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

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 are used to train (N = 1402) and validate (20% holdout sample N = 351) a support-vector machine classifying 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 (TW) application sample. Subsequently, the classifier was applied to N = 276 TW. Finally, we compared brain volumes of CG-men, women, and TW-pre/post treatment cross-sex hormone treatment (CHT) 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=male = 56.0%) than for treatment CG-individuals (with (TPR=male = 86.9%) and without depression (TPR=male = 88.5%). The univariate analysis of the transgender representation 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.

Claes Flindt, Katharina Förster, Sophie A. Koser, Carsten Konrad, Pienie Zwisterlo, Klaus Berger, Marco Hermsdorf, Tilo Kircher, Igor Nedančić, Axel Krug, Bernhard T. Baune, Katharina Dohn, Ronny Redlich, Nils Opel, Volker Arolt, Tim Hahn, Xiaoyi Jiang, Udo Dannowski, Dominik Grotegerd