用Transformer实现零样本药代动力学预测,仅凭少量数据就能精准估算患者用药反应。
Amortized In-Context Mixed Effect Transformer Models: A Zero-Shot Approach for Pharmacokinetics
- 基于预训练的Transformer框架,融合生理模型先验与上下文贝叶斯推断
- 在多个公开数据集上超越传统混合效应模型和神经ODE方法,预测精度领先
- 适合需要快速个性化给药方案的临床研究,无需重新建模
在稀疏采样条件下准确预测剂量-反应关系是精准药物治疗的核心。我们提出一种基于Transformer的隐变量框架——自洽上下文混合效应变压器(AICMET),将机制性隔室模型先验与自洽上下文贝叶斯推断相结合。AICMET在数十万条具有奥恩斯坦-乌伦贝克过程参数先验的合成药代动力学轨迹上预训练,具备强归纳偏置,可实现对新化合物的零样本适应。推理时,解码器基于已有受试者群体的上下文信息,仅需少数早期血药浓度测量即可生成校准后的后验预测。该方法将传统建模周期从数周缩短至数小时,同时保留部分专家建模能力。跨多个公开数据集的实验表明,AICMET在预测精度和个体间变异量化方面均达到当前最优水平,优于非线性混合效应基线和近期神经微分方程变体。结果表明,基于Transformer的群体感知神经架构为定制化药代动力学建模提供了新路径,有望推动真正面向群体的个性化给药方案实现。
原文摘要 · Abstract (English)
Accurate dose-response forecasting under sparse sampling is central to precision pharmacotherapy. We present the Amortized In-Context Mixed-Effect Transformer (AICMET) model, a transformer-based latent-variable framework that unifies mechanistic compartmental priors with amortized in-context Bayesian inference. AICMET is pre-trained on hundreds of thousands of synthetic pharmacokinetic trajectories with Ornstein-Uhlenbeck priors over the parameters of compartment models, endowing the model with strong inductive biases and enabling zero-shot adaptation to new compounds. At inference time, the decoder conditions on the collective context of previously profiled trial participants, generating calibrated posterior predictions for newly enrolled patients after a few early drug concentration measurements. This capability collapses traditional model-development cycles from weeks to hours while preserving some degree of expert modelling. Experiments across public datasets show that AICMET attains state-of-the-art predictive accuracy and faithfully quantifies inter-patient variability -- outperforming both nonlinear mixed-effects baselines and recent neural ODE variants. Our results highlight the feasibility of transformer-based, population-aware neural architectures as offering a new alternative for bespoke pharmacokinetic modeling pipelines, charting a path toward truly population-aware personalized dosing regimens.
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