The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders

Loth, Eva; Charman, Tony; Mason, Luke; Tillmann, Julian; Jones, Emily J. H.; Wooldridge, Caroline; Ahmad, Jumana; Auyeung, Bonnie; Brogna, Claudia; Ambrosino, Sara; Banaschewski, Tobias; Baron-Cohen, Simon; Baumeister, Sarah; Beckmann, Christian; Brammer, Michael; Brandeis, Daniel; Bölte, Sven; Bourgeron, Thomas; Bours, Carsten; de Bruijn, Yvette; Chakrabarti, Bhismadev; Crawley, Daisy; Cornelissen, Ineke; Acqua, Flavio Dell’; Dumas, Guillaume; Durston, Sarah; Ecker, Christine; Faulkner, Jessica; Frouin, Vincent; Garces, Pilar; Goyard, David; Hayward, Hannah; Ham, Lindsay M.; Hipp, Joerg; Holt, Rosemary J.; Johnson, Mark H.; Isaksson, Johan; Kundu, Prantik; Lai, Meng-Chuan; D’ardhuy, Xavier Liogier; Lombardo, Michael V.; Lythgoe, David J.; Mandl, René; Meyer-Lindenberg, Andreas; Moessnang, Carolin; Mueller, Nico; O’Dwyer, Laurence; Oldehinkel, Marianne; Oranje, Bob; Pandina, Gahan; Persico, Antonio M.; Ruigrok, Amber N. V.; Ruggeri, Barbara; Sabet, Jessica; Sacco, Roberto; Cáceres, Antonia San José; Simonoff, Emily; Toro, Roberto; Tost, Heike; Waldman, Jack; Williams, Steve C. R.; Zwiers, Marcel P.; Spooren, Will; Murphy, Declan G. M.; Buitelaar, Jan K.

