Biological sex classification with structural MRI data shows increased misclassification in transgender women

TL;DR

This study demonstrates that a brain-based classifier for biological sex shows reduced accuracy in transgender women, indicating unique brain structural features that differ from cisgender individuals and are affected by hormone treatment.

Contribution

It provides evidence that transgender women's brain structures differ from both their biological and perceived genders, highlighting specific structural alterations.

Findings

Classifier accuracy was lower in transgender women (56%) compared to cisgender individuals (~87%).

Brain structural differences in transgender women were observed in the putamen, insula, and whole-brain analyses.

Depression status did not significantly affect classifier performance.

Abstract

Transgender individuals (TIs) show brain structural alterations that differ from their biological sex as well as their perceived gender. To substantiate evidence that the brain structure of TIs differs from male and female, we use a combined multivariate and univariate approach. Gray matter segments resulting from voxel-based morphometry preprocessing of $N = 1753$ cisgender (CG) healthy participants were used to train ($N=1402$) and validate (20 % hold-out; $N = 351$) a support-vector machine classifying the biological sex. As a second validation, we classified $N = 1104$ patients with depression. A third validation was performed using the matched CG sample of the transgender women (TWs) application-sample. Subsequently, the classifier was applied to $N = 26$ TWs. Finally, we compared brain volumes of CG-men, women and TW-pre/post treatment (cross-sex hormone treatment) in a univariate analysis controlling for sexual orientation, age and total brain volume. The application of our biological sex classifier to the transgender sample resulted in a significantly lower true positive rate (TPR) (TPR-male = 56.0 %). The TPR did not differ between CG-individuals with (TPR-male = 86.9 %) and without depression (TPR-male = 88.5 %). The univariate analysis of the transgender application-sample revealed that TW-pre/post treatment show brain structural differences from CG-women and CG-men in the putamen and insula, as well as the whole-brain analysis. Our results support the hypothesis that brain structure in TW differs from brain structure of their biological sex (male) as well as their perceived gender (female). This finding substantiates evidence that TIs show specific brain structural alterations leading to a different pattern of brain structure than CG-individuals.