Observational Study

. 2017 Jun 23:8:24.

doi: 10.1186/s13229-017-0146-8. eCollection 2017.

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

Eva Loth^{1

2}, Tony Charman³, Luke Mason⁴, Julian Tillmann³, Emily J H Jones⁴, Caroline Wooldridge⁵, Jumana Ahmad², Bonnie Auyeung^{6

7}, Claudia Brogna⁸, Sara Ambrosino⁹, Tobias Banaschewski¹⁰, Simon Baron-Cohen⁶, Sarah Baumeister¹⁰, Christian Beckmann¹¹, Michael Brammer⁵, Daniel Brandeis^{10

12}, Sven Bölte¹³, Thomas Bourgeron¹⁴, Carsten Bours¹¹, Yvette de Bruijn¹¹, Bhismadev Chakrabarti^{6

15}, Daisy Crawley², Ineke Cornelissen¹¹, Flavio Dell' Acqua^{1

2}, Guillaume Dumas¹⁴, Sarah Durston⁹, Christine Ecker^{1

16}, Jessica Faulkner², Vincent Frouin¹⁷, Pilar Garces¹⁸, David Goyard¹⁷, Hannah Hayward², Lindsay M Ham¹⁹, Joerg Hipp¹⁸, Rosemary J Holt⁶, Mark H Johnson⁴, Johan Isaksson^{13

20}, Prantik Kundu²¹, Meng-Chuan Lai^{6

22}, Xavier Liogier D'ardhuy¹⁸, Michael V Lombardo^{6

23}, David J Lythgoe⁵, René Mandl⁹, Andreas Meyer-Lindenberg²⁴, Carolin Moessnang²⁴, Nico Mueller¹⁰, Laurence O'Dwyer¹¹, Marianne Oldehinkel¹¹, Bob Oranje⁹, Gahan Pandina²⁵, Antonio M Persico^{8

26}, Amber N V Ruigrok⁶, Barbara Ruggeri²⁷, Jessica Sabet², Roberto Sacco⁸, Antonia San José Cáceres², Emily Simonoff²⁸, Roberto Toro¹⁴, Heike Tost²⁴, Jack Waldman⁶, Steve C R Williams⁵, Marcel P Zwiers¹¹, Will Spooren¹⁸, Declan G M Murphy^{1

2}, Jan K Buitelaar¹¹

Affiliations

¹ Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
² Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
³ Clinical Child Psychology, Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
⁴ Centre for Brain and Cognitive Development, Birkbeck, University of London, Henry Wellcome Building, Malet Street, London, WC1E 7HX UK.
⁵ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
⁶ Autism Research Centre, Department of Psychiatry, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge, CB2 8AH UK.
⁷ Department of Psychology, The School of Philosophy, Psychology, and Language Sciences, University of Edinburgh, Dugald Stewart Building, 3 Charles Street, Edinburgh, EH8 9AD UK.
⁸ University Campus Bio-Medico, via Álvaro del Portillo, 21, Rome, Italy.
⁹ Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
¹⁰ Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany.
¹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands.
¹² Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zürich, Neumünsterallee 9, 8032 Zürich, Switzerland.
¹³ Center for Neurodevelopmental Disorders at Karolinska Institutet (KIND), Stockholm, Sweden.
¹⁴ Human Genetics and Cognitive Functions Unit, Institut Pasteur, 25 Rue du Docteur Roux, Paris, Cedex 15 France.
¹⁵ Centre for Autism, School of Psychology and Clinical Language Sciences, University of Reading, Whiteknights, Reading, RG6 6AL UK.
¹⁶ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Deutschordenstrasse 50, 60528 Frankfurt, Germany.
¹⁷ Neurospin Centre CEA, Saclay, 91191 Gif sur Yvette, France.
¹⁸ Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, Grenzacherstrasse 124, B.001 N.667, CH-4070 Basel, Switzerland.
¹⁹ Regulatory Affairs, Product Development, F. Hoffmann-La Roche Pharmaceuticals, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
²⁰ Department of Neuroscience, Uppsala University, Uppsala, Sweden.
²¹ Department of Radiology, Icahn School of Medicine at Mount Sinai, NY, USA.
²² Child and Youth Mental Health Collaborative, Centre for Addiction and Mental Health and The Hospital for Sick Children, Department of Psychiatry, University of Toronto, 80, Workman Way, Toronto, ON M6J 1H4 Canada.
²³ Center for Applied Neuroscience, Department of Psychology, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus.
²⁴ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.
²⁵ Janssen Research & Development, 1125 Trenton Harbourton Road, Titusville, NJ 08560 USA.
²⁶ Child and Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, University of Messina, Via Consolare Valeria 1, I-98125 Messina, Italy.
²⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, London, UK.
²⁸ Department of Child and Adolescent Psychiatry, Institute of Psychology, Psychiatry and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.

PMID: 28649312
PMCID: PMC5481887
DOI: 10.1186/s13229-017-0146-8

Observational Study

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

Eva Loth et al. Mol Autism. 2017.

. 2017 Jun 23:8:24.

doi: 10.1186/s13229-017-0146-8. eCollection 2017.

