Association Between the Probability of Autism Spectrum Disorder and Normative Sex-Related Phenotypic Diversity in Brain Structure

Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) Consortium

doi:10.1001/jamapsychiatry.2016.3990

Association Between the Probability of Autism Spectrum Disorder and Normative Sex-Related Phenotypic Diversity in Brain Structure

Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) Consortium

Research output: Contribution to journal › Article › peer-review

Abstract

Importance: Autism spectrum disorder (ASD) is 2 to 5 times more common in male individuals than in female individuals. While the male preponderant prevalence of ASD might partially be explained by sex differences in clinical symptoms, etiological models suggest that the biological male phenotype carries a higher intrinsic risk for ASD than the female phenotype. To our knowledge, this hypothesis has never been tested directly, and the neurobiological mechanisms that modulate ASD risk in male individuals and female individuals remain elusive.

Objectives: To examine the probability of ASD as a function of normative sex-related phenotypic diversity in brain structure and to identify the patterns of sex-related neuroanatomical variability associated with low or high probability of ASD.

Design, Setting, and Participants: This study examined a cross-sectional sample of 98 right-handed, high-functioning adults with ASD and 98 matched neurotypical control individuals aged 18 to 42 years. A multivariate probabilistic classification approach was used to develop a predictive model of biological sex based on cortical thickness measures assessed via magnetic resonance imaging in neurotypical controls. This normative model was subsequently applied to individuals with ASD. The study dates were June 2005 to October 2009, and this analysis was conducted between June 2015 and July 2016.

Main Outcomes and Measures: Sample and population ASD probability estimates as a function of normative sex-related diversity in brain structure, as well as neuroanatomical patterns associated with low or high ASD probability in male individuals and female individuals.

Results: Among the 98 individuals with ASD, 49 were male and 49 female, with a mean (SD) age of 26.88 (7.18) years. Among the 98 controls, 51 were male and 47 female, with a mean (SD) age of 27.39 (6.44) years. The sample probability of ASD increased significantly with predictive probabilities for the male neuroanatomical brain phenotype. For example, biological female individuals with a more male-typic pattern of brain anatomy were significantly (ie, 3 times) more likely to have ASD than biological female individuals with a characteristically female brain phenotype (P = .72 vs .24, respectively; χ21 = 20.26; P < .001; difference in P values, 0.48; 95% CI, 0.29-0.68). This finding translates to an estimated variability in population prevalence from 0.2% to 1.3%, respectively. Moreover, the patterns of neuroanatomical variability carrying low or high ASD probability were sex specific (eg, in inferior temporal regions, where ASD has different neurobiological underpinnings in male individuals and female individuals).

Conclusions and Relevance: These findings highlight the need for considering normative sex-related phenotypic diversity when determining an individual's risk for ASD and provide important novel insights into the neurobiological mechanisms mediating sex differences in ASD prevalence.

Original language	English
Pages (from-to)	329-338
Number of pages	10
Journal	JAMA PSYCHIATRY
Volume	74
Issue number	4
DOIs	https://doi.org/10.1001/jamapsychiatry.2016.3990
Publication status	Published - 1 Apr 2017

Keywords

Adolescent
Adult
Autism Spectrum Disorder/diagnostic imaging
Case-Control Studies
Cerebral Cortex/diagnostic imaging
Cross-Sectional Studies
Female
Gray Matter/diagnostic imaging
Humans
Image Enhancement
Image Interpretation, Computer-Assisted
Magnetic Resonance Imaging
Male
Models, Statistical
Multivariate Analysis
Phenotype
Reference Values
Risk Factors
Sex Characteristics
White Matter/diagnostic imaging
Young Adult

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10.1001/jamapsychiatry.2016.3990

Cite this

@article{dfde48a07c7e4c1c992a651a612e194d,

title = "Association Between the Probability of Autism Spectrum Disorder and Normative Sex-Related Phenotypic Diversity in Brain Structure",

