Extended Data Fig. 6: CelMod predictions and endophenotype associations.
From: Cellular communities reveal trajectories of brain ageing and Alzheimer’s disease
(a) Evaluation of CelMod prediction of subpopulation proportions in bulk RNA samples with matching snRNA-seq measurements in the same participant (n = 419 samples). Spearman correlation between snRNA-seq (actual) and CelMod bulk-predicted proportions, over the held-out set (test set) of participants (Methods). * = FDR corrected p-value. (b) Comparison of the estimated effect sizes regressing endophenotypes on subpopulation proportions, for the snRNA-seq (Discovery cohort, x-axis) and the bulk predictions (Replication cohort, y-axis). n = 419. The Spearman correlation between the effect sizes and FDR corrected p-value are shown for each comparison. (c) Associating subpopulation proportions to endophenotypes: CERAD score, Braak stage and AD dementia (linear regression controlled for cofounders, FDR<0.05, Methods), showing subpopulations significantly associated with at least one of the tested traits in one on the cohorts: Discovery (left, n = 437), Replication (centre, n = 673) and the meta-analysis of both cohorts (right, n = 1,110). Colour scale: t-stat. (d-h) Causal mediation models which together with Fig. 3f–i position Mic.12, Mic.13, Ast.10 and Oli.7 within the Aβ→tau→cognitive decline AD cascade, indicating direct and mediated effects, as well as proportion of effect mediated. Number of participants: (d,e,g) n = 432, (f) n = 413, (h) n = 433. (i) Validation of the structural equation model (SEM; as in Fig. 3j) in the CelMod predicted subpopulation proportions of the Replication cohort. Arrows show association directionality and relative strength.
