Sex-Stratified Machine Learning for the Prediction of Post-COVID Condition: A Longitudinal Cohort Study

Background: Post-COVID-19 condition (PCC) affects many survivors, with evidence of sex-specific differences in prevalence and symptom profiles. However, few prediction studies have examined whether sex-stratified models improve prediction or generalize across sexes. This study aimed primarily to develop and compare sex-stratified machine learning models for PCC prediction using routinely available baseline variables, and secondarily to assess cross-sex generalizability and adversarial robustness. Methods: We analyzed a prospective longitudinal cohort of 1006 adults hospitalized with COVID-19 at Sechenov University Hospital Network (Moscow, Russia). Demographics, smoking status, and pre-existing comorbidities were extracted from medical records, and PCC status was assessed at 6-month follow-up. Machine learning models-including classical algorithms and graph-based neural networks-were trained separately for males and females. Cross-sex validation evaluated generalizability, variable importance aided interpretation, and adversarial perturbations assessed model robustness. Results: PCC prevalence was higher in females (53.9%) than males (39.1%). Overall predictive performance was modest across all models, with AUC values ranging approximately 0.50-0.61. Graph-based models achieved the highest discrimination, with the best AUC reaching approximately 0.61, while classical approaches provided limited predictive value. Cross-sex validation showed minor asymmetry: models trained on male data performed slightly better on female cases than vice versa. Adversarial testing revealed sensitivity of all models to input perturbations. Conclusions: Demographics and comorbidities alone provide insufficient information for reliable PCC prediction. Modest sex-specific differences in model generalizability suggest distinct, sex-associated PCC phenotypes, but richer multimodal data-including clinical biomarkers, wearable-derived measures, and patient-reported outcomes-will be required to develop clinically useful and equitable predictive models. Sex-stratified approaches should be considered in future post-viral syndrome prediction studies.