Ferguson Erin L, Zimmerman Scott C, Jiang Chen, Choi Minhyuk, Meyers Travis J, Hoffmann Thomas J, Gilsanz Paola, Wang Jingxuan, Oni-Orisan Akinyemi, Whitmer Rachel A, Risch Neil, Krauss Ronald M, Patel Chirag J, Schaefer Catherine A, Glymour M Maria
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA.
Department of Epidemiology, Boston University School of Public Health, Boston, MA, 02118, USA.
Eur J Epidemiol. 2025 May 3. doi: 10.1007/s10654-025-01231-y.
Mixed evidence on how statins affect dementia risk may reflect variability in model specifications. Alternate specifications are rarely systematically compared. Using an emulated trial design framework, we investigated variation in the estimated effect of statin initiation on dementia across alternative (1) eligibility criteria, (2) confounding variable sets, and (3) outcome definitions. Kaiser Permanente Northern California members' linked electronic health records from 1996 to 2020 were used to identify statin initiation and dementia diagnoses. Statin initiators were matched on age and low-density lipoprotein cholesterol with up to 5 non-initiators. Possible covariates included clinical (n = 1.4 million); socioeconomic and behavioral (n = 265,224); and genetic (n = 69,573) variables. Using Cox proportional-hazards models, we estimated variation across 1.27 million intent-to-treat estimates for statin initiation varying specification of eligibility, outcome definition, and covariates. Estimated hazard ratios (HRs) for statin initiation on dementia across all specifications ranged from 0.93 to 1.47. The variance of estimates due to model specification differences was 7.6 times larger than the average variance of specific estimates due to finite sample size. Three modeling decisions notably attenuated coefficients [ln(HR)]: requiring a run-in period prior to the emulated trial start date (0.034); adjustment for diabetes (0.030) and cardiovascular disease (0.039); and excluding the first year of follow-up (0.041). HRs from models with all three specifications ranged from 0.99 to 1.15. No specification we evaluated consistently generated protective effects. Estimates of the association between statin initiation and dementia leveraging real world data are sensitive to model specification, especially decisions related to clinical covariates and time-at-risk.
关于他汀类药物如何影响痴呆风险的证据不一,这可能反映了模型设定的差异。很少有系统地比较替代设定。使用模拟试验设计框架,我们研究了在替代方案下(1)纳入标准、(2)混杂变量集和(3)结局定义中,他汀类药物起始治疗对痴呆估计效应的变化。利用北加利福尼亚州凯撒医疗集团1996年至2020年成员的关联电子健康记录来确定他汀类药物起始治疗情况和痴呆诊断。他汀类药物起始使用者按年龄和低密度脂蛋白胆固醇与多达5名非起始使用者进行匹配。可能的协变量包括临床变量(n = 140万);社会经济和行为变量(n = 265,224);以及遗传变量(n = 69,573)。使用Cox比例风险模型,我们估计了127万个他汀类药物起始治疗意向性分析估计值的变化,这些估计值因纳入标准、结局定义和协变量的不同设定而有所差异。所有设定下他汀类药物起始治疗对痴呆的估计风险比(HR)范围为0.93至1.47。由于模型设定差异导致的估计值方差比由于有限样本量导致的特定估计值平均方差大7.6倍。三个建模决策显著降低了系数[ln(HR)]:在模拟试验开始日期之前要求有一个导入期(0.034);对糖尿病(0.030)和心血管疾病(0.039)进行调整;以及排除随访的第一年(0.041)。具有所有这三个设定的模型的HR范围为0.99至1.15。我们评估的任何设定都没有始终产生保护作用。利用真实世界数据对他汀类药物起始治疗与痴呆之间关联的估计对模型设定敏感,尤其是与临床协变量和风险时间相关的决策。