CHU Ste-Justine Research Center, Montréal, H3T1C5, Canada.
University Paris-Saclay, CESP, INSERM, Villejuif, 94807, France.
BMC Med Res Methodol. 2020 Mar 20;20(1):69. doi: 10.1186/s12874-020-00941-z.
With the growth in use of biotherapic drugs in various medical fields, the occurrence of anti-drug antibodies represents nowadays a serious issue. This immune response against a drug can be due either to pre-existing antibodies or to the novel production of antibodies from B-cell clones by a fraction of the exposed subjects. Identifying genetic markers associated with the immunogenicity of biotherapeutic drugs may provide new opportunities for risk stratification before the introduction of the drug. However, real-world investigations should take into account that the population under study is a mixture of pre-immune, immune-reactive and immune-tolerant subjects.
In this work, we propose a novel test for assessing the effect of genetic markers on drug immunogenicity taking into account that the population under study is a mixed one. This test statistic is derived from a novel two-part semiparametric improper survival model which relies on immunological mechanistic considerations.
Simulation results show the good behavior of the proposed statistic as compared to a two-part logrank test. In a study on drug immunogenicity, our results highlighted findings that would have been discarded when considering classical tests.
We propose a novel test that can be used for analyzing drug immunogenicity and is easy to implement with standard softwares. This test is also applicable for situations where one wants to test the equality of improper survival distributions of semi-continuous outcomes between two or more independent groups.
随着生物治疗药物在各个医学领域的广泛应用，药物抗体的产生现在是一个严重的问题。这种针对药物的免疫反应可能是由于预先存在的抗体，也可能是由于暴露于药物的一部分受试者中 B 细胞克隆产生的新抗体。确定与生物治疗药物免疫原性相关的遗传标记，可能为药物引入前的风险分层提供新的机会。然而，实际情况调查应考虑到所研究的人群是由未免疫、免疫反应性和免疫耐受的受试者混合而成的。
在这项工作中，我们提出了一种新的测试方法，用于评估遗传标记对药物免疫原性的影响，同时考虑到所研究的人群是混合的。该检验统计量来源于一种新的两部分半参数不当生存模型，该模型依赖于免疫学的机制考虑。
模拟结果表明，与两部分对数秩检验相比，该统计量具有良好的性能。在一项药物免疫原性研究中，我们的结果突出了那些在考虑经典检验时会被忽略的发现。
我们提出了一种新的可以用于分析药物免疫原性的检验方法，并且易于使用标准软件实现。该检验也适用于需要检验两个或多个独立组之间半连续结果的不当生存分布是否相等的情况。
