Fig. 4: Mediation analysis of treatment-CMRF associations.

a Heatmap summarizing treatment-CMRF pairs with evidence of DNAm mediation (N = 2938 survivors). “Strong mediators” are defined as CpG sites with a statistically significant average causal mediation effect (ACME; two-sided BH p < 0.05) and a mediation proportion >10%, estimated using regression-based mediation analysis. Each cell is annotated with the maximum proportion of the total treatment effect mediated and the number of mediator CpGs identified (total: independent), where independent CpGs represent correlation-pruned mediators. b, c Composite mediation models for abnormal glucose (N = 2938 survivors). For each analysis, correlated mediator CpGs were grouped by correlation structure and four representative CpGs were selected. Composite mediators were constructed as the sum of centered and scaled DNAm values across representative CpGs. Mediation was assessed using regression-based mediation analysis with two-sided hypothesis testing, in which path a was estimated using linear regression of the composite mediator on treatment, path b using logistic regression of abnormal glucose on the composite mediator conditional on treatment, and paths c and c’ using logistic regression models of abnormal glucose on treatment without and with adjustment for the mediator, respectively. Path coefficients (a, b, c, c’), effect estimates, and exact p values are shown in the schematic. The composite mediator exhibited a statistically significant ACME (two-sided p < 0.05), accounting for b 11.7% of the total brain-RT effect and c 22.4% of the total body-trunk-RT effect on abnormal glucose. Source data are provided as a Source Data file. CMRF cardiometabolic risk factor, Max. maximum, RT radiotherapy.