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 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 Holt 5 Mark Johnson 17 Johan Isaksson 18, 11 Prantik Kundu 19 Meng-Chuan Lai 20, 5 Xavier D’ardhuy 15 Michael Lombardo 5, 21 David 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 Persico 6, 24 Amber Ruigrok 5 Barbara Ruggeri 2 Jessica Sabet 2 Roberto Sacco 6 Antonia Cáceres 1 Emily Simonoff 2 Roberto Toro 12 Heike Tost 9 Jack Waldman 5 Steve Williams 1 Marcel Zwiers 25 Will Spooren 15 Declan Murphy 1 Jan Buitelaar 25
Abstract : 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.
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Eva Loth, Tony Charman, Luke Mason, Julian Tillmann, Emily 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, BioMed Central, 2017, 8 (24), ⟨10.1186/s13229-017-0146-8⟩. ⟨pasteur-01967232⟩

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