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Sex differences in cortical volume and gyrification in autism.

Schaer M, Kochalka J, Padmanabhan A, Supekar K, Menon V - Mol Autism (2015)

Bottom Line: We detected a main effect of sex in the bilateral superior temporal cortex, driven by greater cortical volume in females compared to males in both the ASD and TD groups.Post-hoc analyses revealed that sex-by-diagnosis interaction was driven by reduced vmPFC/OFC gyrification in males with ASD, compared to females with ASD as well as TD males and females.Stability analyses provide novel quantitative insights into why smaller samples may have previously failed to detect sex differences.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305 USA.

ABSTRACT

Background: Male predominance is a prominent feature of autism spectrum disorders (ASD), with a reported male to female ratio of 4:1. Because of the overwhelming focus on males, little is known about the neuroanatomical basis of sex differences in ASD. Investigations of sex differences with adequate sample sizes are critical for improving our understanding of the biological mechanisms underlying ASD in females.

Methods: We leveraged the open-access autism brain imaging data exchange (ABIDE) dataset to obtain structural brain imaging data from 53 females with ASD, who were matched with equivalent samples of males with ASD, and their typically developing (TD) male and female peers. Brain images were processed with FreeSurfer to assess three key features of local cortical morphometry: volume, thickness, and gyrification. A whole-brain approach was used to identify significant effects of sex, diagnosis, and sex-by-diagnosis interaction, using a stringent threshold of p < 0.01 to control for false positives. Stability and power analyses were conducted to guide future research on sex differences in ASD.

Results: We detected a main effect of sex in the bilateral superior temporal cortex, driven by greater cortical volume in females compared to males in both the ASD and TD groups. Sex-by-diagnosis interaction was detected in the gyrification of the ventromedial/orbitofrontal prefrontal cortex (vmPFC/OFC). Post-hoc analyses revealed that sex-by-diagnosis interaction was driven by reduced vmPFC/OFC gyrification in males with ASD, compared to females with ASD as well as TD males and females. Finally, stability analyses demonstrated a dramatic drop in the likelihood of observing significant clusters as the sample size decreased, suggesting that previous studies have been largely underpowered. For instance, with a sample of 30 females with ASD (total n = 120), a significant sex-by-diagnosis interaction was only detected in 50 % of the simulated subsamples.

Conclusions: Our results demonstrate that some features of typical sex differences are preserved in the brain of individuals with ASD, while others are not. Sex differences in ASD are associated with cortical regions involved in language and social function, two domains of deficits in the disorder. Stability analyses provide novel quantitative insights into why smaller samples may have previously failed to detect sex differences.

No MeSH data available.


Related in: MedlinePlus

Sex-by-diagnosis interaction: local gyrification. a Whole-brain analyses (p < 0.01, corrected). In this vmPFC/OFC cluster, we found a significant sex-by-diagnosis interaction, males with ASD show a selective reduction in gyrification as compared to all three other groups. When the smaller brain size of females is not taken into account (upper panel), TD females typically show reduced gyrification. This is however not the case within the ASD group, where even raw lGI values tend to be higher in females than males with ASD. For the post-hoc two-by-two analyses, the following p values are depicted: *p < 0.05, **p < 0.01, ***p < 0.001. b Bootstrapping analyses. The likelihood to observe a significant sex-by-diagnosis interaction in the vmPFC/OFC cluster was tested using a similar bootstrap procedure as for the main effect of sex. Again, the pattern of a decrease in the likelihood to observe any significant effect as the sample size decreases suggests that previous studies of sex differences in ASD were likely underpowered to estimate robust and reproducible effects. c Power analyses. Plot depicting the relationship between statistical power and sample size, computed a posteriori based on the effect sizes obtain in the full dataset
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Fig2: Sex-by-diagnosis interaction: local gyrification. a Whole-brain analyses (p < 0.01, corrected). In this vmPFC/OFC cluster, we found a significant sex-by-diagnosis interaction, males with ASD show a selective reduction in gyrification as compared to all three other groups. When the smaller brain size of females is not taken into account (upper panel), TD females typically show reduced gyrification. This is however not the case within the ASD group, where even raw lGI values tend to be higher in females than males with ASD. For the post-hoc two-by-two analyses, the following p values are depicted: *p < 0.05, **p < 0.01, ***p < 0.001. b Bootstrapping analyses. The likelihood to observe a significant sex-by-diagnosis interaction in the vmPFC/OFC cluster was tested using a similar bootstrap procedure as for the main effect of sex. Again, the pattern of a decrease in the likelihood to observe any significant effect as the sample size decreases suggests that previous studies of sex differences in ASD were likely underpowered to estimate robust and reproducible effects. c Power analyses. Plot depicting the relationship between statistical power and sample size, computed a posteriori based on the effect sizes obtain in the full dataset

Mentions: We used a general linear model (GLM) to estimate the effect of sex, diagnosis, and sex-by-diagnosis interactions on all neuroanatomical variables, including age as a covariate. Cortical volume was also included as a covariate in the analyses of local cortical volume and gyrification to account for sex-related differences in brain scaling (see Table 2). Given that mean cortical thickness did not differ between males and females, we did not include any additional covariate in the cortical thickness analysis (see Results). A statistical threshold of p < 0.01 (corrected for multiple comparisons using Monte Carlo simulations [56]) was used for all analyses, to provide stringent criteria to minimize false positives. Clusters with significant effects of diagnosis, sex, or sex-by-diagnosis interactions were further tested using two-by-two analysis of covariance (ANCOVA) analyses between the four groups. For the post-hoc analyses, a more permissive significance threshold is reported on the plots, with the following p values provided in Figs. 1 and 2: *p < 0.05, **p < 0.01, ***p < 0.001.Table 2


Sex differences in cortical volume and gyrification in autism.

