parkinson-plasma-prodromal-panel-r4

Hällqvist J., Bartl M., Dakna M., ..., Mollenhauer B., Trenkwalder C. (Nat Commun 15:4759, 2024; DOI 10.1038/s41467-024-48961-3; PMC11189460; PRIDE PXD046355) reported that an 8-protein plasma panel (Granulin/GRN, MASP2, HSPA5/BiP, PTGDS, ICAM1, complement C3, DKK3, SERPING1) distinguishes individuals with isolated REM-sleep behaviour disorder (iRBD) who will convert to Parkinson's disease within 7 years from those who will not, with area under the curve up to 1.0 in their internal cohort.

The result is rare in PD biomarker literature: a small, interpretable panel measured by LC-MS/MS DIA in real plasma from a longitudinal prodromal cohort (DeNoPa + Oxford Discovery). It has not been formally replicated on the deposited MS spectra by an independent analysis pipeline, and the cross-platform generalisability (LC-MS/MS → other quantification) has not been established with deposited public data only.

This OmiCairn run formally tests:

H1 (primary — re-analysis of the deposited MS spectra replicates the 8-protein panel's predictive performance): Re-processing PXD046355 spectra with a from-scratch DIA-NN / Spectronaut-equivalent pipeline (DIA-NN 1.9.2 or Skyline) → protein-level intensities → log-transform + quantile normalisation → 5-fold cross-validated logistic regression with the 8 published proteins as features, labels = iRBD-converter vs. iRBD-non-converter at 7-year follow-up. Primary success = 5-fold CV AUC ≥ 0.85 (the published Hällqvist 7-year AUC is ≈ 1.0; we allow margin for spectra → intensity pipeline divergence).

H2 (secondary — individual-protein hazard ratios reproduce): Each of the 8 proteins, modeled univariately in a Cox proportional-hazards model on time-to-conversion, shows the same sign of hazard ratio as published (Hällqvist Supplementary Table 3). Concordance metric = 8/8 sign agreement; loose acceptance = ≥ 6/8.

H3 (secondary — panel beats clinical-only baseline): Adding the 8-protein panel to a clinical-baseline Cox model (age + sex + MoCA + UPSIT) improves time-dependent AUC at 5 years by ΔAUC > 0.05 with paired bootstrap CI excluding 0. The clinical baseline serves as the Venet-style floor.

H4 (secondary — out-of-cohort signature alignment to UK Biobank Olink): Of the 8 panel proteins, 6 are on the UK Biobank Olink Explore 1536 panel. We test whether the directionality (HR sign) reported for these 6 proteins in the Gan/You 2025 UKB Olink incident-PD analysis (Nat Aging 5:642) matches the Hällqvist signs. Concordance = 6/6 expected; loose acceptance ≥ 4/6 with binomial p < 0.05 vs. chance 0.5.

H5 (secondary — sub-panel decomposition): Decompose the 8-panel into 3 functional sub-panels: (a) inflammation / complement: ICAM1, C3, SERPING1 (b) proteostasis: HSPA5, GRN (c) lipid / cell signaling: PTGDS, DKK3, MASP2 Test whether any single sub-panel achieves AUC > 0.75 on its own — i.e., is the predictive signal carried by one of three functional axes or distributed?

A negative-leaning result on H1 (cross-pipeline AUC < 0.7) would be a major methodological caveat for the field and would imply that quantitative biomarker panels are sensitive to MS pipeline choice — itself an informative finding given the rapid uptake of the Hällqvist panel in trial design.

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