Gilbert P B
Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, USA.
Stat Med. 2000 Nov 30;19(22):3065-86. doi: 10.1002/1097-0258(20001130)19:22<3065::aid-sim600>3.0.co;2-d.
In a preventive vaccine efficacy trial of a vaccine for a genotypically and phenotypically diverse pathogen, it is important to assess if and how vaccine protection against infection or disease varies with characteristics of the exposing pathogen. Gilbert, Self and Ashby developed statistical methods for this problem when the outcome data are counts of the number of vaccinated and unvaccinated trial participants infected by each pathogen strain. However, in many vaccine trials time-to-case information is available, and the extent to which this information improves investigation of differential vaccine protection is unclear. We describe how cause-specific proportional hazards models and other popular competing risks failure time techniques can be applied to this problem. This includes new results on the assumptions required for these methods to give valid inferences about strain-specific vaccine efficacy, and a comparison of theoretical and finite-sample properties between these methods and the time-independent methods. Theoretical considerations, a cholera vaccine trial example, and an extensive simulation study of a human immunodeficiency virus type 1 (HIV-1) vaccine trial show that information about failure times does not appreciably improve estimation or testing unless the pathogen has a high attack rate and the relative prevalence of pathogen strains shifts substantially during the trial follow-up period. An important implication is that practically optimal evaluation of strain-specific vaccine efficacy in HIV-1 vaccine trials will not require knowledge of infection times.
在针对基因型和表型多样的病原体的预防性疫苗效力试验中，评估疫苗对感染或疾病的保护作用是否以及如何随暴露病原体的特征而变化非常重要。吉尔伯特、塞尔夫和阿什比针对这一问题开发了统计方法，此时的结果数据是每种病原体菌株感染的接种和未接种试验参与者数量的计数。然而，在许多疫苗试验中，可以获得发病时间信息，而这些信息在多大程度上能改善对不同疫苗保护作用的研究尚不清楚。我们描述了如何将病因特异性比例风险模型和其他常用的竞争风险失效时间技术应用于这个问题。这包括关于这些方法对菌株特异性疫苗效力做出有效推断所需假设的新结果，以及这些方法与时间独立方法之间理论和有限样本性质的比较。理论考量、霍乱疫苗试验实例以及对人类免疫缺陷病毒1型（HIV-1）疫苗试验的广泛模拟研究表明，除非病原体具有高攻击率且在试验随访期间病原体菌株的相对流行率发生大幅变化，否则关于失效时间的信息不会显著改善估计或检验。一个重要的启示是，在HIV-1疫苗试验中对菌株特异性疫苗效力进行实际最优评估并不需要了解感染时间。
