The effect of treatment delay on time-to-recovery in the presence of unobserved heterogeneity.

We study the effect of delaying treatment in the presence of (unobserved) heterogeneity. In a homogeneous population and assuming a proportional treatment effect, a treatment delay period will result in notably lower cumulative recovery percentages. We show in theoretical scenarios using frailty models that if the population is heterogeneous, the effect of a delay period is much smaller. This can be explained by the selection process that is induced by the frailty. Patient groups that start treatment later have already undergone more selection. The marginal hazard ratio for the treatment will act differently in such a more homogeneous patient group. We further discuss modeling approaches for estimating the effect of treatment delay in the presence of heterogeneity, and compare their performance in a simulation study. The conventional Cox model that fails to account for heterogeneity overestimates the effect of treatment delay. Including interaction terms between treatment and starting time of treatment or between treatment and follow up time gave no improvement. Estimating a frailty term can improve the estimation, but is sensitive to misspecification of the frailty distribution. Therefore, multiple frailty distributions should be used and the results should be compared using the Akaike Information Criterion. Non-parametric estimation of the cumulative recovery percentages can be considered if the dataset contains sufficient long term follow up for each of the delay strategies. The methods are demonstrated on a motivating application evaluating the effect of delaying the start of treatment with assisted reproductive techniques on time-to-pregnancy in couples with unexplained subfertility.