Bollaerts Kaatje, Shinde Vivek, Dos Santos Gaël, Ferreira Germano, Bauchau Vincent, Cohet Catherine, Verstraeten Thomas
P95 Pharmacovigilance and Epidemiology Services, Koning Leopold III Laan 1, 3001 Leuven, Belgium.
GSK Vaccines, 2301 Renaissance Boulevard, King of Prussia, PA 19406, United States of America.
PLoS One. 2016 Feb 22;11(2):e0149289. doi: 10.1371/journal.pone.0149289. eCollection 2016.
An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine Pandemrix™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies.
We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible.
Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72-28.11) reduced to a median value of 6.06 (2.5th- 97.5th percentile: 2.49-15.1) and the French odds ratio of 5.43 (95% CI: 2.6-10.08) to 1.85 (2.5th-97.5th percentile: 0.85-4.08).
We illustrate multiple-bias analyses using two studies on the Pandemrix™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed Pandemrix™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive.
在2009年甲型H1N1流感大流行接近尾声时，芬兰和瑞典的发作性睡病病例有所增加。初步观察性研究表明，这与大流行性流感疫苗“帕兰尼克”（Pandemrix™）存在时间上的关联，从而在欧洲引发了多项其他研究。鉴于公共卫生的紧迫性，这些研究使用了来自各种来源的现成回顾性数据。人们普遍认识到在这种情况下存在偏差的可能性。尽管主要意见领袖和国际卫生当局普遍提倡，但这些研究均未对偏差的潜在联合影响进行系统的定量评估。
我们对两项已发表的发作性睡病研究应用了偏差水平多重偏差分析：一项来自芬兰的儿科队列研究和一项来自法国的病例对照研究。特别是，我们开发了蒙特卡洛模拟模型来评估潜在的偏差级联，包括年龄、适应证和自然感染甲型H1N1流感造成的混杂、选择偏差、疾病和暴露错误分类。所有偏差参数尽可能以证据为依据。
根据用于混杂、选择偏差和错误分类的假设，芬兰的率比13.78（95%可信区间：5.72 - 28.11）降至中位数6.06（第2.5至97.5百分位数：2.49 - 15.1），法国的比值比5.43（95%可信区间：2.6 - 10.08）降至1.85（第2.5至97.5百分位数：0.85 - 4.08）。
我们通过两项关于“帕兰尼克”（Pandemrix™）与发作性睡病关联的研究阐述了多重偏差分析，并提倡使用这种方法来更好地理解研究结果的稳健性。基于我们的多重偏差模型，在芬兰的研究中观察到的“帕兰尼克”（Pandemrix™）与发作性睡病的关联持续存在。对于法国的研究，我们多重偏差模型的结果尚无定论。
