Fig. 3: Variant allele frequency associates with features of disease presentation and overall survival.

a VAF distribution for frequent mutations in our de novo cohort (n = 1636 patients). Mutations were assigned as high or low VAF based on the median copy number-corrected VAF for each gene. Red points represent cases where the VAF is above the median while blue points represent those below the median VAF. For each distribution, the boxplot represents the boundaries for the first and third quartiles with a line at each median; whiskers delimit the highest data point below the third quartile +1.5× the interquartile distance and the lowest data point above the first quartile −1.5× the interquartile distance. b Distribution of effect sizes for differences in clinical features of AML based on high or low VAF for each mutation. Points represent the effect size (Cohen’s d) between high and low VAF for each genotype across the different clinical variables (n patients: WBC = 1507; Hemoglobin = 1280; Platelet = 1292; LDH = 1228; BM blasts = 1472; PB blasts = 1385; Age = 1643). Significant associations are colored based on the level of significance (Bonferroni FDR < 0.2); error bars represent the 95% confidence intervals of the effect sizes. c Scatterplots of effect sizes for WBC levels and peripheral blood blast percentages between mutated and wild-type patients versus effect sizes calculated between high and low VAF for each mutation. Points are sized based on the number of patients analyzed and colored based on VAF effect size significance (FDR < 0.1). d Forest plot summarizing univariate Cox proportional-hazards regression modeling of common mutations based on VAF thresholds in the de novo cohort. Points represent the hazard ratio for overall survival between high and low VAF groups based on VAF thresholds calculated using maximally selected rank statistics. Points are sized based on the number of patients above the VAF threshold. Error bars represent the 95% confidence intervals of the hazard ratios. Green hits represent cases where higher VAF correlated with improved survival, while purple hits represent genotypes where increased VAF correlated with worse survival. e Scatterplot of hazard ratios calculated between mutated and wild-type patients versus hazard ratios calculated between high and low VAF for each mutation. Hazard ratios are calculated using a standard Cox proportional-hazards model. Points above the dotted line indicate mutations where greater VAF associates with worse outcomes compared to patients with lower VAF for that mutation. Points are colored by significance of VAF hazard ratio calculations (red points = Bonferroni FDR < 0.1) and sized relative to the VAF threshold for each genotype. Source data are provided as a Source Data file.