doi:10.1186/s13229-017-0146-8

Molecular Autism

Table 1 LEAP summary of study protocol, by schedule

From: The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders

Level	IA/OA	Domain/task	Time point	Schedule^a
Level	IA/OA	Domain/task	Time point	A	B	C	D
Clinical diagnosis
Level 1	IA	Autism Diagnostic Interview-Revised (ADI-R)^c	Base	P^b	P^b	P^b	P^b
Level 1	IA	Autism Diagnostic Observation Schedule (ADOS or ADOS-2)^c	Base & FU	S^b	S^b	S^b	S^b
Dimensional measures of ASD symptoms
Level 2	OA	Social Responsiveness Scale-2nd Edition (SRS-II)^c	Base & FU	S & P^b	S & P	P	P
Level 2	OA	Repetitive Behaviour Scale-Revised (RBS-R)^c	Base & FU	P^b	P	P	P
Level 2	OA	Short Sensory Profile (SSP)^c	Base & FU	P^b	P	P	P
Level 2	OA	Children’s Social Behaviour Questionnaire (CSBQ)^c Adults’ Social Behaviour Questionnaire (ASBQ)^c	Base & FU	– S & P^b	P –	P –	P –
Level 2	OA	Autism Quotient (AQ), AQ-Adol, AQ-Child^c	Base & FU	S & P^b	P	P	P
Level 2	OA	Aberrant Behaviour Checklist	FU	P^b	P	P	P
Level 2	OA	Adult Routines Inventory (ARI) or Childhood Routines Inventory-Revised (CRI-R)	FU	S –	– P	– P	– P
Level 2	OA	Sensory Experiences Questionnaire—short version (SEQ 3.0)	FU	P^b	P	P	P
Level 2	OA	Global Score of Change	FU	P^b	P^b	P^b	P^b
Comorbidities
Level 2	OA	Development and Well-Being Assessment (DAWBA)^c	Base	S & P^b	S & P	P	P
Level 2	OA	Strengths and Difficulties Questionnaire (SDQ)^c	Base & FU	S & P^b	S & P	P	P
Level 2	OA	DSM-5 ADHD rating scale^c	Base & FU	S & P^b	P	P	P
Level 3	OA	Beck Anxiety Inventory (BAI)	Base & FU	S	S	P	P
Level 3	OA	Beck Depression Inventory (BDI)	Base & FU	S	S	P	P
Quality of life/adaptive behaviour
Level 1	IA	Vineland Adaptive Behaviour Scale-2nd Ed (VABS-2)	Base & FU	P^b	P^b	P	P
Level 2	OA	Columbia Impairment Scale (CIS)^c	Base & FU	S & P^b	S & P	P	P
	OA	Child Health and Illness Profile (CHIP-CE) or World Health Organisation Quality of Life (WHOQOL-BREF)	Base & FU	– S	P –	P –	P –
Medical or psychiatric history
Level 1	OA	NIH ACE Subject Medical History Questionnaire^c	Base	S’ or P^b	P	P	P
Level 2	OA	NIH ACE Family History Form	Base	S’ or P^b	P	P	P
Level 2	OA	Medical Psychiatric History Perinatal Environmental Risk Questionnaire^c	FU	P^b	P	P	P
Level 2	OA	Brief Life Events Questionnaire, anchored in pregnancy	FU	P^b	P	P	P
Level 2	OA	Children’s Sleep Habits Questionnaire or Adult version (FU only)	Base & FU	– S	S & P –	P –	P –
Level 2	IA	Family Medical History Interview	FU	S’ or P^b	P	P	P
Cognitive and psychological profile
Level 1	IA	WASI or WISC / WAIS (4 subtests)^c	Base	S	S	S	S
Level 1	IA	WASI or WISC / WAIS (2 subtests)^c	FU	S	S	S	S
Level 1	IA	BPVS and RCPM	Base & FU	S	S	S	S
Level 2	OA	HRS-MAT online adaptive IQ test	FU	S	S	S	S
Level 2	IA	Probabilistic reversal learning^c	Base & FU	S	S	S	S
Level 2	IA	Spatial working memory^c	Base & FU	S	S	S	S
Level 2	IA	Un/Segmented block design task^c	Base	S	S	S	S
Level 2	IA	Animated shapes narratives task^c	Base & FU	S	S	S	S
Level 3	OA	Empathy Quotient	Base & FU	S	P	–	–
Level 3	OA	Systemising Quotient	Base & FU	S	P	–	–
Level 3	OA	Child EQ-SQ	Base & FU	–	–	P	–
Level 3	OA	Toronto Alexithymia Scale (TAS)	Base & FU	S	S	P	P
Level 3	IA	Reading the Mind in the Eyes task (RMET)	Base & FU	S	S	S	S
Level 3	IA	Karolinska Directed Emotional Faces (KDEF)	FU	S	S	S	S
Level 3	IA	Sandbox continuous false belief task	Base & FU	S	S	S	S
Cognitive tests assessed as part of the eye-tracking battery:
Level 3	IA	Event memory task	FU	S	S	S	S
Level 3	IA	Emotion matching task	Base	S	S	S	S
Level 3	IA	Films expression task	FU	S	S	S	S
Level 3	IA	Visual processing task	FU	S	S	S	S
Level 3	IA	Change detection task	Base or FU	S	S	S	S
Eye-tracking
Level 2	IA	Natural scenes: static and dynamic^c	Base & FU	S	S	S	S
Level 2	IA	Gap overlap^c	Base & FU	S	S	S	S
Level 2	IA	Implicit false belief^c	Base & FU	S	S	S	S
Level 2	IA	Pupillary light reflex^c	Base & FU	S	S	S	S
Level 3	IA	Biological motion	Base & FU	S	S	S	S
Neuroimaging
Level 1	IA	Structural MRI^c	Base & FU	S	S	S	S
Level 1	IA	FLAIR sequence or localiser sequence MRI^c	Base & FU	S	S	S	S
Level 2	IA	Diffusion tensor imaging (DTI)^c	Base & FU	S	S	S	S
Level 2	IA	Resting-state fMRI^c	Base & FU	S	S	S	S
Level 2	IA	Social/non-social reward fMRI^c	Base & FU	S	S	S	S
Level 2	IA	Animated shapes theory of mind fMRI^c	Base & FU	S	S	S	-
Level 2	IA	Flanker Go/No-Go task^c	Base & FU	S	S	-	-
Level 3	IA	Hariri emotion processing fMRI	Base & FU	S	S	S	-
EEG
Level 2	IA	Resting state^c	Base & FU	S	S	S	S
Level 2	IA	Auditory oddball task^c	Base & FU	S	S	S	S
Level 2	IA	Upright-inverted Faces (gamma)^c	Base & FU	S	S	S	S
Level 2	IA	Social / non-social videos^c	Base & FU	S	S	S	S
Biological samples
Level 2	IA	Blood sample (for genomic analyses)^c	Base or FU	S	S	S	S
Level 2	IA	Saliva (for genomic analyses where blood samples cannot be obtained and for epigenetics)^c	Base & FU	S	S	S	S
Level 2	IA	Urine (at home, for biochemical biomarkers)^c	Base or FU	S	S	S	S
Level 2	IA	Hair roots (to generate iPSCs)^c	Base or FU	S	S	S	S
Level 2	IA	Head circumference^c, weight^c, height^c	Base & FU	S	S	S	S
Assessment of clinical symptoms and cognition in both biological parents
Level 3	OA	Social Responsiveness Scale (SRS-2)	Base	P^b	P^b	P^b	P^b
Level 3	OA	DSM-5 ADHD rating scale	Base	P^b	P^b	P^b	P^b
Level 3	OA	Beck Anxiety Inventory (BAI)	Base	P^b	P^b	P^b	P^b
Level 3	OA	Beck Depression Inventory (BDI)	Base	P^b	P^b	P^b	P^b
Level 3	OA	Adult Routines Inventory (ARI)	FU	P^b	P	P	P
Level 2	OA	HRS-MAT online adaptive IQ test	FU	P^b	P	P	P

