Fig. 5
Overview of the SIDES algorithm. *The splitting criterion is used to determine which child subgroups have improved efficacy and either comparable or improved safety compared with other child subgroups; for each biomarker, only the best split according to the splitting criterion is considered in the next step. There are four types of splitting criteria, one of which is applied to each SIDES run [24]: Criterion 1: maximising the differential effect between the two child subgroups. Criterion 2: maximising the treatment effect in at least one of the two child subgroups. Criterion 3: criterion 3 is a combination of criteria 1 and 2; it is used if criterion 1 is met (i.e. a difference is identified and the p-value is significant), but criterion 2 is not (the treatment effect in either subgroup is not significant). Criterion 4: maximising the differential effect between the two child subgroups in terms of both efficacy and safety. †The continuation criterion aims to reduce the number of child subgroups tested by only pursuing those that demonstrate improvements compared with their parent [24]. ‡The selection criterion is used to screen subgroups to identify only those in which the treatment effect reaches a threshold of clinical relevance [24]. BM, biomarker; L, maximum number of covariates defining a subgroup; M, maximum number of best candidate covariates to be considered at each step to define child subgroups; Ns, size of the subgroup with largest treatment effect based on the split; Nmin, minimum allowed subgroup size