GSK Vaccines, Rue Fleming 2, B-1300, Wavre, Belgium.
Present address: Galapagos Pharma, Mechelen, Belgium.
BMC Med Res Methodol. 2021 Feb 15;21(1):35. doi: 10.1186/s12874-021-01220-1.
Randomized controlled trials are considered the gold standard to evaluate causal associations, whereas assessing causality in observational studies is challenging.
We applied Hill's Criteria, counterfactual reasoning, and causal diagrams to evaluate a potentially causal relationship between an exposure and outcome in three published observational studies: a) one burden of disease cohort study to determine the association between type 2 diabetes and herpes zoster, b) one post-authorization safety cohort study to assess the effect of AS04-HPV-16/18 vaccine on the risk of autoimmune diseases, and c) one matched case-control study to evaluate the effectiveness of a rotavirus vaccine in preventing hospitalization for rotavirus gastroenteritis.
Among the 9 Hill's criteria, 8 (Strength, Consistency, Specificity, Temporality, Plausibility, Coherence, Analogy, Experiment) were considered as met for study c, 3 (Temporality, Plausibility, Coherence) for study a, and 2 (Temporary, Plausibility) for study b. For counterfactual reasoning criteria, exchangeability, the most critical assumption, could not be tested. Using these tools, we concluded that causality was very unlikely in study b, unlikely in study a, and very likely in study c. Directed acyclic graphs provided complementary visual structures that identified confounding bias and helped determine the most accurate design and analysis to assess causality.
Based on our assessment we found causal Hill's criteria and counterfactual thinking valuable in determining some level of certainty about causality in observational studies. Application of causal inference frameworks should be considered in designing and interpreting observational studies.
随机对照试验被认为是评估因果关系的金标准，而评估观察性研究中的因果关系具有挑战性。
我们应用了希尔斯标准、反事实推理和因果关系图，以评估三个已发表的观察性研究中暴露与结局之间的潜在因果关系：a）一项疾病负担队列研究，以确定 2 型糖尿病与带状疱疹之间的关联；b）一项上市后安全性队列研究，以评估 AS04-HPV-16/18 疫苗对自身免疫性疾病风险的影响；c）一项匹配病例对照研究，以评估轮状病毒疫苗预防轮状病毒胃肠炎住院的效果。
在 9 项希尔斯标准中，有 8 项（强度、一致性、特异性、时间性、真实性、一致性、类推、实验）被认为在研究 c 中得到满足，3 项（时间性、真实性、一致性）在研究 a 中得到满足，2 项（时间性、真实性）在研究 b 中得到满足。对于反事实推理标准，最关键的假设可交换性无法进行检验。使用这些工具，我们得出结论，在研究 b 中因果关系极不可能，在研究 a 中不太可能，在研究 c 中非常可能。有向无环图提供了补充的可视化结构，可识别混杂偏倚并帮助确定评估因果关系最准确的设计和分析。
基于我们的评估，我们发现因果希尔斯标准和反事实思维在确定观察性研究中因果关系的某种确定性方面具有价值。因果推理框架的应用应在设计和解释观察性研究中得到考虑。
