AI 中文总结
该研究针对传染病预防试验中常规协变量调整精度不足的问题，提出调整阴性对照结局事件时间的估计方法，经HVTN 704/HPTN 085试验验证，可显著提升预防效果估计的精度。
AI 中文摘要
基线协变量调整可通过提高治疗效果估计的精度来增强随机试验的效率，但精度提升取决于基线协变量对主要结局的预后作用强度。在传染病预防干预（如疫苗或被动给药抗体）的随机试验中，个体对病原体的暴露是主要预后因素，但基线时通常无法测量，因此常规协变量调整在预防试验中提供的精度提升有限。本文提出调整阴性对照结局（NCO）事件时间，该结局不受干预的因果影响，但与主要结局共享重叠的暴露机制。我们明确了调整NCO事件时间有效的假设条件，并表明NCO事件时间的右删失会进一步使调整复杂化。当主要结局和NCO事件时间均存在右删失时，我们推导了治疗组特异性主要结局生存函数的有效影响函数，并用其构建了交叉拟合的一步估计量，该估计量对干扰项误设定具有多重鲁棒性，且在干扰项估计准确时渐近有效。数值实验显示，当NCO事件时间无预后作用时，我们的估计量与基准方法表现相当；当NCO事件时间对主要结局的预后作用越强，精度提升越显著。我们将该方法应用于HVTN 704/HPTN 085试验，这是一项针对VRC01（一种抗HIV-1的广谱中和抗体）的随机双盲试验。与基线协变量调整仅减少约2.5%的估计方差相比，调整细菌性性传播感染的时间（HIV-1获得的阴性对照结局）使预防效果估计的方差减少了约27%。
英文摘要
Baseline covariate adjustment can enhance the efficiency of randomized trials by improving precision of treatment effect estimates. However, the precision gain depends on how strongly the baseline covariates are prognostic for the primary outcome. In randomized trials of infectious disease prevention interventions (e.g., vaccines or passively administered antibodies), an individual's exposure to the pathogen is a leading prognostic factor but is rarely measurable at baseline. Hence, conventional covariate adjustment offers limited precision gain in prevention trials. We propose adjusting for a negative control outcome (NCO) event time, which is causally unaffected by the intervention but shares overlapping exposure mechanisms with the primary outcome. We formalize assumptions under which adjustment for the NCO event time is valid, and show that right-censoring of the NCO event time further complicates adjustment. We derive the efficient influence function for the treatment-arm-specific survivor function of the primary outcome when both the primary outcome and the NCO event time are right-censored, and use it to construct a cross-fitted, one-step estimator that is multiply robust to nuisance misspecification and asymptotically efficient when the nuisances are estimated accurately. In numerical experiments, our estimator compares comparably to benchmarks when the NCO event time is uninformative, and gains precision as the NCO event time is more prognostic for the primary outcome. We apply our method to HVTN 704/HPTN 085, a randomized, double-blinded trial of VRC01, a broadly neutralizing antibody against HIV-1. Adjusting for the time to a bacterial sexually transmitted infection --- a negative control outcome for HIV-1 acquisition --- reduced the estimated variance of the prevention efficacy estimate by approximately 27%, compared to roughly 2.5% for baseline covariate adjustment.
