The main objective of this study is to identify prognostic, stratification, and/or outcome biomarkers for ASD. Prognostic marker refers to any objectively measurable test that helps to predict a child's likely developmental course; whether his…
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Source
Brief title
Condition
- Developmental disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome measures:
- severity of ASD symptoms, as measured by diagnostic interview (ADI-R) and
observation schedules (ADOS) and by questionnaires completed by parents. The
core measures are: Social Responsiveness Scale -Preschool (SRS-P), Childhood
Routines Inventory-Revised (CRI-R), and Sensory Experience Questionnaire (SEQ)
Primary predictors / potential biomarkers:
1) cognitive measures (from touch screen tests) that index various aspects of
executive functioning and attention (sustained attention, inhibitory control,
motion-coherence, reinforcement learning), social cognition (false Belief,
emotion recognition, social reinforcement learning, gaze dot probe) and sensory
processing (tactile sensory processing, auditory sensory processing)
2) eye-tracking measures of social motivation (gazing at dynamic and static
natural social scenes with/without language), processing of predictability
(predictability contingency), and sensory processing (pupillary light reflex,
multisensory integration)
3) EEG/ERP measures of face processing (in particular the N170 latency),
auditory processing (habituation or auditory gamma), functional brain
connectivity (social/ non-social videos and resting state), sensory processing
(tactile gating)
4) MRI measures of structural and functional brain connectivity (from
structural MRI, DTI and resting-state scan, all during sleep) and MRS spectra
of the thalamus (to measure GABA, glutamine and glutamate concentrations)
Secondary outcome
Secundary outcome measures are measures of comorbid disorders and temperament
- Early/ Childhood Behaviour Questionnaire (CBQ)
- Strength and Difficulties Questionnaire (SDQ)
- Child Sleep Habits Questionnaire
- Intolerance of uncertainty questionnaire
- High Sensitivity Child Scale
- Epilepsy questionnaire
- Diet questionnaire
Background summary
Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder
(ADHD), and Developmental Delay (DD) are highly genetic, heterogenous,
neurodevelopmental disorders (NDDs) that frequently co-occur in the same
individual and families. ASD is reliably diagnosed in clinical settings from
around the age of 3 years. Previous studies reported distinct developmental
trajectories in core symptom development (impairments in social-communication
and repetitive and restricted behaviours and interests) across childhood (Lord
et al., 2015, Fountain et al., 2012). In addition, approximately 40% of
autistic children develop ADHD symptoms, and 20% epilepsy as they enter school.
Moreover, around 40% of people with ASD have mild and 15% severe DD. Currently,
language and overall intelligence level are the best predictors of long-term
outcome (Howlin et al., 2008). However, beyond this, relatively little is known
about the origins of individual differences in symptom development among
autistic children. Hence, there is a need for prognostic biomarkers for autism.
A prognostic biomarker is a measure or test that helps clinicians to predict a
child*s likely prognosis - a key concern for parents. A better understanding
why a child may likely improve/ worsen in a particular area is also crucial to
initiate early therapies or inform the development of new therapies.
ASD is likely also a collection of several conditions/diseases that are
characterized by a common set of symptoms, as defined by the DSM-5 algorithm.
The other aim of this study is to establish and validate stratification and/or
outcome markers of ASD. Stratification markers allow to subtype ASD into
biologically more homogeneous subgroups and to develop and test treatments
according to the precision medicine paradigm.
Research into stratification, prognostic and outcome markers is ongoing in
older patients with ASD (age 6 and older), and candidate biomarkers from the
study in older participants will also be examined in this project in
preschoolers.
This study will also investigate whether there may be shared biomarkers between
NDDs (i.e. ASD, ADHD, DD), vs markers that are distinct for specific subgroups
within or across categorical diagnostic boundaries.
Study objective
The main objective of this study is to identify prognostic, stratification,
and/or outcome biomarkers for ASD. Prognostic marker refers to any objectively
measurable test that helps to predict a child's likely developmental course;
whether his or her core symptoms (in social communication, repetitive
behaviours or sensory processing anomalies) become better or worse across the
preschool years or whether he or she will develop co-occurring psychiatric and/
or medical conditions (e g., ADHD, epilepsy). Stratification marker refers to
any test to subtype ASD into biologically more homogeneous subtypes, and
outcome marker refers to any test that can be used as a proxy for later
clinical improvement.
