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Reconciling Dimensional and Categorical Models of Autism Heterogeneity: a Brain Connectomics & Behavioral Study

By Siyi Tang, Nanbo Sun, Dorothea L. Floris, Xiuming Zhang, Adriana Di Martino, B.T. Thomas Yeo

Posted 04 Jul 2019
bioRxiv DOI: 10.1101/692772 (published DOI: 10.1016/j.biopsych.2019.11.009)

Background: Heterogeneity in autism spectrum disorder (ASD) has hindered the development of biomarkers, thus motivating subtyping efforts. Most subtyping studies divide ASD individuals into non-overlapping (categorical) subgroups. However, continuous inter-individual variation in ASD suggests the need for a dimensional approach. Methods: A Bayesian model was employed to decompose resting-state functional connectivity (RSFC) of ASD individuals into multiple abnormal RSFC patterns, i.e., categorical subtypes henceforth referred to as "factors". Importantly, the model allowed each individual to express one or more factors to varying degrees (dimensional subtyping). The model was applied to 306 ASD individuals (age 5.2-57 years) from two multisite repositories. Posthoc analyses associated factors with symptoms and demographics. Results: Analyses yielded three factors with dissociable whole-brain hypo/hyper RSFC patterns. Most participants expressed multiple (categorical) factors, suggestive of a mosaic of subtypes within individuals. All factors shared abnormal RSFC involving the default network, but the directionality (hypo/hyper RSFC) differed across factors. Factor 1 was associated with core ASD symptoms, while factor 2 was associated with comorbid symptoms. Older males preferentially expressed factor 3. Factors were robust across multiple control analyses and not associated with IQ, nor head motion. Conclusions: There exist at least three ASD factors with dissociable patterns of whole-brain RSFC, behaviors and demographics. Heterogeneous default network hypo/hyper RSFC across the factors might explain previously reported inconsistencies. The factors differentiated between core ASD and comorbid symptoms - a less appreciated domain of heterogeneity in ASD. These factors are co-expressed in ASD individuals with different degrees, thus reconciling categorical and dimensional perspectives of ASD heterogeneity.

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