abstract = "Importance: Autism spectrum disorder (ASD) is 2 to 5 times more common in male individuals than in female individuals. While the male preponderant prevalence of ASD might partially be explained by sex differences in clinical symptoms, etiological models suggest that the biological male phenotype carries a higher intrinsic risk for ASD than the female phenotype. To our knowledge, this hypothesis has never been tested directly, and the neurobiological mechanisms that modulate ASD risk in male individuals and female individuals remain elusive.Objectives: To examine the probability of ASD as a function of normative sex-related phenotypic diversity in brain structure and to identify the patterns of sex-related neuroanatomical variability associated with low or high probability of ASD.Design, Setting, and Participants: This study examined a cross-sectional sample of 98 right-handed, high-functioning adults with ASD and 98 matched neurotypical control individuals aged 18 to 42 years. A multivariate probabilistic classification approach was used to develop a predictive model of biological sex based on cortical thickness measures assessed via magnetic resonance imaging in neurotypical controls. This normative model was subsequently applied to individuals with ASD. The study dates were June 2005 to October 2009, and this analysis was conducted between June 2015 and July 2016.Main Outcomes and Measures: Sample and population ASD probability estimates as a function of normative sex-related diversity in brain structure, as well as neuroanatomical patterns associated with low or high ASD probability in male individuals and female individuals.Results: Among the 98 individuals with ASD, 49 were male and 49 female, with a mean (SD) age of 26.88 (7.18) years. Among the 98 controls, 51 were male and 47 female, with a mean (SD) age of 27.39 (6.44) years. The sample probability of ASD increased significantly with predictive probabilities for the male neuroanatomical brain phenotype. For example, biological female individuals with a more male-typic pattern of brain anatomy were significantly (ie, 3 times) more likely to have ASD than biological female individuals with a characteristically female brain phenotype (P = .72 vs .24, respectively; χ21 = 20.26; P < .001; difference in P values, 0.48; 95% CI, 0.29-0.68). This finding translates to an estimated variability in population prevalence from 0.2% to 1.3%, respectively. Moreover, the patterns of neuroanatomical variability carrying low or high ASD probability were sex specific (eg, in inferior temporal regions, where ASD has different neurobiological underpinnings in male individuals and female individuals).Conclusions and Relevance: These findings highlight the need for considering normative sex-related phenotypic diversity when determining an individual's risk for ASD and provide important novel insights into the neurobiological mechanisms mediating sex differences in ASD prevalence.",

keywords = "Adolescent, Adult, Autism Spectrum Disorder/diagnostic imaging, Case-Control Studies, Cerebral Cortex/diagnostic imaging, Cross-Sectional Studies, Female, Gray Matter/diagnostic imaging, Humans, Image Enhancement, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Male, Models, Statistical, Multivariate Analysis, Phenotype, Reference Values, Risk Factors, Sex Characteristics, White Matter/diagnostic imaging, Young Adult",

author = "{Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) Consortium} and Christine Ecker and Andrews, {Derek S} and Gudbrandsen, {Christina M} and Marquand, {Andre F} and Ginestet, {Cedric E} and Daly, {Eileen M} and Murphy, {Clodagh M} and Meng-Chuan Lai and Lombardo, {Michael V} and Ruigrok, {Amber N V} and Bullmore, {Edward T} and John Suckling and Williams, {Steven C R} and Simon Baron-Cohen and Craig, {Michael C} and Murphy, {Declan G M}",

year = "2017",

month = apr,

day = "1",

doi = "10.1001/jamapsychiatry.2016.3990",

language = "English",

volume = "74",

pages = "329--338",

journal = "JAMA PSYCHIATRY",

issn = "2168-622X",

publisher = "American Medical Association",

number = "4",

}

TY - JOUR

T1 - Association Between the Probability of Autism Spectrum Disorder and Normative Sex-Related Phenotypic Diversity in Brain Structure

