Decoding Parkinson's progression: A multi-modal SuStaIn ensemble approach validated on real-world PPMI data.

BACKGROUND

Parkinson's disease (PD) exhibits substantial heterogeneity in clinical presentation and longitudinal progression, complicating prognosis, trial design, and precision therapeutics. While the Subtype and Stage Inference (SuStaIn) algorithm family offers probabilistic disease progression modeling, comprehensive comparative analyses and real-world validation remain limited.

OBJECTIVE

To systematically compare major SuStaIn variants for PD progression modeling and validate their stability and prognostic utility using both controlled simulated data and real-world Parkinson's Progression Markers Initiative (PPMI) cohorts.

METHODS

We constructed a biologically grounded simulated PD cohort (n=400; 5 visits over 4 years; 12 motor and non-motor biomarkers) with three predefined progression subtypes reflecting realistic noise, missingness (7.7%), and effect sizes informed by PPMI literature. Six SuStaIn variants were benchmarked: Z-score, Ordinal, Event-based Mixture, Missing Data, s-SuStaIn, and Temporal SuStaIn. We then applied identical variants to baseline PPMI data (N=624; PD=427; prodromal=197) using MDS-UPDRS I-IV, MoCA, GDS, STAI, SCOPA-AUT, RBD screening, ESS, and UPSIT. We assessed cross-sectional subtype structure, test-retest stability (Cohen's κ), and prognostic performance for motor worsening, cognitive decline, dyskinesia, and advanced therapy using Cox models with concordance indices and 95% confidence intervals.

RESULTS

Simulation analyses revealed six clinically interpretable biomarker domains (motor complications, olfactory, cognitive-sleep, neuropsychiatric/autonomic, early non-motor, motor-depression) and three progression subtypes (slow 26.5%, intermediate 46.8%, fast 26.8%). Temporal and s-SuStaIn variants achieved optimal balance of accuracy (ARI: 0.058 and 0.047), stability, and cluster separation (silhouette: 0.284 and 0.267). In PPMI validation, all variants converged on three subtypes: benign motor-predominant (30.0%, age 61.4 ± 9.2 years), intermediate mixed (42.9%, age 64.8 ± 8.7 years), and diffuse-malignant (27.1%, age 67.3 ± 7.9 years, PIGD-dominant). Augmenting clinical covariates with ensemble SuStaIn subtypes improved motor progression prediction (c-index: 0.674 [0.648-0.701] to 0.741 [0.718-0.765], Δc=+0.067, p<0.001) and cognitive decline prediction (0.628 [0.598-0.658] to 0.764 [0.739-0.789], Δc=+0.136, p<0.001). Ensemble fusion enhanced test-retest stability (Cohen's κ=0.81 [0.77-0.86]) and outperformed single variants by 15% (relative gain). A reduced panel (UPDRS I-III, MoCA, GDS, ESS, UPSIT; 7 biomarkers) retained 94% of full-model performance.

CONCLUSIONS

SuStaIn variants capture complementary PD progression patterns. A principled ensemble strategy, validated on 624 PPMI participants, yields stable and prognostically informative subtypes. The diffuse-malignant subtype enables trial enrichment with 63% sample size reduction. Our dual-cohort framework establishes which algorithmic findings generalize to real-world constraints, providing a practical template for PD precision medicine.