. Comparison scores range from 1 to 10, with scores of 1-2 indicating minimal-to-no concern, 3-4 indicating mild concern, 5-7 indicating moderate concern, and 8-10 indicating high likelihood of autism spectrum disorder.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Quality of Life - OS1
Assessment of infant/child quality of life using the Pediatric Quality of Life Inventory (PedsQL) parent proxy-report version, completed by parents/caregivers. Total scores range from 0 to 100, with higher scores indicating better health-related quality of life.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Dietary Intake - Methyl Donor Nutrients - OS1
Assessment of dietary intake of methyl-donor nutrients (folate, vitamin B12, choline, betaine, and methionine) relevant to DNA methylation analyses using validated Food Frequency and Food Preference Questionnaires completed by parents/caregivers. At 6 and 12 months, feeding mode (exclusively breast-fed, formula-fed, or mixed feeding) is recorded. Nutrient intake is reported in micrograms or milligrams per day depending on the nutrient, with values compared to age-appropriate dietary reference intakes.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, 24 months, and 42 months
Personal Natural Environment (PNE) Factors Causally Associated with Anxiety and Depression - OS2
Identification and quantification of personal natural environmental factors (e.g., sleep patterns, physical activity, social interactions, screen time) causally associated with age-specific anxiety and depression symptom severity and developmental progression, measured through repeated assessments of validated mental health questionnaires combined with ecological momentary assessment data. Analysis uses the PNE-GGB-MH (Personal Natural Environment-Granger-causality Graph-Based Mental Health) computational model to establish directional causal relationships. Results report the strength of causal associations (standardized coefficients ranging from -1 to +1), with higher absolute values indicating stronger causal effects, and positive/negative signs indicating the direction of effect on mental health outcomes.
Time frame: Through study completion, up to 36 weeks
Depression Symptoms (Ages 5-10) - OS2
Assessment of depressive symptoms using the Children's Depression Inventory (CDI), a validated self-report questionnaire. Total scores range from 0 to 54, with higher scores indicating greater depressive symptoms.
Time frame: Baseline, 3 months, 6 months and 9 months.
Depression Symptoms (Ages 11-18) - OS2
Assessment of depressive symptoms using the Children's Depression Inventory (CDI; total score range 0-54) or Beck Depression Inventory-II (BDI-II; total score range 0-63) depending on age and clinical appropriateness. For both scales, higher scores indicate greater depressive symptoms.
Time frame: Baseline, 3 months, 6 months and 9 months.
Depression Symptoms (Ages 19-25) - OS2
Assessment of depressive symptoms using the Beck Depression Inventory-II (BDI-II), a validated self-report questionnaire. Total scores range from 0 to 63, with higher scores indicating greater depressive symptoms.
Time frame: Baseline, 3 months, 6 months and 9 months.
Autism Spectrum Disorder Traits (Ages 5-10) - OS2
Assessment of autism traits using the Childhood Autism Rating Scale (CARS), completed by parents/caregivers. Total scores range from 15 to 60, with higher scores indicating greater severity of autism-related behaviors.
Time frame: Baseline only
Autism Spectrum Disorder Traits (Ages 11-25) - OS2
Assessment of autism traits using the Autism Spectrum Quotient-10 (AQ-10), a brief screening questionnaire. Total scores range from 0 to 10, with higher scores indicating greater likelihood of autism spectrum traits.
Time frame: Baseline only
ADHD Symptoms (Ages 5-18) - OS2
Assessment of ADHD symptoms using the Adult ADHD Self-Report Scale Version 1.1 (ASRS v1.1). Part A scores range from 0 to 24, with higher scores indicating greater ADHD symptom severity.
Time frame: Baseline, 3 months, 6 months and 9 months.
Quality of Life (Ages 5-10) - OS2
Assessment of health-related quality of life using KIDSCREEN-27 Proxy version completed by parents/caregivers. Scores are transformed to T-values (mean=50, SD=10) for five dimensions, with higher scores indicating better health-related quality of life.