Authors

Affiliations

¹ Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
² Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
³ Clinical Child Psychology, Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
⁴ Centre for Brain and Cognitive Development, Birkbeck, University of London, Henry Wellcome Building, Malet Street, London, WC1E 7HX UK.
⁵ Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
⁶ Autism Research Centre, Department of Psychiatry, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge, CB2 8AH UK.
⁷ Department of Psychology, The School of Philosophy, Psychology, and Language Sciences, University of Edinburgh, Dugald Stewart Building, 3 Charles Street, Edinburgh, EH8 9AD UK.
⁸ University Campus Bio-Medico, via Álvaro del Portillo, 21, Rome, Italy.
⁹ Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
¹⁰ Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany.
¹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands.
¹² Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zürich, Neumünsterallee 9, 8032 Zürich, Switzerland.
¹³ Center for Neurodevelopmental Disorders at Karolinska Institutet (KIND), Stockholm, Sweden.
¹⁴ Human Genetics and Cognitive Functions Unit, Institut Pasteur, 25 Rue du Docteur Roux, Paris, Cedex 15 France.
¹⁵ Centre for Autism, School of Psychology and Clinical Language Sciences, University of Reading, Whiteknights, Reading, RG6 6AL UK.
¹⁶ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Deutschordenstrasse 50, 60528 Frankfurt, Germany.
¹⁷ Neurospin Centre CEA, Saclay, 91191 Gif sur Yvette, France.
¹⁸ Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, Grenzacherstrasse 124, B.001 N.667, CH-4070 Basel, Switzerland.
¹⁹ Regulatory Affairs, Product Development, F. Hoffmann-La Roche Pharmaceuticals, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
²⁰ Department of Neuroscience, Uppsala University, Uppsala, Sweden.
²¹ Department of Radiology, Icahn School of Medicine at Mount Sinai, NY, USA.
²² Child and Youth Mental Health Collaborative, Centre for Addiction and Mental Health and The Hospital for Sick Children, Department of Psychiatry, University of Toronto, 80, Workman Way, Toronto, ON M6J 1H4 Canada.
²³ Center for Applied Neuroscience, Department of Psychology, University of Cyprus, PO Box 20537, 1678 Nicosia, Cyprus.
²⁴ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.
²⁵ Janssen Research & Development, 1125 Trenton Harbourton Road, Titusville, NJ 08560 USA.
²⁶ Child and Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, University of Messina, Via Consolare Valeria 1, I-98125 Messina, Italy.
²⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, London, UK.
²⁸ Department of Child and Adolescent Psychiatry, Institute of Psychology, Psychiatry and Neuroscience, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.

PMID: 28649312
PMCID: PMC5481887
DOI: 10.1186/s13229-017-0146-8

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

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Figures

**Fig. 1**
LEAP recruitment and assessment procedures. a Participants are concurrently recruited and assessed at seven European study sites: the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom Autism Research Centre at the University of Cambridge, United Kingdom, Radboud University Nijmegen Medical Centre, University Medical Centre Utrecht, the Netherlands, Central Institute of Mental Health, Mannheim, Germany, and the University Campus Bio-Medico, Rome, Italy. Twins are predominantly recruited from the Roots of Autism and ADHD Twin Study in Sweden (RATSS) at Karolinska Institute, Stockholm, Sweden [17]. At each study site, participants with ASD and mild ID are recruited from existing local databases, clinic contacts, and local and national support groups. TD participants are recruited via mainstream schools, flyers (e.g. left at youth centres, colleges, churches, etc.), and existing databases. Participants (or parents) who express interest are sent an information sheet and then screened over the phone for eligibility. If inclusion criteria are confirmed, written consent is obtained and the participant is assigned to a study schedule based on their age and ability level. b Parents (as well as adolescents and adults without ID) are sent login details to an online questionnaire (Delosis Ltd., London) to complete at home. c and d The participant and a parent visit the study centre on two separate occasions within 4 weeks. For participants who travel from far, visits take place on two consecutive days with an overnight stay at a local hotel arranged by the research team. Clinical assessments and interviews are conducted with the participant (e.g. ADOS-2) and a parent (ADI-R, Vineland, Family History Interview). If parents stay with their child during his/her assessments, these interviews are later conducted over the phone. Most cognitive tests are administered using the computerised platform Psytools (Delosis, London Ltd.); some are paper-pencil tests. Eye-tracking is acquired using Tobii-Eye-trackers with a standard acquisition rate of 120 Hz. Tasks are presented interleaved to minimise attentional requirements. Each participant completes a 60–90-min MRI scan session to acquire structural and DTI scans, a resting-state functional MRI scan, and (depending on schedule) one to four task-related fMRI scans. During a training session before the scan, they are instructed to keep still, familiarised with the scanner noise, trained in the functional tasks, and, where possible, are given the opportunity to lie in a mock scanner. During the structural scans, participants watch videos from a video library or DVD brought from home, to make the scan experience more enjoyable. The EEG session tests functional activation during face processing, social and non-social processing, an auditory oddball paradigm (MMN), and resting state. Blood, urine, and saliva samples are taken from the participant and, where possible, both parents for biochemical and genomic analyses. Hair samples are taken to derive induced pluripotent stem cells from selected participants

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

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

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