Fig. 4: Clonal dominance of co-occurring mutations stratifies survival.

a Summary of pairwise clonal relationships for recurrent mutations present in de novo AML. Color represents the fraction of patients where mutations in gene 1 occurred before gene 2 (i.e. are clonally dominant; green = gene 1 before gene 2; brown = gene 1 after gene 2). Size is scaled to reflect the total number of patients with co-occurring mutations. b Schematic depicting how pairwise VAF relationships were used to bin patients into groups (left) and forest plot of hazard ratios calculated from univariate Cox proportional-hazards modeling based on the order of pairwise mutations (right). Points represent the hazard ratio, as calculated using standard Cox proportional-hazards regression, between patients with different mutation order. Bars represent the 95% confidence intervals of the hazard ratios and points are sized based on the number of patients with defined mutation ordering. c Scatterplot (left) and Kaplan–Meier plot (right) showing how the order of mutation acquisition in patients with co-occurring mutations in NRAS and GATA2 robustly improved patient stratification. Green points/line represent cases where NRAS mutations occur before those in GATA2. Brown points/line represent cases where GATA2 mutations occur before those in NRAS. The reported p-value was calculated using a two-sided log-rank test. d A Bradley–Terry model was used to assign the relative order of global mutation acquisition from pairwise relationships as determined in a. Only patients with at least two mutations were considered in this model. Density plots (left) represent the VAF distribution for each mutation in the analysis (corrected for copy number and X-linkage in males) and are ordered on the y-axis based on their relative order of acquisition compared to all other genes in the analysis. Points and error bars (right) represent the Bradley–Terry model results for the point estimate and 95% confidence interval, respectively, for relative gene ordering in temporal acquisition. e Schematic depicting how pairwise VAF relationships were used to bin patients into groups (left) and forest plot of hazard ratios calculated from univariate Cox proportional-hazards regression modeling based on the order of mutation category acquisition (right). Bars represent the 95% confidence intervals of the hazard ratios. f, g Kaplan–Meier plots for significant pairs from e. p-values in c, f, g were calculated between nonambiguous groups using a two-sided log-rank test. Source data are provided as a Source Data file.