Estimating the Causal Effect of Realistic Treatment Strategies Using Longitudinal Observational Data

Background: Real-world data can inform health care decisions by allowing the evaluation of nuanced treatment strategies. Longitudinal observational data enable the assessment of dynamic treatment regimes (DTRs), strategies that adapt treatment over time based on patient history, but require causal inference methods to address time-varying confounding. Longitudinal targeted minimum loss-based estimation (LTMLE) is a machine learning–based double-robust approach for improved causal effect estimation. Methods: We applied LTMLE to longitudinal registry data to evaluate the impact of erythropoiesis-stimulating agents (ESAs) in the clinical management of low to intermediate-1 risk myelodysplastic syndrome (MDS). We defined DTRs based on clinically relevant decision rules (e.g., commencing treatment when the hemoglobin level falls below a threshold) and compared them to static treatment regimes (always or never giving ESAs). Outcomes include mortality and health-related quality of life measured by EQ-5D scores. Results: The static regime of never administering ESAs resulted in declining counterfactual EQ-5D scores and increasing mortality risk over time. In contrast, both the static regime of continuous administration of ESAs and the use of dynamic regimes improved the EQ-5D scores and tended to reduce mortality, although the mortality differences were not statistically significant. Conclusions: The article provides a case study application of the LTMLE method to evaluate realistic treatment policies under time-varying confounding. The findings support the potential benefits of dynamic treatment strategies for the management of MDS, highlighting the importance of personalized treatment adaptation. The study contributes methodological insights into the applications of LTMLE in small-sample, long-follow-up settings relevant to health technology assessment and policy making. Highlights: This study applies the longitudinal targeted minimum loss estimation (LTMLE) method to evaluate the causal effect of static and dynamic treatment strategies using longitudinal observational data. We demonstrate the use of the LTMLE method to assess the impact of erythropoiesis stimulating agents (ESAs) on quality of life and mortality in patients with low to intermediate-1 risk myelodysplastic syndromes. The findings suggest that patients treated under dynamic ESA treatment regimes show an improved quality of life measured by EQ-5D scores and survival compared with those treated under the static treatment regime of never administering ESAs. This study contributes to the methodological literature by showcasing the application of the LTMLE method in a small-sample, long-follow-up setting with time-varying confounding, informing health technology assessment and policy decisions.