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

Eva Loth (1) , Tony Charman (2) , Luke Mason (3) , Julian Tillmann (2) , Emily J H Jones (3) , Caroline Wooldridge (1) , Jumana Ahmad (2) , Bonnie Auyeung (4, 5) , Claudia Brogna (6) , Sara Ambrosino (7) , Tobias Banaschewski (8) , Simon Baron-Cohen (5) , Sarah Baumeister (9) , Christian Beckmann (10) , Michael Brammer (1) , Daniel Brandeis (9) , Sven Bölte (11) , Thomas Bourgeron (12) , Carsten Bours (10) , Yvette de Bruijn (10) , Bhismadev Chakrabarti (13) , Daisy Crawley (2) , Ineke Cornelissen (10) , Flavio Dell’ Acqua (1) , Guillaume Dumas (12) , Sarah Durston (7) , Christine Ecker (1) , Jessica Faulkner (1) , Vincent Frouin (14) , Pilar Garcés (15) , David Goyard (14) , Hannah Hayward (1) , Lindsay Ham (16) , Joerg Hipp (15) , Rosemary J Holt (5) , Mark Johnson (17) , Johan Isaksson (18, 11) , Prantik Kundu (19) , Meng-Chuan Lai (20, 5) , Xavier Liogier D’ardhuy (15) , Michael V Lombardo (5, 21) , David J Lythgoe (1) , René Mandl (7) , Andreas Meyer-Lindenberg (22) , Carolin Moessnang (9) , Nico Mueller (9) , Laurence O’dwyer (10) , Marianne Oldehinkel (10) , Bob Oranje (7) , Gahan Pandina (23) , Antonio M Persico (6, 24) , Amber N V Ruigrok (5) , Barbara Ruggeri (2) , Jessica Sabet (2) , Roberto Sacco (6) , Antonia San José Cáceres (1) , Emily Simonoff (2) , Roberto Toro (12) , Heike Tost (9) , Jack Waldman (5) , Steve C R Williams (1) , Marcel Zwiers (25) , Will Spooren (15) , Declan G. Murphy (1) , Jan Buitelaar (25)

1 King‘s College London
2 Institute of Psychiatry, Psychology & Neuroscience, King's College London
3 Centre for Brain and Cognitive Development [Birkbeck College]
4 University of Edinburgh
5 CAM - University of Cambridge [UK]
6 UCBM - Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome
7 University Medical Center [Utrecht]
8 Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim]
9 Universität Heidelberg [Heidelberg]
10 Radboud University Medical Center [Nijmegen]
11 Karolinska Institutet [Stockholm]
12 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
13 UOR - University of Reading
14 NEUROSPIN - Service NEUROSPIN
15 pRED - Roche Pharma Research and Early Development [Basel]
16 F. Hoffmann-La Roche [Basel]
17 University of London [London]
18 Uppsala University
19 MSSM - Icahn School of Medicine at Mount Sinai [New York]
20 University of Toronto
21 UCY - University of Cyprus [Nicosia]
22 Heidelberg University
23 Janssen Research & Development
24 University of Messina
25 Donders Institute for Brain, Cognition and Behaviour

BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

Keywords: Biomarkers; Cognition; EEG; Eye-tracking; Genetics; MRI; Neuroimaging

Domains: Life Sciences [q-bio]

Eva Loth, Tony Charman, Luke Mason, Julian Tillmann, Emily J H Jones, et al.. The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders. Molecular Autism, 2017, 8 (24), ⟨10.1186/s13229-017-0146-8⟩. ⟨pasteur-01967232⟩