Level 1 measures are defined as the minimal data set that must be acquired for any one participant to be included in the ‘head count’. Level 2 measures are (a) central to primary and/or secondary study objectives, (b) suitable for the entire targeted participant age and ability range, and (c) have previously shown ASD case-control differences or have been validated in ASD group(s). Level 3 measures are measures that are either (a) more exploratory (e.g. related to novel/emerging hypotheses), (b) less central to the primary or secondary study objectives, and/or (c) only suitable for some schedules. Within each assessment module, in the order of assessments, level 1 and level 2 assessments should be administered before level 3 assessments. Level 3 measures are omitted first in the event of, e.g. participant fatigue or if assessments take considerably longer than average
ADHD attention-deficit hyperactivity disorder, ASD autism spectrum disorder, Base baseline assessment wave, DSM Diagnostic and Statistical Manual of Mental Disorders, fMRI functional magnetic resonance imaging, FU follow-up assessment wave, IA investigator administered assessment at the institute, iPSCs induced pluripotent stem cells, NIH ACE US National Institutes of Health Autism Centers of Excellence, OA online assessment, P reported by parent, S self-reported, S’ self-reported in the TD adult group in which parents are not enrolled in the study, sMRI structural magnetic resonance imaging, TD typical development
^aSchedule A: adults with ASD or TD (aged 18–30 years, with IQ greater than 70); schedule B: adolescents with ASD or TD (aged 12–17 years, with IQ greater than 75); schedule C: children with ASD or TD (aged 6–11 years, with IQ greater than 75); schedule D: adolescents and adults with mild ID (with or without ASD) (aged 12–30 years, with IQ 50–74); schedule E: monozygotic or dizygotic twins (schedule E is not shown but is based on schedules A–C)
^bASD groups only
^cCore measures that were submitted to the European Medicines Agency for QA

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