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

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% holdout 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 (TW) application sample. Subsequently, the classifier was applied to N = 26 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%). 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.

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Fig. 1: Application of the trained classifier for biological sex prediction.
Fig. 2: Box plot for the predicted probabilities of male sex based on the application-sample and the third validation-sample, including transgender and cisgender individuals.
Fig. 3: Significant results of the univariate gray matter analysis.

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Acknowledgements

Statement identifying the institutional committee approving the experiments. The data are part of four separate studies (the Münster Neuroimaging Cohort, the BiDirect Study, the TSS study and the FOR2107 study) and represent original work. Data collection for all of the studies have been approved by the local ethics committee of the medical faculty of the University of Muenster and for the FOR2107 study at the study site Marburg of the local ethics committee of the medical faculty in Marburg. Alle participants provided informed consent before participating in the studies.

FOR2017

Principal investigators (PIs) with respective areas of responsibility in the FOR2107 consortium are:

Work Package WP1, FOR2107/MACS cohort and brain imaging: TK (speaker FOR2107; DFG grant numbers KI 588/14–1, KI 588/14–2), UD (co-speaker FOR2107; DA 1151/5–1, DA 1151/5–2), AK (KR 3822/5–1, KR 3822/7–2), IN (NE 2254/1–2), CK (KO 4291/3–1). WP2, animal phenotyping: Markus Wöhr (WO 1732/4–1, WO 1732/4–2), Rainer Schwarting (SCHW 559/14–1, SCHW 559/14–2). WP3, miRNA: Gerhard Schratt (SCHR 1136/3–1, 1136/3–2). WP4, immunology, mitochondriae: Judith Alferink (AL 1145/5–2), Carsten Culmsee (CU 43/9–1, CU 43/9–2), Holger Garn (GA 545/5–1, GA 545/7–2). WP5, genetics: Marcella Rietschel (RI 908/11–1, RI 908/11–2), Markus Nöthen (NO 246/10–1, NO 246/10–2), Stephanie Witt (WI 3439/3–1, WI 3439/3–2). WP6, multi-method data analytics: Andreas Jansen (JA 1890/7–1, JA 1890/7–2), Tim Hahn (HA 7070/2–2), Bertram Müller-Myhsok (MU1315/8–2), Astrid Dempfle (DE 1614/3–1, DE 1614/3–2). CP1, biobank: Petra Pfefferle (PF 784/1–1, PF 784/1–2), Harald Renz (RE 737/20–1, 737/20–2). CP2, administration. TK (KI 588/15–1, KI 588/17–1), UD (DA 1151/6–1), CK (KO 4291/4–1).

Data access and responsibility: all PIs take responsibility for the integrity of the respective study data and their components. All authors and coauthors had full access to all study data.

Acknowledgements and members by Work Package (WP):

WP1: Henrike Bröhl, Katharina Brosch, Bruno Dietsche, Rozbeh Elahi, Jennifer Engelen, Sabine Fischer, Jessica Heinen, Svenja Klingel, Felicitas Meier, Tina Meller, Torsten Sauder, Simon Schmitt, Frederike Stein, Annette Tittmar, Dilara Yüksel (Dept. of Psychiatry, Marburg University). Mechthild Wallnig, Rita Werner (Core-Facility Brainimaging, Marburg University). Carmen Schade-Brittinger, Maik Hahmann (Coordinating Center for Clinical Trials, Marburg). Michael Putzke (Psychiatric Hospital, Friedberg). Rolf Speier, Lutz Lenhard (Psychiatric Hospital, Haina). Birgit Köhnlein (Psychiatric Practice, Marburg). Peter Wulf, Jürgen Kleebach, Achim Becker (Psychiatric Hospital Hephata, Schwalmstadt-Treysa). Ruth Bär (Care facility Bischoff, Neunkirchen). Matthias Müller, Michael Franz, Siegfried Scharmann, Anja Haag, Kristina Spenner, Ulrich Ohlenschläger (Psychiatric Hospital Vitos, Marburg). Matthias Müller, Michael Franz, Bernd Kundermann (Psychiatric Hospital Vitos, Gießen). Christian Bürger, Fanni Dzvonyar, Verena Enneking, Stella Fingas, Janik Goltermann, Hannah Lemke, Susanne Meinert, Jonathan Repple, Kordula Vorspohl, Bettina Walden, Dario Zaremba (Dept. of Psychiatry, University of Münster). Harald Kugel, Jochen Bauer, Walter Heindel, Birgit Vahrenkamp (Dept. of Clinical Radiology, University of Münster). Gereon Heuft, Gudrun Schneider (Dept. of Psychosomatics and Psychotherapy, University of Münster). Thomas Reker (LWL-Hospital Münster). Gisela Bartling (IPP Münster). Ulrike Buhlmann (Dept. of Clinical Psychology, University of Münster).

