用神经微分方程建模环孢素药代动力学,更准预测个体用药暴露量。
Latent Neural-ODE for Model-Informed Precision Dosing: Overcoming Structural Assumptions in Pharmacokinetics
- 用隐变量常微分方程直接从稀疏临床数据学个体药代动力学规律。
- 内部验证均方相对误差仅7.99%,优于传统方法的9.24%。
- 适合需精准用药的移植患者,也适配多模态个性化医疗研究。
准确估算他克莫司暴露量(以药时曲线下面积AUC衡量)对肾移植后精准给药至关重要。现有方法依赖非线性混合效应(NLME)的种群药代动力学(PopPK)模型,但其依赖预设结构假设,难以捕捉复杂个体动态,易导致模型误设。本研究提出基于隐变量常微分方程(Latent ODE)的数据驱动新方法,直接从稀疏临床数据学习个体化药代动力学行为,提升建模灵活性。通过多场景模拟和两项临床验证(开发集n=178,独立外部队列n=75)评估性能。模拟中,该模型在机制偏离标准假设时仍保持高精度;内部验证中,平均均方相对百分比误差(RMSPE)为7.99%,显著低于it2B方法的9.24%(p<0.001);外部队列中,其RMSPE为10.82%,与两标准方法(11.48%和11.54%)相当。结果表明,该模型是可靠且强大的AUC预测工具,其灵活架构为下一代多模态个性化医疗模型奠定基础。
原文摘要 · Abstract (English)
Accurate estimation of tacrolimus exposure, quantified by the area under the concentration-time curve (AUC), is essential for precision dosing after renal transplantation. Current practice relies on population pharmacokinetic (PopPK) models based on nonlinear mixed-effects (NLME) methods. However, these models depend on rigid, pre-specified assumptions and may struggle to capture complex, patient-specific dynamics, leading to model misspecification. In this study, we introduce a novel data-driven alternative based on Latent Ordinary Differential Equations (Latent ODEs) for tacrolimus AUC prediction. This deep learning approach learns individualized pharmacokinetic dynamics directly from sparse clinical data, enabling greater flexibility in modeling complex biological behavior. The model was evaluated through extensive simulations across multiple scenarios and benchmarked against two standard approaches: NLME-based estimation and the iterative two-stage Bayesian (it2B) method. We further performed a rigorous clinical validation using a development dataset (n = 178) and a completely independent external dataset (n = 75). In simulation, the Latent ODE model demonstrated superior robustness, maintaining high accuracy even when underlying biological mechanisms deviated from standard assumptions. Regarding experiments on clinical datasets, in internal validation, it achieved significantly higher precision with a mean RMSPE of 7.99% compared with 9.24% for it2B (p < 0.001). On the external cohort, it achieved an RMSPE of 10.82%, comparable to the two standard estimators (11.48% and 11.54%). These results establish the Latent ODE as a powerful and reliable tool for AUC prediction. Its flexible architecture provides a promising foundation for next-generation, multi-modal models in personalized medicine.
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