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基于全面触发工具与机器学习的贝伐珠单抗严重不良反应预测模型研究
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| 篇名： | 基于全面触发工具与机器学习的贝伐珠单抗严重不良反应预测模型研究 |
| TITLE： | Predictive model for severe adverse reaction associated with bevacizumab based on the global trigger tool and machine learning |
| 摘要： | 目的 确定贝伐珠单抗相关不良反应（ADR）的触发器条目，判定并分析相关ADR发生情况，构建该药致严重不良反应（SAR）的预测模型。方法基于全面触发工具（GTT）理念，参考GTT白皮书、药品说明书及相关文献，结合单轮德尔菲法确定贝伐珠单抗相关ADR触发器条目；利用所建条目，基于中国医院药物警戒系统对桂林市人民医院2020年1月至2024年9月相关患者的电子病历进行主动筛查，由药师判定并统计贝伐珠单抗致ADR的发生情况。以所得触发器条目阳性患者的资料为对象（按7∶3划分训练集和测试集），通过Boruta算法从训练集相关39项变量中筛选候选特征变量，以是否发生SAR为因变量进行多因素Lo‐gistic回归分析；以上述候选特征变量为基础，构建Logistic回归、极端梯度提升、轻量级梯度提升机、随机森林、类别特征提升模型，通过受试者操作特征曲线的曲线下面积（AUC）、召回率等指标评估模型性能，应用Shapley加性解释（SHAP）法分析解释各变量的贡献，并基于最优模型构建列线图。结果最终确定用于贝伐珠单抗相关ADR主动监测的触发器条目38项，含检验指标17项、临床表现13项、干预措施8项。共纳入触发器条目阳性患者483例，其中发生ADR者318例，发生SAR者83例；触发器条目和病例阳性预测值分别为43.57%（708/1625）和63.84%（318/483）。贝伐珠单抗致ADR涉及7个系统/器官，以血液系统受累最为常见（64.15%）。经Boruta算法共筛选到血钾、红细胞压积、白/球蛋白比值、前白蛋白、既往高血压史、年龄、红细胞计数7个候选变量。多因素Logistic回归分析显示，血钾水平升高（OR＝0.234，P＝0.002）与贝伐珠单抗致SAR风险降低相关，既往高血压史（OR＝2.642，P＝0.006）和年龄增加（OR＝1.040，P＝0.025）与贝伐珠单抗致SAR风险升高有关。Logistic回归模型的AUC、F1值、召回率（0.761、0.447、0.607）均高于其他模型；SHAP评估结果显示，血钾、红细胞压积、年龄等变量的重要性位居前列。结论成功确定38项触发器条目用于贝伐珠单抗相关ADR的主动筛查。血钾水平升高是贝伐珠单抗致SAR的保护因素，而既往高血压史、年龄增加则是危险因素；Logistic回归模型为贝伐珠单抗致SAR的最优预测模型。 |
| ABSTRACT： | OBJECTIVE To confirm trigger items for adverse drug reaction （ADR） induced by bevacizumab， to identify and analyze the occurrence of related ADR， and to establish a predictive model for severe adverse reaction （SAR） caused by this drug. METHODS Based on the global trigger tool （GTT） theory， and referencing the GTT White Paper， drug package inserts and relevant literature， trigger items for bevacizumab-related ADR were confirmed using a single-round Delphi method. Utilizing these established items， electronic medical records of relevant patients at Guilin People’s Hospital from January 2020 to September 2024 were actively screened via the China Hospital Pharmacovigilance System. Pharmacists then identified and tallied the occurrence of bevacizumab-induced ADR. Data from patients with any positive trigger item served as the study subjects （divided into training and test sets at a ratio of 7∶3）， candidate feature variables were selected from 39 related variables using the Boruta algorithm， and the multivariable Logistic regression analysis was performed with the occurrence of SAR as the dependent variable. Based on these candidate features， Logistic Regression， Extreme Gradient Boosting， Light Gradient Boosting Machine， Random Forest， and Categorical Boosting models were constructed. Model performance was evaluated using metrics including the area under the curve （AUC） of receiver operating characteristic curve and recall rate. The Shapley Additive exPlanations （SHAP） method was applied to analyze and interpret the contribution of each variable. A nomogram was constructed based on the optimal model. RESULTS A total of 38 trigger items for active monitoring of bevacizumab-related ADR were determined， comprising 17 laboratory indicators， 13 clinical manifestations， and 8 intervention measures. In total， 483 patients with positive trigger items were included， and 318 patients with bevacizumab-induced ADR were identified， including 83 SARs. The positive predictive values for the trigger items and cases were 43.57% （708/1 625） and 63.84% （318/483）， respectively. Bevacizumab-induced ADR involved 7 systems/organs， with the hematological system being the most frequently involved （64.15%）. The Boruta algorithm selected 7 vari ables： serum potassium， hematocrit， albumin-to-globulin ratio， prealbumin， hypertension history， age and red blood cell count. Multivariable Logistic regression showed that elevated serum potassium levels were associated with a decreased risk of bevacizumab-induced SAR （OR＝0.234， P ＝0.002）， while a history of hypertension （OR＝2.642， P ＝0.006） and increased age （OR＝1.040， P ＝0.025） were associated with an increased risk. The Logistic Regression model demonstrated superior performance with higher AUC， F1 score and recall rate （0.761， 0.447， 0.607）， compared to other models. SHAP evaluation results indicated that variables such as serum potassium， hematocrit， and age ranked highest in importance. CONCLUSIONS Totally 38 trigger entries have been successfully identified for active screening of bevacizumab-related ADR. Elevated serum potassium levels are a protective factor against bevacizumab-induced SAR， whereas the hypertension history and increased age are risk factors. The Logistic Regression model is the optimal predictive model. |
| 期刊： | 2026年第37卷第04期 |
| 作者： | 符永妃；龙芯；徐宏珍；唐健；利向晴；龙钰程；覃东 |
| AUTHORS： | FU Yongfei，LONG Xin，XU Hongzhen，TANG Jian，LI Xiangqing，LONG Yucheng，QIN Dong |
| 关键字： | 贝伐珠单抗；药品不良反应；全面触发工具；机器学习；预测模型 |
| KEYWORDS： | bevacizumab； adverse drug reaction； global trigger tool； machine learning； predictive model |
| 阅读数： | 2 次 |
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