Time frame: Baseline, 3 months, 6 months and 9 months.
Quality of Life (Ages 11-18) - OS2
Assessment of health-related quality of life using KIDSCREEN-27 self-report version. Scores are transformed to T-values (mean=50, SD=10) for five dimensions, with higher scores indicating better health-related quality of life.
Time frame: Baseline, 3 months, 6 months and 9 months.
Quality of Life (Ages 19-25) - OS2
Assessment of health-related quality of life using the Short Form-36 (SF-36) questionnaire. Scores range from 0 to 100 for each of eight domains, with higher scores indicating better health-related quality of life.
Time frame: Baseline, 3 months, 6 months and 9 months.
Anxiety Symptoms (Ages 5-18) - OS2
Assessment of anxiety symptoms using the Spence Children's Anxiety Scale (SCAS; total score range 0-114) or Beck Anxiety Inventory (BAI; total score range 0-63) depending on age. For both scales, higher scores indicate greater anxiety symptoms.
Time frame: Baseline, 3 months, 6 months and 9 months.
Anxiety Symptoms (Ages 19-25) - OS2
Assessment of anxiety symptoms using the Generalized Anxiety Disorder-7 (GAD-7) questionnaire. Total scores range from 0 to 21, with higher scores indicating greater anxiety symptom severity.
Time frame: Baseline, 3 months, 6 months and 9 months.
Physical Activity Level (Ages 5-18) - OS2
Assessment of physical activity using the Physical Activity Questionnaire for Children (PAQ-C; for ages below 14) or Physical Activity Questionnaire for Adolescents (PAQ-A; for ages 14-18) as age-appropriate. Scores range from 1 to 5, with higher scores indicating higher levels of physical activity.
Time frame: Baseline, 3 months, 6 months and 9 months.
Physical Activity Level (Ages 19-25) - OS2
Assessment of physical activity using the International Physical Activity Questionnaire Short Form (IPAQ-SF). Results are reported as metabolic equivalent of task minutes per week (MET-min/week), with higher values indicating greater physical activity levels.
Time frame: Baseline, 3 months, 6 months and 9 months.
Objective Physical Activity Measurement - OS2
Objective measurement of physical activity using Axivity AX-3 wearable accelerometer worn for 7 consecutive days. Data recorded as 3-axis acceleration for activity recognition analysis.
Time frame: Between baseline and visit 1 (approximately 2 weeks); then at 12-week intervals through study completion
Dietary Intake - Methyl Donor Nutrients - OS2
Assessment of dietary intake using validated Food Frequency and Food Preference Questionnaires to capture information on methyl-donor nutrient intake relevant to DNA methylation analyses.
Time frame: Food frequency every 2 weeks and food preference at baseline only
Sleep pattern - Adolescent Sleep Wake Scale (ASWS) - OS2
The Adolescent Sleep Wake Scale (ASWS) is a 28-item self-report questionnaire designed to assess sleep quality and sleep-wake patterns in adolescents. The scale includes five behavioral subscales: going to bed, falling asleep, maintaining sleep, reinitiating sleep, and returning to wakefulness. Items are rated on a 6-point Likert scale (1 = always to 6 = never). Higher scores indicate better sleep quality. Total scores range from 28-168.
Time frame: Baseline, 3 months, 6 months and 9 months.
Outcome 1.b: fNIRS-Based Effective Brain Connectivity Network (EBCN) Features for ASD/ADHD Prediction - OS1
Quantitative features extracted from single-layer and multi-layer effective brain connectivity networks using functional near-infrared spectroscopy (fNIRS). These features characterize directional, causal interactions between brain regions using Granger Causality and Dynamic Causal Modelling, generating dimensionless connectivity indices (ranging 0-1) to identify early neurophysiological markers predictive of Autism Spectrum Disorder (ASD) and/or Attention-Deficit/Hyperactivity Disorder (ADHD) diagnosis at 42 months of age.
Time frame: Baseline (6 months corrected age), 12 months, 18 months, and 24 months
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