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bioRxiv · 10.64898/2026.05.19.726341

The Regional Vulnerability Index (RVI) as a Neuroimaging-Based Biomarker for Autism: Associations with Likelihood, Cognition, and Longitudinal Social Outcomes

Pagan, A. F.·Lawrence, K. E.·Buitelaar, J.·Gao, S.·Thompson, P. M.·Ma, Y.·Cosgrove, K. T.·Laezza, F.·Hafeman, D. M.·Donohue, B.·Adhikari, B. M.·Pillai, A.·Jahanshad, N.·Li, W.·Thomopoulos, S.·Loveland, K. A.·Acierno, R.·Warner, A.·Montiel-Nava, C.·Demopoulos, C.·Temple, J. R.·Soares, J. C.·Chen, S.·Hong, L. E.·The ENIGMA autism Working Group,·Kochunov, P.
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Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with symptoms spanning cognitive, social and behavioral domains and leading to lifelong challenges. Autism is heritable but specific genetic and environmental factors that shape its early neurodevelopmental trajectory remain unknown. Despite the clinical variability, neuroimaging findings from Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA)-ASD consortium identified stable and replicable patterns of cortical and subcortical differences that were consistent with those reported by an independent consortium, the Cognitive Genetics Collaborative Research Organization (COCORO) in Japan. Here we developed and evaluated a regional vulnerability index (RVI), a similarity metric that quantifies how closely a persons brain resembles the specific pattern of an individual with autism. RVI-ASD is based on combining the regional effect sizes for regional brain measurements published by the ENIGMA-ASD group with microstructural white matter integrity differences reported by COCORO. RVI-ASD showed significantly higher effect size for case-control differences relative to any individual brain measure (d=0.30 vs. d=0.01-0.21) in individuals with autism, particularly in the adolescent-to-adult sample (N=2,577; Mean age = 16.1; SD=5.0). We next calculated RVI-ASD in the baseline and follow-up (ages 10 and 12) data from normally developing participants of the ABCD study (N=4,201). We tested the longitudinal stability, heritability, genotype-by-age interaction and sensitivity of RVI-ASD to known factors and cognitive measurements. RVI-ASD were stable on the 2-year follow up (ICC=0.76-0.92); showed significant heritability (h{superscript 2}=0.55-0.83, p<10-16) but was not affected by gene-by-age interaction. RVI-ASD showed significant positive correlation with paternal age, while correlation with maternal age was non-significant. Baseline and follow-up RVI-ASD were negatively correlated with cognitive measures including total, fluid and crystallized intelligence (r=-0.09 to -0.11, p<10-6). RVI-ASD scores tracked with core autism phenotypes including poor eye contact and rigid routines (p < .01). In a sub-sample of children with symptoms of autism (N=20), we found that earlier age of symptom onset was strongly correlated with higher White Matter RVI (r = -0.61), linking early behavioral emergence to the neuroanatomical signature. Longitudinal changes in subcortical RVI-ASD are significantly correlated with change in social functioning. The RVI-ASD is a neuroimaging-based biomarker linked to stable and reproducible brain patterns in autism. RVI-ASD allows researchers to study associations with factors associated with the likelihood for autism and cognition across large and inclusive non-clinical samples, thus moving beyond simple case-control models to understand the biological pathways of autism.

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Pagan, A. F., Lawrence, K. E., Buitelaar, J., Gao, S., Thompson, P. M., Ma, Y., Cosgrove, K. T., Laezza, F., Hafeman, D. M., Donohue, B., Adhikari, B. M., Pillai, A., Jahanshad, N., Li, W., Thomopoulos, S., Loveland, K. A., Acierno, R., Warner, A., Montiel-Nava, C., Demopoulos, C., Temple, J. R., Soares, J. C., Chen, S., Hong, L. E., The ENIGMA autism Working Group,, Kochunov, P.. 2026-05-26. The Regional Vulnerability Index (RVI) as a Neuroimaging-Based Biomarker for Autism: Associations with Likelihood, Cognition, and Longitudinal Social Outcomes. https://doi.org/10.64898/2026.05.19.726341

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