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A normative modelling approach reveals age-atypical cortical thickness in a subgroup of males with autism spectrum disorder.

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Bethlehem, Richard AI  ORCID logo
Seidlitz, Jakob 
Romero-Garcia, Rafael 


Understanding heterogeneity is an important goal on the path to precision medicine for autism spectrum disorders (ASD). We examined how cortical thickness (CT) in ASD can be parameterized as an individualized metric of atypicality relative to typically-developing (TD) age-related norms. Across a large sample (n = 870 per group) and wide age range (5-40 years), we applied normative modelling resulting in individualized whole-brain maps of age-related CT atypicality in ASD and isolating a small subgroup with highly age-atypical CT. Age-normed CT scores also highlights on-average differentiation, and associations with behavioural symptomatology that is separate from insights gleaned from traditional case-control approaches. This work showcases an individualized approach for understanding ASD heterogeneity that could potentially further prioritize work on a subset of individuals with cortical pathophysiology represented in age-related CT atypicality. Only a small subset of ASD individuals are actually highly atypical relative to age-norms. driving small on-average case-control differences.



Adolescent, Age Factors, Autism Spectrum Disorder, Case-Control Studies, Cerebral Cortex, Female, Humans, Linear Models, Male, Models, Biological, Phenotype

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Commun Biol

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Springer Science and Business Media LLC


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British Academy (PFO\170517)
Medical Research Council (MR/M009041/1)
This work was further supported by a European Research Council (ERC) Starting Grant (755816; AUTISMS) awarded to MVL. RRG was funded by the Guarantors of Brain. JS was funded by the National Institutes of Health Oxford-Cambridge Scholars Program. RAIB was funded by a British Academy Post-Doctoral Fellowship and Autism Research Trust.