The secondary research objectives are to a) determine the link between
individual variation in "typical" brain development and cognitive/ affective
development over the preschool age range. b) Understand whether there may be
shared biomarkers between NDDs (i.e. ASD, ADHD, DD), vs markers that are
distinct for specific subgroups within or across categorical diagnostic
boundaries. c) validate stratification biomarkers that are currently identified
in older children, adolescents and adults with ASD in this younger age group.
Study design
The present multi-site study employs a longitudinal, multi-disciplinary design
with the overarching goal to identify prognostic, stratification and/or outcome
markers for ASD and related neurodevelopmental conditions. We aim to follow
N=460 children (ASD=180, ADHD=50, developmental delay (DD)=50, typical
development (TD)=180) from approximately 3 to 7 years. Each child will be seen
at three time-points (~3-4 years, ~4-5 years, ~5-6 years; the ADHD group will
only be included in the last two time-points). Clinical core and associated
symptoms will be assessed at all time-points to fit longitudinal developmental
symptom trajectories. *Deep-phenotypic* measures of candidate biomarkers
(including cognition, eye-tracking, EEG, and MRI acquired during natural sleep)
will be assessed at the two earlier time points. This enables us to examine
whether particular neurocognitive/ neurobiological abnormalities at Time 1, or
the rate of change between Time 1 and Time 2, correlates with changes in
symptom trajectories and/ or clinical outcome at Time 3.
Study burden and risks
This is a longitudinal project with assessments at timepoints. At timepoint 1
and 2 there is a visit to the Donders Centre (scheduled in 2 days, in total
10-12 hours). This visit at timepoint 1 and 2 involves as invasive measure a
MRI scan during sleep. Other measures include psychological testing using touch
screens, and eye-tracking and EEG/ERP assessments, and completion of
questionnaires by the parents, online.
At time point 2, blood samples will be obtained by venapuncture.
Time point 3 involves only completion of questionnaires by the parents, online.
All procedures will be conducted by experienced and trained personnel. We will
take extensive measures (see section J above) to ensure the preschooler is as
comfortable as possible and to minimize discomfort and stress.
There are no specific risks associated with any of the procedures.
Potential benefits for the participants are that the study will establish
biomarkers that add to the prognosis of the disorder, and/or stratify the
disorder in subgroups, and/or can be used to monitor the outcome of treatments.
Further, participating families will receive a brief report of the
psychological and behavioural tests.
Kapittelweg 29
Nijmegen 6525 EN
NL
Kapittelweg 29
Nijmegen 6525 EN
NL
Listed location countries
Age
Inclusion criteria
ASD group:
- established or suspected clinical diagnosis of autism spectrum disorder
according to the DSM-5 criteria
- males or females, from age 3 year onward
- non-verbal mental age >= 18 months (Mullen Scales)
- all comorbidities allowed
ADHD group:
- established clinical diagnosis of ADHD according to the DSM-5 criteria
- males or females, from age 4 year onward
- non-verbal mental age >= 18 months (Mullen Scales)
- all comorbidities allowed
DD group:
- clinical evaluation of developmental delay
- males or females, from age 3 year onward
- non-verbal mental age >= 18 months (Mullen Scales)
- all comorbidities allowed
Typically developing controls (TD):
- males and females from the age of 30 months
- no known developmental or medical condition affecting brain development and
behaviour
All groups:
- Availability of a parent or caregiver who has sufficient command of language
to a) provide written confirmed consent, and b) to provide information about
the child*s behaviour, developmental history and symptoms.
Exclusion criteria
All groups:
- Significant hearing or visual impairments not corrected by glasses or hearing
aids.
- Presence of any MRI contraindications (e.g., metal implants, braces) ,
failure of a parent/ legal caregiver to give informed written consent to MRI
scanning, or to provide contact details for a primary care physician at centres
where this is a precondition for scanning; other reasons why a particular child
may not tolerate the sleep scan (claustrophobia, sensitivity to noise, 'tummy
sleeper')
- MRI counterindications in the parent, or unavailability of any parent, legal
guardian or otherwise familiar and trusted adult person to accompany the child
to the MRI sleep scan.
ASD and ADHD groups:
- The presence of known genetic syndromes that have been associated with ASD,
such as Tubereuze Sclerose, Fragiel X, Rett, Williams, etc.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL68615.091.19 |