Schaer M, Kochalka J, Padmanabhan A, Supekar K, Menon V - Mol Autism (2015)

Sex-by-diagnosis interaction: local gyrification. a Whole-brain analyses (p < 0.01, corrected). In this vmPFC/OFC cluster, we found a significant sex-by-diagnosis interaction, males with ASD show a selective reduction in gyrification as compared to all three other groups. When the smaller brain size of females is not taken into account (upper panel), TD females typically show reduced gyrification. This is however not the case within the ASD group, where even raw lGI values tend to be higher in females than males with ASD. For the post-hoc two-by-two analyses, the following p values are depicted: *p < 0.05, **p < 0.01, ***p < 0.001. b Bootstrapping analyses. The likelihood to observe a significant sex-by-diagnosis interaction in the vmPFC/OFC cluster was tested using a similar bootstrap procedure as for the main effect of sex. Again, the pattern of a decrease in the likelihood to observe any significant effect as the sample size decreases suggests that previous studies of sex differences in ASD were likely underpowered to estimate robust and reproducible effects. c Power analyses. Plot depicting the relationship between statistical power and sample size, computed a posteriori based on the effect sizes obtain in the full dataset
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4491212&req=5

Fig2: Sex-by-diagnosis interaction: local gyrification. a Whole-brain analyses (p < 0.01, corrected). In this vmPFC/OFC cluster, we found a significant sex-by-diagnosis interaction, males with ASD show a selective reduction in gyrification as compared to all three other groups. When the smaller brain size of females is not taken into account (upper panel), TD females typically show reduced gyrification. This is however not the case within the ASD group, where even raw lGI values tend to be higher in females than males with ASD. For the post-hoc two-by-two analyses, the following p values are depicted: *p < 0.05, **p < 0.01, ***p < 0.001. b Bootstrapping analyses. The likelihood to observe a significant sex-by-diagnosis interaction in the vmPFC/OFC cluster was tested using a similar bootstrap procedure as for the main effect of sex. Again, the pattern of a decrease in the likelihood to observe any significant effect as the sample size decreases suggests that previous studies of sex differences in ASD were likely underpowered to estimate robust and reproducible effects. c Power analyses. Plot depicting the relationship between statistical power and sample size, computed a posteriori based on the effect sizes obtain in the full dataset
Mentions: We used a general linear model (GLM) to estimate the effect of sex, diagnosis, and sex-by-diagnosis interactions on all neuroanatomical variables, including age as a covariate. Cortical volume was also included as a covariate in the analyses of local cortical volume and gyrification to account for sex-related differences in brain scaling (see Table 2). Given that mean cortical thickness did not differ between males and females, we did not include any additional covariate in the cortical thickness analysis (see Results). A statistical threshold of p < 0.01 (corrected for multiple comparisons using Monte Carlo simulations [56]) was used for all analyses, to provide stringent criteria to minimize false positives. Clusters with significant effects of diagnosis, sex, or sex-by-diagnosis interactions were further tested using two-by-two analysis of covariance (ANCOVA) analyses between the four groups. For the post-hoc analyses, a more permissive significance threshold is reported on the plots, with the following p values provided in Figs. 1 and 2: *p < 0.05, **p < 0.01, ***p < 0.001.Table 2

Bottom Line: We detected a main effect of sex in the bilateral superior temporal cortex, driven by greater cortical volume in females compared to males in both the ASD and TD groups.Post-hoc analyses revealed that sex-by-diagnosis interaction was driven by reduced vmPFC/OFC gyrification in males with ASD, compared to females with ASD as well as TD males and females.Stability analyses provide novel quantitative insights into why smaller samples may have previously failed to detect sex differences.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305 USA.

ABSTRACT

Background: Male predominance is a prominent feature of autism spectrum disorders (ASD), with a reported male to female ratio of 4:1. Because of the overwhelming focus on males, little is known about the neuroanatomical basis of sex differences in ASD. Investigations of sex differences with adequate sample sizes are critical for improving our understanding of the biological mechanisms underlying ASD in females.

Methods: We leveraged the open-access autism brain imaging data exchange (ABIDE) dataset to obtain structural brain imaging data from 53 females with ASD, who were matched with equivalent samples of males with ASD, and their typically developing (TD) male and female peers. Brain images were processed with FreeSurfer to assess three key features of local cortical morphometry: volume, thickness, and gyrification. A whole-brain approach was used to identify significant effects of sex, diagnosis, and sex-by-diagnosis interaction, using a stringent threshold of p < 0.01 to control for false positives. Stability and power analyses were conducted to guide future research on sex differences in ASD.

Results: We detected a main effect of sex in the bilateral superior temporal cortex, driven by greater cortical volume in females compared to males in both the ASD and TD groups. Sex-by-diagnosis interaction was detected in the gyrification of the ventromedial/orbitofrontal prefrontal cortex (vmPFC/OFC). Post-hoc analyses revealed that sex-by-diagnosis interaction was driven by reduced vmPFC/OFC gyrification in males with ASD, compared to females with ASD as well as TD males and females. Finally, stability analyses demonstrated a dramatic drop in the likelihood of observing significant clusters as the sample size decreased, suggesting that previous studies have been largely underpowered. For instance, with a sample of 30 females with ASD (total n = 120), a significant sex-by-diagnosis interaction was only detected in 50 % of the simulated subsamples.

Conclusions: Our results demonstrate that some features of typical sex differences are preserved in the brain of individuals with ASD, while others are not. Sex differences in ASD are associated with cortical regions involved in language and social function, two domains of deficits in the disorder. Stability analyses provide novel quantitative insights into why smaller samples may have previously failed to detect sex differences.

No MeSH data available.


Related in: MedlinePlus