Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, UK.
J R Soc Interface. 2011 Dec 7;8(65):1720-35. doi: 10.1098/rsif.2011.0125. Epub 2011 May 18.
Dose-response experiments characterize the relationship between infectious agents and their hosts. These experiments are routinely used to estimate the minimum effective infectious dose for an infectious agent, which is most commonly characterized by the dose at which 50 per cent of challenged hosts become infected-the ID(50). In turn, the ID(50) is often used to compare between different agents and quantify the effect of treatment regimes. The statistical analysis of dose-response data typically makes the assumption that hosts within a given dose group are independent. For social animals, in particular avian species, hosts are routinely housed together in groups during experimental studies. For experiments with non-infectious agents, this poses no practical or theoretical problems. However, transmission of infectious agents between co-housed animals will modify the observed dose-response relationship with implications for the estimation of the ID(50) and the comparison between different agents and treatments. We derive a simple correction to the likelihood for standard dose-response models that allows us to estimate dose-response and transmission parameters simultaneously. We use this model to show that: transmission between co-housed animals reduces the apparent value of the ID(50) and increases the variability between replicates leading to a distinctive all-or-nothing response; in terms of the total number of animals used, individual housing is always the most efficient experimental design for ascertaining dose-response relationships; estimates of transmission from previously published experimental data for Campylobacter spp. in chickens suggest that considerable transmission occurred, greatly increasing the uncertainty in the estimates of dose-response parameters reported in the literature. Furthermore, we demonstrate that accounting for transmission in the analysis of dose-response data for Campylobacter spp. challenges our current understanding of the differing response of chickens with respect to host-age and in vivo passage of bacteria. Our findings suggest that the age-dependence of transmissibility between hosts-rather than their susceptibility to colonization-is the mechanism behind the 'lag-phase' reported in commercial flocks, which are typically found to be Campylobacter free for the first 14-21 days of life.
剂量反应实验描述了病原体与其宿主之间的关系。这些实验通常用于估计病原体的最小有效感染剂量，该剂量通常以感染挑战的 50%宿主的剂量来表示，即 ID(50)。反过来，ID(50) 常用于比较不同的病原体，并量化治疗方案的效果。剂量反应数据的统计分析通常假设给定剂量组内的宿主是独立的。对于群居动物，特别是鸟类，在实验研究中，宿主通常会被一起分组饲养。对于非传染性病原体的实验，这不会带来实际或理论上的问题。然而，共养动物之间的病原体传播会改变观察到的剂量反应关系，从而影响 ID(50)的估计以及不同病原体和处理方法之间的比较。我们推导出了一个简单的修正方法，可以对标准剂量反应模型的似然进行修正，从而允许我们同时估计剂量反应和传播参数。我们使用该模型表明：共养动物之间的传播会降低 ID(50)的表观值，并增加重复之间的变异性，导致明显的全有或全无反应；就使用的动物总数而言，个体饲养始终是确定剂量反应关系最有效的实验设计；从先前发表的鸡源弯曲杆菌实验数据中得出的传播估计表明，大量的传播发生了，这大大增加了文献中报告的剂量反应参数估计的不确定性。此外，我们证明，在分析弯曲杆菌的剂量反应数据时，考虑到传播因素，这对我们目前对宿主年龄和细菌体内传代对鸡的不同反应的理解提出了挑战。我们的研究结果表明，宿主之间传播的年龄依赖性——而不是它们对定植的易感性——是商业鸡群中报告的“滞后期”的机制，这些鸡群通常在生命的前 14-21 天被发现没有弯曲杆菌。
