Mapping the Heterogeneous Brain Structural Phenotype of Autism Spectrum Disorder Using the Normative Model

Xiaolong Shan, Lucina Q. Uddin, Jinming Xiao, Changchun He, Zihan Ling, Lei Li, Xinyue Huang, Huafu Chen, Xujun Duan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by substantial clinical and biological heterogeneity. Quantitative and individualized metrics for delineating the heterogeneity of brain structure in ASD are still lacking. Likewise, the extent to which brain structural metrics of ASD deviate from typical development (TD) and whether deviations can be used for parsing brain structural phenotypes of ASD is unclear. Methods: T1-weighted magnetic resonance imaging data from the Autism Brain Imaging Data Exchange (ABIDE) II (nTD = 564) were used to generate a normative model to map brain structure deviations of ABIDE I subjects (nTD = 560, nASD = 496). Voxel-based morphometry was used to compute gray matter volume. Non-negative matrix factorization was employed to decompose the gray matter matrix into 6 factors and weights. These weights were used for normative modeling to estimate the factor deviations. Then, clustering analysis was used to identify ASD subtypes. Results: Compared with TD, ASD showed increased weights and deviations in 5 factors. Three subtypes with distinct neuroanatomical deviation patterns were identified. ASD subtype 1 and subtype 3 showed positive deviations, whereas ASD subtype 2 showed negative deviations. Distinct clinical manifestations in social communication deficits were identified among the three subtypes. Conclusions: Our findings suggest that individuals with ASD have heterogeneous deviation patterns in brain structure. The results highlight the need to test for subtypes in neuroimaging studies of ASD. This study also presents a framework for understanding neuroanatomical heterogeneity in this increasingly prevalent neurodevelopmental disorder.

Original languageEnglish (US)
JournalBiological Psychiatry
StateAccepted/In press - 2022
Externally publishedYes


  • Deviation
  • Gray matter volume
  • Neuroanatomical heterogeneity
  • Neurodevelopmental disorders
  • Non-negative matrix factorization

ASJC Scopus subject areas

  • Biological Psychiatry


Dive into the research topics of 'Mapping the Heterogeneous Brain Structural Phenotype of Autism Spectrum Disorder Using the Normative Model'. Together they form a unique fingerprint.

Cite this