Personalized statin treatment plan using counterfactual approach with multi-objective optimization over benefits and risks

Background: Statins are a class of drugs that lower cholesterol levels in the blood by inhibiting an enzyme called 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. High cholesterol levels can lead to plaque buildup in the arteries, which can cause Atherosclerotic Cardiovascular Disease(ASCVD). Statins can reduce the risk of ASCVD events by about 25–35% but they might be associated with symptoms such as muscle pain, liver damage, or diabetes. As a result, this leads to a strong reason to discontinue statin therapy, which increases the risk of cardiovascular events and mortality and becomes a public-health problem. To solve this problem, in the previous work, we proposed a framework to produce a proactive strategy, called a personalized statin treatment plan (PSTP) to minimize the risks of statin-associated symptoms and therapy discontinuation when prescribing statin. In our previous PSTP framework, three limitations remain, and they can influence PSTP usability: (1) Not taking the counterfactual predictions and confounding bias into account. (2) The balance between multiple drug-prescribing objectives (especially trade-off objectives), such as tradeoff between benefits and risks. (3) Evaluating PSTP in retrospective data. Objectives: This manuscript aimed to provide solutions for the three abovementioned problems to improve PSTP robustness to produce a proactive strategy for statin prescription that can maximize the benefits (low-density lipoprotein cholesterol (LDL-C) reduction) and minimize risks (statin-associated symptoms and therapy discontinuation) at the same time. Methods: We applied overlapping weighting counterfactual survival risk prediction (CP), multiple objective optimization (MOO), and clinical trial simulation (CTS) which consists of Random Arms, Clinical Guideline arms, PSTP Arms, and Practical Arms to improve the PSTP framework and usability. Results: In addition to highly balanced covariates, in the CTS, the revised PSTP showed improvements in lowering the SAS risks overall compared to other arms across all time points by at most 7.5% to at least 1.0% (Fig. 8(a)). It also has the better flexibility of identifying the optimal Statin across all time points within one year. Conclusion: We demonstrated feasibility of robust and trustworthy counterfactual survival risk prediction model. In CTS, we also demonstrated the PSTP with Pareto optimization can personalize optimal balance between Statin benefits and risks.