Extended Data Fig. 6. Cross-cohort recovery and protein-level support of CSF proteomic meta-programs.

(a) Null-standardized variance capture by cohort compared with size-matched random protein sets. Points, cohort-level z-scores with 95% CI; point size, cohort size; shaded band, random-effects pooled estimate. (b) Threshold operating curves for leave-one-study-out (LOSO) correlations treated as observed positives and sample-size-matched random correlations treated as negatives. Dashed line, prespecified threshold Spearman ρ = 0.20. (c) Density distributions for the same observed and random correlations. (d) Leave-one-study-out transferability across 35 held-out cohorts. The heatmap shows the Spearman correlation (ρ) between predicted and observed meta-program activity for each held-out study–meta-program pair. Red crosses indicate failure to meet the prespecified recovery threshold (ρ < 0.20). Marginal summaries show median correlation and fraction recovered. (e) Proteins rank-ordered by random-effects pooled Spearman correlation with meta-program activity. Coloured points, meta-program member proteins. (f) Meta-program evidence comprising contributing discovery studies, assigned component programs, enriched terms, and contributing genes. Bar lengths are scaled separately within each column.