The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders
Open accessAbstract
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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Several major collaborative efforts in ASD, such as EU-AIMS, specifically aim to understand biomarkers potentially relevant to stratification.
“Several major collaborative efforts in ASD, such as the EU-AIMS (eu-aims.eu) specifically aim to understand biomarkers potentially relevant to stratification [266–268].”
From The contribution of environmental exposure to the etiology of autism spectrum disorder (2019) · cites this paper as [267]
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“This behavioural marker of social impairment has been linked to either reduced social reward sensitivity or increased (social) anxiety, which may in turn be mediated by the neuropeptides oxytocin [62] and vasopressin [63], or serotonin [64].”
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Flagged first, then by citations
Research works printed but not linked: 1
- [5]Charman T. Variability in neurodevelopmental disorders: evidence from autism. In: Riby D, Van Herwegen J, editors. Applied Research and Key Issues in Neurodevelopmental Disorders. Routledge Psychology Press; 2015. p. 117–40.
Cited by
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- Authors
- Loth, E., Charman, T., Mason, L., Tillmann, J., Jones, E. J. H., Wooldridge, C., Ahmad, J., Auyeung, B., Brogna, C., Ambrosino, S., Banaschewski, T., Baron-Cohen, S., Baumeister, S., Beckmann, C., Brammer, M., Brandeis, D., Bölte, S., Bourgeron, T., Bours, C., de Bruijn, Y., Chakrabarti, B., Crawley, D., Cornelissen, I., Acqua, F. D., Dumas, G., Durston, S., Ecker, C., Faulkner, J., Frouin, V., Garces, P., Goyard, D., Hayward, H., Ham, L. M., Hipp, J., Holt, R. J., Johnson, M. H., Isaksson, J., Kundu, P., Lai, M.-C., D’ardhuy, X. L., Lombardo, M. V., Lythgoe, D. J., Mandl, R., Meyer-Lindenberg, A., Moessnang, C., Mueller, N., O’Dwyer, L., Oldehinkel, M., Oranje, B., Pandina, G., Persico, A. M., Ruigrok, A. N. V., Ruggeri, B., Sabet, J., Sacco, R., Cáceres, A. S. J., Simonoff, E., Toro, R., Tost, H., Waldman, J., Williams, S. C. R., Zwiers, M. P., Spooren, W., Murphy, D. G. M., & Buitelaar, J. K.
- Affiliations
- King's College London (GB)
- University of London (GB)
- Università Campus Bio-Medico (IT)
- University Medical Center Utrecht (NL)
- Heidelberg University (DE)
- Radboud University Medical Center (NL)
- University of Zurich (CH)
- Karolinska Institutet (SE)
- Institut Pasteur (FR)
- University of Cambridge (GB)
- Goethe University Frankfurt (DE)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- F. Hoffmann-La Roche AG (CH)
- Uppsala University (SE)
- Icahn School of Medicine at Mount Sinai (US)
- Centre for Addiction and Mental Health (CA)
- University of Messina (IT)
- Corresponding author
- Loth, Eva
- ORCID
- Loth, Eva
- Charman, Tony
- Mason, Luke
- Tillmann, Julian
- Jones, Emily J. H.
- Ahmad, Jumana
- Brogna, Claudia
- Ambrosino, Sara
- Banaschewski, Tobias
- Baumeister, Sarah
- Beckmann, Christian
- Brammer, Michael
- Bölte, Sven
- Bourgeron, Thomas
- Bours, Carsten
- Chakrabarti, Bhismadev
- Crawley, Daisy
- Dumas, Guillaume
- Ecker, Christine
- Faulkner, Jessica
- Frouin, Vincent
- 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
- Moessnang, Carolin
- Oldehinkel, Marianne
- Oranje, Bob
- Pandina, Gahan
- Persico, Antonio M.
- Ruigrok, Amber N. V.
- Ruggeri, Barbara
- Sacco, Roberto
- Cáceres, Antonia San José
- Simonoff, Emily
- Toro, Roberto
- Tost, Heike
- Zwiers, Marcel P.
- Murphy, Declan G. M.
- Buitelaar, Jan K.
- Venue
- Molecular Autism
- Published
- 2017-06-23
- Volume
- 8
- Issue
- 1
- Pages
- 24-24
- ISSN
- 2040-2392 (ISSN-L)
- PMC
- PMC5481887
- OpenAlex
- W2625516444
- Cited by
- 299
- References
- 124
- Citations by year
- 2026: 26 · 2025: 25 · 2024: 30 · 2023: 32 · 2022: 40 · 2021: 40 · 2020: 57 · 2019: 17 · 2018: 27 · 2017: 5
- FWCI
- 16.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Autism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (acceptedVersion)
- BIROn (Birkbeck, University of London) (acceptedVersion)
- Greenwich Academic Literature Archive (University of Greenwich) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- TSpace (University of Toronto) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eSpace (Curtin University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Apollo
- Apollo (cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Innovative Medicines Initiative (FP7/2007-2013)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- autism spectrum disorder, precision medicine, phenotypic heterogeneity, accelerated longitudinal design, twin studies, genetic and environmental factors, neuropsychological profile, brain structure and function, biochemical markers, genomics, preregistration
- MeSH terms
- Autism Spectrum Disorder, Adult, Brain, Child, Female, Hair, Humans, Individuality, Longitudinal Studies, Magnetic Resonance Imaging, Male, Phenotype, Saliva, Biomarkers, Patient Selection, Genetic Heterogeneity, Siblings, Eye Movement Measurements, Precision Medicine, Neuroimaging
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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