{"doi":"10.1101/2025.11.25.690402","title":"Linking White-Matter Development to Clinical Variation in Autism: Longitudinal Normative Modelling of Fractional Anisotropy (FA) in the EU-AIMS LEAP Cohort","abstract":"Abstract Background Autism is characterised by neurobiological and clinical heterogeneity, which often limits the sensitivity of traditional group comparisons. Longitudinal normative modelling offers a way to capture heterogeneity and to describe an individual’s brain–behaviour relationships beyond diagnostic categories. Methods We analysed diffusion MRI scans from 3 waves of the EU-AIMS Longitudinal European Autism Project (LEAP). Using normative models of white matter fractional anisotropy (FA) trained on a neurotypical reference cohort, we computed individual deviations relative to age-typical norms. Our sample included 544 individuals (Wave 1: 189 autistic 162 non-autistic; Wave 2: 162 autistic136 non-autistic; Wave 3: 145 autistic 84 non-autistic), aged 7–37 years, with mean intervals of ∼1.5 years (W1–W2) and ∼6 years (W2–W3). We first tested for group level differences between autistic and non-autistic participants in FA deviations across 48 white matter tracts and then examined the associations between these deviation scores and sensory, adaptive, cognitive, and behavioural measures across development within the autism group. Results Group-wise comparisons revealed no significant differences in FA deviations between autistic and non-autistic participants. Within the autism group, multivariate analysis (CCA) showed significant (p<0.05) cross-sectional brain-behaviour associations at Wave 1 (r=0.26) and Wave 2 (r=0.32), but not at Wave 3. Longitudinally, we found significant multivariate associations only for the W1–W3 interval (r=0.36). Follow-up univariate correlations supported these findings, with Wave 2 showing widespread moderate (r≈0.35) associations while longitudinally, the univariate associations were generally weaker (r≈0.2). Across analyses, higher FA was generally associated with higher Vineland Adaptive Behaviour Scales (VABS) and lower Short Sensory Profile (SSP) scores. Associations with the Autism Diagnostic Observation Schedule (ADOS) were mixed, and the Social Responsiveness Scale (SRS) and Repetitive Behaviour Scale (RBS) showed wave-dependent relationships, with specific tract involvement varying across timepoints. Conclusions White-matter organisation in autism does not differ from that of non-autistic on average but rather follows a dimensional architecture within the autism phenotype. We showed that person-specific deviations from shared neurodevelopmental pathways are linked to behavioural variation among autistic individuals, which cannot be captured by group-level approaches alone. Longitudinal normative modelling provides a practical approach to understand and quantify this heterogeneity. EU-AIMS LEAP Group Zuzana Suchomelova, Mee Rim Oh, Chirag Mehra, Mei Lin Law, Sanjana Gandhi, Laura Bravo Balsa, Maria Dauvermann, Isabel Yorke, Beth Oakley, Rosemary J. Holt, Edward Bullock, Yumnah Kahn, Esme Hayes, Leona Strauss, Noel Lam, Anouk Dykstra, Kim Lamers, Marije Mars, Lucas Geelen, Lotte Beckers, Anna Praat, Feline van Aagten, Sjors Reith, Viola Hollestein, Sanne Kluin, Natalie Forde, Jill Naaijen, Anna Kaiser, Sarah Baumeister, Pascal-M. Aggensteiner, Jumana Ahmad, Sara Ambrosino, Bonnie Auyeung, Tobias Banaschewski, Simon Baron-Cohen, Sarah Baumeister, Christian F. Beckmann, Sven Bölte, Thomas Bourgeron, Carsten Bours, Michael Brammer, Daniel Brandeis, Claudia Brogna, Yvette de Bruijn, Jan K. Buitelaar, Bhismadev Chakrabarti, Tony Charman, Ineke Cornelissen, Daisy Crawley, Flavio Dell’Acqua, Guillaume Dumas, Sarah Durston, Christine Ecker, Jessica Faulkner, Vincent Frouin, Pilar Garcés, David Goyard, Lindsay Ham, Hannah Hayward, Joerg Hipp, Rosemary J. Holt, Mark H. Johnson, Emily J. H. Jones, Prantik Kundu, Meng-Chuan Lai, Xavier Liogier D’ardhuy, Michael V. Lombardo, Eva Loth, David J. Lythgoe, René Mandl, Andre Marquand, Luke Mason, Maarten Mennes, Andreas Meyer-Lindenberg, Carolin Moessnang, Nico Mueller, Declan G. M. Murphy, Laurence O’Dwyer, Marianne Oldehinkel, Bob Oranje, Gahan Pandi","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":583204,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.7229,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":342818,"name":"Natalie J. Forde","orcid":"0000-0002-1452-0600","position":1,"is_corresponding":false},{"id":45320,"name":"Barbora Rehák Bučková","orcid":"0000-0001-5619-3946","position":2,"is_corresponding":false},{"id":817058,"name":"Flavio Dell’Acqua","orcid":"0000-0001-5313-5476","position":3,"is_corresponding":false},{"id":105643,"name":"Tony Charman","orcid":"0000-0003-1993-6549","position":4,"is_corresponding":false},{"id":562268,"name":"Eva Loth","orcid":"0000-0001-9458-9167","position":5,"is_corresponding":false},{"id":1083945,"name":"Bethany Oakley","orcid":"0000-0002-1968-134X","position":6,"is_corresponding":false},{"id":1495830,"name":"Laura Colomar Molla","orcid":null,"position":7,"is_corresponding":false},{"id":1495445,"name":"Isabel Yorke","orcid":"0000-0001-8603-0910","position":8,"is_corresponding":false},{"id":1495446,"name":"Richard Stones","orcid":"0000-0002-6576-6328","position":9,"is_corresponding":false},{"id":232634,"name":"Declan Murphy","orcid":"0000-0002-6664-7451","position":10,"is_corresponding":false},{"id":237618,"name":"Tobias Banaschewski","orcid":"0000-0003-4595-1144","position":11,"is_corresponding":false},{"id":109357,"name":"Jan K. Buitelaar","orcid":"0000-0001-8288-7757","position":12,"is_corresponding":false},{"id":1495831,"name":"EU-AIMS LEAP Group","orcid":null,"position":13,"is_corresponding":false},{"id":107839,"name":"André F. Marquand","orcid":"0000-0001-5903-203X","position":14,"is_corresponding":false},{"id":341865,"name":"Christian F. Beckmann","orcid":"0000-0002-3373-3193","position":15,"is_corresponding":false},{"id":1338861,"name":"Ramona Cîrstian","orcid":"0000-0001-7302-6314","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:59:03.725721Z","pmid":"41394674","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}