Multi-stage disease histories derived from longitudinal data are becoming increasingly available as registry data and biobanks expand. Multi-state models are suitable to investigate transitions between different disease stages in presence of competing risks. In this context, however, their estimation is complicated by dependent left-truncation, multiple time scales, index event bias, and interval-censoring. In this work, we investigate the extension of piecewise exponential additive models (PAMs) to this setting and their applicability given the above challenges. In simulation studies we show that PAMs can handle dependent left-truncation and accommodate multiple time scales. Compared to a stratified single time scale model, a multiple time scales model is found to be less robust to the data generating process. We also quantify the extent of index event bias in multiple settings, demonstrating its dependence on the completeness of covariate adjustment. In general, PAMs recover baseline and fixed effects well in most settings, except for baseline hazards in interval-censored data. Finally, we apply our framework to estimate multi-state transition hazards and probabilities of chronic kidney disease (CKD) onset and progression in a UK Biobank dataset (n=142,667). We observe CKD progression risk to be highest for individuals with early CKD onset and to further increase over age. In addition, the well-known genetic variant rs77924615 in the UMOD locus is found to be associated with CKD onset hazards, but not with risk of further CKD progression.

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