Molecular Autism (Jun 2017)
The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders
- Eva Loth,
- Tony Charman,
- Luke Mason,
- Julian Tillmann,
- Emily J. H. Jones,
- Caroline Wooldridge,
- Jumana Ahmad,
- Bonnie Auyeung,
- Claudia Brogna,
- Sara Ambrosino,
- Tobias Banaschewski,
- Simon Baron-Cohen,
- Sarah Baumeister,
- Christian Beckmann,
- Michael Brammer,
- Daniel Brandeis,
- Sven Bölte,
- Thomas Bourgeron,
- Carsten Bours,
- Yvette de Bruijn,
- Bhismadev Chakrabarti,
- Daisy Crawley,
- Ineke Cornelissen,
- Flavio Dell’ Acqua,
- Guillaume Dumas,
- Sarah Durston,
- Christine Ecker,
- Jessica Faulkner,
- Vincent Frouin,
- Pilar Garces,
- David Goyard,
- Hannah Hayward,
- Lindsay M. Ham,
- Joerg Hipp,
- Rosemary J. Holt,
- Mark H. Johnson,
- Johan Isaksson,
- Prantik Kundu,
- Meng-Chuan Lai,
- Xavier Liogier D’ardhuy,
- Michael V. Lombardo,
- David J. Lythgoe,
- René Mandl,
- Andreas Meyer-Lindenberg,
- Carolin Moessnang,
- Nico Mueller,
- Laurence O’Dwyer,
- Marianne Oldehinkel,
- Bob Oranje,
- Gahan Pandina,
- Antonio M. Persico,
- Amber N. V. Ruigrok,
- Barbara Ruggeri,
- Jessica Sabet,
- Roberto Sacco,
- Antonia San José Cáceres,
- Emily Simonoff,
- Roberto Toro,
- Heike Tost,
- Jack Waldman,
- Steve C. R. Williams,
- Marcel P. Zwiers,
- Will Spooren,
- Declan G. M. Murphy,
- Jan K. Buitelaar
Affiliations
- Eva Loth
- Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Tony Charman
- Clinical Child Psychology, Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Luke Mason
- Centre for Brain and Cognitive Development, Birkbeck, University of London
- Julian Tillmann
- Clinical Child Psychology, Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Emily J. H. Jones
- Centre for Brain and Cognitive Development, Birkbeck, University of London
- Caroline Wooldridge
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Jumana Ahmad
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Bonnie Auyeung
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- Claudia Brogna
- University Campus Bio-Medico
- Sara Ambrosino
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht
- Tobias Banaschewski
- Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Simon Baron-Cohen
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- Sarah Baumeister
- Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Christian Beckmann
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- Michael Brammer
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Daniel Brandeis
- Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Sven Bölte
- Center for Neurodevelopmental Disorders at Karolinska Institutet (KIND)
- Thomas Bourgeron
- Human Genetics and Cognitive Functions Unit, Institut Pasteur
- Carsten Bours
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- Yvette de Bruijn
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- Bhismadev Chakrabarti
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- Daisy Crawley
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Ineke Cornelissen
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- Flavio Dell’ Acqua
- Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Guillaume Dumas
- Human Genetics and Cognitive Functions Unit, Institut Pasteur
- Sarah Durston
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht
- Christine Ecker
- Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Jessica Faulkner
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Vincent Frouin
- Neurospin Centre CEA
- Pilar Garces
- Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel
- David Goyard
- Neurospin Centre CEA
- Hannah Hayward
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Lindsay M. Ham
- Regulatory Affairs, Product Development, F. Hoffmann-La Roche Pharmaceuticals
- Joerg Hipp
- Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel
- Rosemary J. Holt
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- Mark H. Johnson
- Centre for Brain and Cognitive Development, Birkbeck, University of London
- Johan Isaksson
- Center for Neurodevelopmental Disorders at Karolinska Institutet (KIND)
- Prantik Kundu
- Department of Radiology, Icahn School of Medicine at Mount Sinai
- Meng-Chuan Lai
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- Xavier Liogier D’ardhuy
- Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel
- Michael V. Lombardo
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- David J. Lythgoe
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- René Mandl
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht
- Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Carolin Moessnang
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Nico Mueller
- Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Laurence O’Dwyer
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- Marianne Oldehinkel
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- Bob Oranje
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht
- Gahan Pandina
- Janssen Research & Development
- Antonio M. Persico
- University Campus Bio-Medico
- Amber N. V. Ruigrok
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- Barbara Ruggeri
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Jessica Sabet
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Roberto Sacco
- University Campus Bio-Medico
- Antonia San José Cáceres
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Emily Simonoff
- Department of Child and Adolescent Psychiatry, Institute of Psychology, Psychiatry and Neuroscience, King’s College London
- Roberto Toro
- Human Genetics and Cognitive Functions Unit, Institut Pasteur
- Heike Tost
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
- Jack Waldman
- Autism Research Centre, Department of Psychiatry, University of Cambridge
- Steve C. R. Williams
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Marcel P. Zwiers
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- Will Spooren
- Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel
- Declan G. M. Murphy
- Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Jan K. Buitelaar
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre
- DOI
- https://doi.org/10.1186/s13229-017-0146-8
- Journal volume & issue
-
Vol. 8,
no. 1
pp. 1 – 19
Abstract
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.
Keywords
