From Entropy to Outcome: Multimodal Digital Biomarkers in Stroke — NEURO-PERSIST Pre-Registration (English version, v2)

NEURO-PERSIST is a pre-registered clinical study protocol for predicting 90-day functional outcome after ischaemic or haemorrhagic stroke using interpretable multimodal digital biomarkers. The proposed biomarker domains include heart-rate-variability entropy, prosody stability, gait and motor microvariability, and baseline imaging/radiomics features. This Zenodo v2 release provides the English-language version of the previously deposited German-language manuscript v0. 5; the manuscript itself is labelled v0. 6. The scientific design, primary outcome, sample size rationale, validation logic, ethics framing, and Persistence Score structure remain unchanged in substance. The protocol defines the modified Rankin Scale at 90 days (mRS-90d) as the primary outcome, analysed both ordinally and dichotomously (mRS 0–2 vs. 3–6). It introduces the Persistence Score C (PSC), a replication-oriented feature robustness framework across sites, devices, time, and missingness. The planned sample size is N=300 with an assumed poor-outcome rate of approximately 35%, yielding about 105 events. The protocol constrains the baseline model to a maximum of 10 pre-specified predictor parameters, reports AUC power, and explicitly treats AUC power as insufficient on its own. Model robustness is addressed through overfitting control, calibration assessment, PR-AUC, decision curve analysis, resampling/bootstrap internal validation, missingness sensitivity analyses, and an optional time- or site-separated validation layer where the data structure permits. XGBoost is included as exploratory add-on modelling with explainability analyses, not as the primary powered model. This document is a study design and priority deposit. It reports no patient data and does not constitute an ethics approval, clinical trial approval, regulatory trial protocol, or completed clinical study. Before data collection, ethics approval will be sought from the responsible ethics committees of the participating sites, and the study will be conducted in accordance with current human-subject research ethics, the Declaration of Helsinki (WMA 2024), ICH E6 (R3) principles as applicable, GDPR requirements, and site-specific data-protection agreements. The protocol is the clinical translation layer of the Holographic Ledger / NEURO-PERSIST series. The current theoretical framework is Holographic Ledger v3 (DOI: 10. 5281/zenodo. 19956152). The protocol also cites the Negative Dwell Time preprint and the Coherence-Modulated Pre-Commit States preprint as theoretical antecedents.