Estimating the Effects of Treatment Regimes over the Course of Chronic Disease: A Multi-state Causal Framework with Baseline Confounding

The development of chronic disease is a long-term process that involves multiple endpoints, and few methods can assess the health benefits of a treatment regime over the disease course. Existing multi-state Cox models estimate survival risks by state over time, which are difficult to use when comparing the effectiveness of treatment regimes. A discrete-time split-state framework has been proposed, which divides disease states into substates by conditioning on past history. As this framework is both “memoryless” and “memorable”, the time-specific transition parameters can be synthesized into summary measures, substate-specific life year (SSLY), multimorbidity-adjusted life year (MALY), and disease path. In this paper, based on this framework, we propose to investigate the causal effects of static and dynamic treatment regimes on health benefits over the entire disease course, under the assumptions of constant confounders from baseline and instantaneous effects of interventions on transition rates. Our method can identify the optimal treatment regime that generates the most benefits using MALY, and illustrate the mechanisms of treatment regimes affecting disease progression using SSLY and disease path. In the application, we evaluated the cardiovascular benefits of smoking cessation using data from the Atherosclerosis Risk in Communities (ARIC) study, where the course of heart disease was modeled in healthy (S ₀ ), at metabolic risk (S ₁ ), coronary heart disease (S ₂ ), heart failure (S ₃ ), and mortality states (S ₄ ). Compared to the regime “being a smoker in S ₀ -S ₄ ”, the MALY was 0.53 (95% CI: 0.21, 0.96), 6.10 (95% CI: 4.88, 7.19), and 4.34 (95% CI: 3.02, 5.47) years higher for the regimes “being a smoker in S ₀ and S ₁ and stop smoking if a person develops S ₂ , S _3, or S ₄ ”, “no smoking in S ₀ -S ₄ ”, and “being a smoker at the start of intervention and stop smoking if age>65y”, respectively. In summary, our method can evaluate the health benefits of treatment regimes over the disease course, and has the potential to improve the precision of chronic disease prevention.