Fig. 5: Clock and drug sensitivity metrics shape ToD curves.

a Computational approach to investigate how circadian rhythms, cell growth dynamics, and drug sensitivity factors influence the time-of-day (ToD) drug efficacy. b and c Example of linear correlations between ToD_MR and circadian (b) or drug sensitivity parameters (c), for 5-FU (n = 10 cell models) and cisplatin (n = 5 cell models), respectively. Color coding of cell models according to tissue origin. The central black line represents the regression line. Gray-shaded area = 95% CI of the linear regression fit. Model accuracy is indicated by R²-values. d–f Hierarchical clustering of Pearson correlation coefficients (r) between ToD_MR-values of different drugs (rows) and the respective metric (columns) for clock strength (d, n = 10 cell models), growth (e, n = 10 cell models) or drug sensitivity (f, n = 5 cell models). r-values ≥ 0.5 and ≤ -0.5 are shown. Black rectangles indicate examples shown in (b and c). Significant pairwise correlations (two-sided test with no adjustments made) are indicated by stars, where *, and **, denote p-values ≤ 0.05 and 0.01, respectively. Exact p-values: Alisertib-AC-Lag = 0.011; Alisertib-Period-2d = 0.004; Doxorubicin-Ridgelength = 0.030; Doxorubicin-AC-Lag = 0.014; Doxorubicin-Period-2d = 0.012; Alpelisib-Amplitude = 0.002; 5-FU-Circadianicity = 0.044; 5-FU-Amplitude = 0.007. Note: sample size in (d–f) for alpelisib = n-1; and for cisplatin =9. g Bar diagrams ranking the absolute correlation between ToD_MR-values, and each metric depicted in (d–f), ranked by metric (n = 8 drugs) or by drug (n = 14 metrics). Data represents the mean ± s.e.m. For clarity, one-sided error bars are shown. h Hierarchical clustering of the dominance analysis matrix showing the individual contribution of the circadian clock, growth, and drug sensitivity parameters (columns) in predicting drug-dependent ToD_MR-values (rows). Colors indicate the percentage contribution, as detailed in the color bar. See key for d–f for sample sizes (n). i Boxplot of the overall contribution of cellular metrics to predict ToD_MR-values, corresponding to (h). Box bounds are defined by the 25^th and 75^th percentiles. Extending whiskers represent data points within 1.5 times the interquartile range from lower and upper quartiles. Red lines denote the data’s median, and white circles the mean. Source data for b–i are provided as a Source Data file.