Hudgens Michael G, Hoering Antje, Self Steven G
Statistical Center For HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, MW-500, P.O. Box 19024, Seattle, WA 98109, USA.
Stat Med. 2003 Jul 30;22(14):2281-98. doi: 10.1002/sim.1394.
First generation HIV vaccines are not likely to provide complete protection from HIV-1 infection. Therefore, it is important to assess a vaccine's effect on disease progression and infectiousness of infected vaccinees in an efficacy trial; however, direct assessment of such vaccine effects is not feasible within current trial designs. Viral load in HIV-infected individuals correlates with infectiousness and disease progression in a natural history setting, and thus is a reasonable candidate for a surrogate outcome in vaccine efficacy trials. We consider comparisons of viral load of infected vaccinees to that of infected trial participants in the control group. Dramatic differences in viral loads between these groups would suggest a vaccine effect on disease progression. However, modest differences, even if statistically significant, could be consistent with an imperfect vaccine effect on susceptibility to infection and not an effect on disease progression, that is, a selection effect of the vaccine. Thus, the usual statistical tests for no difference between groups do not test the biologically and clinically relevant hypothesis. We propose a model for the possible selective effects of a vaccine and develop several test statistics for assessing a direct effect of the vaccine on viral load given this selection model. Finite sample properties of these tests are evaluated using computer simulations.
第一代HIV疫苗不太可能提供完全的保护以防止HIV-1感染。因此，在疗效试验中评估疫苗对受感染疫苗接种者疾病进展和传染性的影响很重要；然而，在当前的试验设计中，直接评估此类疫苗效果是不可行的。在自然病程中，HIV感染者的病毒载量与传染性和疾病进展相关，因此是疫苗疗效试验中替代结局的合理候选指标。我们考虑比较受感染疫苗接种者与对照组中受感染试验参与者的病毒载量。这些组之间病毒载量的显著差异将表明疫苗对疾病进展有影响。然而，即使差异在统计学上显著，适度的差异也可能与疫苗对感染易感性的不完全疫苗效果一致，而不是对疾病进展的影响，即疫苗的选择效应。因此，用于检验组间无差异的常用统计检验并不能检验生物学和临床相关的假设。我们提出了一个疫苗可能的选择效应模型，并在给定此选择模型的情况下开发了几种检验统计量，用于评估疫苗对病毒载量的直接影响。使用计算机模拟评估这些检验的有限样本性质。