AU - Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) Consortium

AU - Ecker, Christine

AU - Andrews, Derek S

AU - Gudbrandsen, Christina M

AU - Marquand, Andre F

AU - Ginestet, Cedric E

AU - Daly, Eileen M

AU - Murphy, Clodagh M

AU - Lai, Meng-Chuan

AU - Lombardo, Michael V

AU - Ruigrok, Amber N V

AU - Bullmore, Edward T

AU - Suckling, John

AU - Williams, Steven C R

AU - Baron-Cohen, Simon

AU - Craig, Michael C

AU - Murphy, Declan G M

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Importance: Autism spectrum disorder (ASD) is 2 to 5 times more common in male individuals than in female individuals. While the male preponderant prevalence of ASD might partially be explained by sex differences in clinical symptoms, etiological models suggest that the biological male phenotype carries a higher intrinsic risk for ASD than the female phenotype. To our knowledge, this hypothesis has never been tested directly, and the neurobiological mechanisms that modulate ASD risk in male individuals and female individuals remain elusive.Objectives: To examine the probability of ASD as a function of normative sex-related phenotypic diversity in brain structure and to identify the patterns of sex-related neuroanatomical variability associated with low or high probability of ASD.Design, Setting, and Participants: This study examined a cross-sectional sample of 98 right-handed, high-functioning adults with ASD and 98 matched neurotypical control individuals aged 18 to 42 years. A multivariate probabilistic classification approach was used to develop a predictive model of biological sex based on cortical thickness measures assessed via magnetic resonance imaging in neurotypical controls. This normative model was subsequently applied to individuals with ASD. The study dates were June 2005 to October 2009, and this analysis was conducted between June 2015 and July 2016.Main Outcomes and Measures: Sample and population ASD probability estimates as a function of normative sex-related diversity in brain structure, as well as neuroanatomical patterns associated with low or high ASD probability in male individuals and female individuals.Results: Among the 98 individuals with ASD, 49 were male and 49 female, with a mean (SD) age of 26.88 (7.18) years. Among the 98 controls, 51 were male and 47 female, with a mean (SD) age of 27.39 (6.44) years. The sample probability of ASD increased significantly with predictive probabilities for the male neuroanatomical brain phenotype. For example, biological female individuals with a more male-typic pattern of brain anatomy were significantly (ie, 3 times) more likely to have ASD than biological female individuals with a characteristically female brain phenotype (P = .72 vs .24, respectively; χ21 = 20.26; P < .001; difference in P values, 0.48; 95% CI, 0.29-0.68). This finding translates to an estimated variability in population prevalence from 0.2% to 1.3%, respectively. Moreover, the patterns of neuroanatomical variability carrying low or high ASD probability were sex specific (eg, in inferior temporal regions, where ASD has different neurobiological underpinnings in male individuals and female individuals).Conclusions and Relevance: These findings highlight the need for considering normative sex-related phenotypic diversity when determining an individual's risk for ASD and provide important novel insights into the neurobiological mechanisms mediating sex differences in ASD prevalence.

AB - Importance: Autism spectrum disorder (ASD) is 2 to 5 times more common in male individuals than in female individuals. While the male preponderant prevalence of ASD might partially be explained by sex differences in clinical symptoms, etiological models suggest that the biological male phenotype carries a higher intrinsic risk for ASD than the female phenotype. To our knowledge, this hypothesis has never been tested directly, and the neurobiological mechanisms that modulate ASD risk in male individuals and female individuals remain elusive.Objectives: To examine the probability of ASD as a function of normative sex-related phenotypic diversity in brain structure and to identify the patterns of sex-related neuroanatomical variability associated with low or high probability of ASD.Design, Setting, and Participants: This study examined a cross-sectional sample of 98 right-handed, high-functioning adults with ASD and 98 matched neurotypical control individuals aged 18 to 42 years. A multivariate probabilistic classification approach was used to develop a predictive model of biological sex based on cortical thickness measures assessed via magnetic resonance imaging in neurotypical controls. This normative model was subsequently applied to individuals with ASD. The study dates were June 2005 to October 2009, and this analysis was conducted between June 2015 and July 2016.Main Outcomes and Measures: Sample and population ASD probability estimates as a function of normative sex-related diversity in brain structure, as well as neuroanatomical patterns associated with low or high ASD probability in male individuals and female individuals.Results: Among the 98 individuals with ASD, 49 were male and 49 female, with a mean (SD) age of 26.88 (7.18) years. Among the 98 controls, 51 were male and 47 female, with a mean (SD) age of 27.39 (6.44) years. The sample probability of ASD increased significantly with predictive probabilities for the male neuroanatomical brain phenotype. For example, biological female individuals with a more male-typic pattern of brain anatomy were significantly (ie, 3 times) more likely to have ASD than biological female individuals with a characteristically female brain phenotype (P = .72 vs .24, respectively; χ21 = 20.26; P < .001; difference in P values, 0.48; 95% CI, 0.29-0.68). This finding translates to an estimated variability in population prevalence from 0.2% to 1.3%, respectively. Moreover, the patterns of neuroanatomical variability carrying low or high ASD probability were sex specific (eg, in inferior temporal regions, where ASD has different neurobiological underpinnings in male individuals and female individuals).Conclusions and Relevance: These findings highlight the need for considering normative sex-related phenotypic diversity when determining an individual's risk for ASD and provide important novel insights into the neurobiological mechanisms mediating sex differences in ASD prevalence.

KW - Adolescent

KW - Adult

KW - Autism Spectrum Disorder/diagnostic imaging

KW - Case-Control Studies

KW - Cerebral Cortex/diagnostic imaging

KW - Cross-Sectional Studies

KW - Female

KW - Gray Matter/diagnostic imaging

KW - Humans

KW - Image Enhancement

KW - Image Interpretation, Computer-Assisted

KW - Magnetic Resonance Imaging

KW - Male

KW - Models, Statistical

KW - Multivariate Analysis

KW - Phenotype

KW - Reference Values

KW - Risk Factors

KW - Sex Characteristics

KW - White Matter/diagnostic imaging

KW - Young Adult

U2 - 10.1001/jamapsychiatry.2016.3990

DO - 10.1001/jamapsychiatry.2016.3990

M3 - Article

C2 - 28196230

SN - 2168-622X

VL - 74

SP - 329

EP - 338

JO - JAMA PSYCHIATRY

JF - JAMA PSYCHIATRY

IS - 4

ER -