WP2: Marco Bartz, Miriam Becker, Christine Blöcher, Annuska Berz, Moria Braun, Ingmar Conell, Debora dalla Vecchia, Darius Dietrich, Ezgi Esen, Sophia Estel, Jens Hensen, Ruhkshona Kayumova, Theresa Kisko, Rebekka Obermeier, Anika Pützer, Nivethini Sangarapillai, Özge Sungur, Clara Raithel, Tobias Redecker, Vanessa Sandermann, Finnja Schramm, Linda Tempel, Natalie Vermehren, Jakob Vörckel, Stephan Weingarten, Maria Willadsen, Cüneyt Yildiz (Faculty of Psychology, Marburg University).

WP4: Jana Freff, Silke Jörgens, Kathrin Schwarte (Dept. of Psychiatry, University of Münster). Susanne Michels, Goutham Ganjam, Katharina Elsässer (Faculty of Pharmacy, Marburg University). Felix Ruben Picard, Nicole Löwer, Thomas Ruppersberg (Institute of Laboratory Medicine and Pathobiochemistry, Marburg University).

WP5: Helene Dukal, Christine Hohmeyer, Lennard Stütz, Viola Schwerdt, Fabian Streit, Josef Frank, Lea Sirignano (Dept. of Genetic Epidemiology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University).

WP6: Anastasia Benedyk, Miriam Bopp, Roman Keßler, Maximilian Lückel, Verena Schuster, Christoph Vogelbacher (Dept. of Psychiatry, Marburg University). Jens Sommer, Olaf Steinsträter (Core-Facility Brainimaging, Marburg University). Thomas W.D. Möbius (Institute of Medical Informatics and Statistics, Kiel University).

CP1: Julian Glandorf, Fabian Kormann, Arif Alkan, Fatana Wedi, Lea Henning, Alena Renker, Karina Schneider, Elisabeth Folwarczny, Dana Stenzel, Kai Wenk, Felix Picard, Alexandra Fischer, Sandra Blumenau, Beate Kleb, Doris Finholdt, Elisabeth Kinder, Tamara Wüst, Elvira Przypadlo, Corinna Brehm (Comprehensive Biomaterial Bank Marburg, Marburg University).

The FOR2107 cohort project (WP1) was approved by the Ethics Committees of the Medical Faculties, University of Marburg (AZ: 07/14) and University of Münster (AZ: 2014–422-b-S).

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Drafting of the paper: CF, KF, UD, DG. Conception and design: CF, KF, CK, KB, UD, DG, TK, VA. Acquisition, analysis and interpretation of data: CF, KF, SAK, CK, PZ, KB, MH, IN, AK, BTB, KD, RR, NO, TH, XJ, UD, DG, TK, VA. Critical revision of the revised paper: CF, KF, SAK, CK, PZ, KB, MH, IN, AK, BTB, KD, RR, NO, TH, XJ, UD, DG, TK, VA. Final approval of the revised paper: CF, KF, SAK, CK, PZ, KB, MH, IN, AK, BTB, KD, RR, NO, TH, XJ, UD, DG, TK, VA. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Udo Dannlowski.

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Flint, C., Förster, K., Koser, S.A. et al. Biological sex classification with structural MRI data shows increased misclassification in transgender women. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-0666-3

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