Abstract / Summary
Background: Post-COVID Condition (PCC) affected 10-30% of individuals after SARS-CoV-2 infection, and pre-infection predictors of who goes on to develop it are not well established. We compared pre-infection structural brain variation and baseline psychiatric phenotype as candidate predictors of PCC within a common multi-modal framework in the German National Cohort (NAKO). Both are candidate "first hits" under the second-hit hypothesis, which motivates the comparison; this is a prediction study, not a test of that hypothesis. Methods: In 8,464 SARS-CoV-2-infected NAKO neuroimaging participants, of whom 2,304 (27.2%) met PCC criteria (weighted post-COVID syndrome (PCS) score > 10.75) and the rest were symptom-free controls, ten pre-infection modalities (T1-weighted volumetric brain MRI across six parcellations, baseline mental health (PHQ-9, GAD-7), demographics, and seven further biomedical and socioeconomic domains) entered a stacked ensemble with 10x5 nested cross-validation (primary metric: the area under the precision-recall curve, PR-AUC). Pre-specified analyses assessed transportability to a non-imaging cohort and robustness to the mental-health symptom trajectory and to unmeasured confounding. SARS-CoV-2 infection status and the PCC outcome were ascertained by self-report; no clinically confirmed diagnoses were available. Results: Baseline mental health, assessed 3-8 years before infection, was the strongest predictor (38.0% of feature importance; standalone ROC-AUC = 0.640), whereas all six brain-MRI parcellations performed at or near chance (ROC-AUC 0.496-0.516). The multi-modal model achieved moderate, well-calibrated discrimination (ROC-AUC = 0.665, 95% CI 0.653-0.677; PR-AUC = 0.413, 0.392-0.434; ECE = 0.013). A four-modality non-imaging version, applied without retraining to NAKO participants without MRI, retained discrimination (ROC-AUC = 0.660, 0.654-0.665), meeting all three pre-specified equivalence criteria, the calibration intercept narrowly. The baseline mental-health odds ratio was 2.06 (1.83-2.32; E-value 2.66) and essentially unchanged under an alternative control definition (2.07); adjusting for the full mental-health symptom trajectory reduced it to a conservative lower bound of 1.38 (1.20-1.58) that remained independently significant. Baseline mental health did not predict objectively measured hyposmia in participants screened before their infection (0.89) while predicting self-reported smell loss in the same participants (1.92). Conclusions: Baseline mental health years before infection is the strongest pre-infection predictor of PCC among the infected, and the association held across the pre-specified sensitivity analyses. Whether it acts specifically on COVID-19 sequelae is a separate question this design cannot answer, and the indirect evidence points away from specificity: the association is undiminished after mild infection but absent among the hospitalized, and baseline mental health predicts current mental-health symptom load slightly less strongly in infected than in non-infected participants. The volumetric structural candidate is not supported: pre-pandemic T1-weighted volumetry carried no predictive signal in this single neuroimaging cohort. Risk stratification may benefit from incorporating baseline psychiatric phenotype; whether treating it reduces PCC incidence requires interventional study.