Background An increasing proportion of people have a body mass index (BMI) classified as overweight or obese and published studies disagree whether this will be beneficial or detrimental to health. We applied and evaluated two intergenerational instrumental variable methods to estimate the average causal effect of BMI on mortality in a cohort with many deaths: the parents of UK Biobank participants. Methods In Cox regression models, parental BMI was instrumented by offspring BMI using an ‘offspring as instrument’ (OAI) estimation and by offspring BMI-related genetic variants in a ‘proxy-genotype Mendelian randomization’ (PGMR) estimation. Results Complete-case analyses were performed in parents of 233 361 UK Biobank participants with full phenotypic, genotypic and covariate data. The PGMR method suggested that higher BMI increased mortality with hazard ratios per kg/m2 of 1.02 (95% CI: 1.01, 1.04) for mothers and 1.04 (95% CI: 1.02, 1.05) for fathers. The OAI method gave considerably higher estimates, which varied according to the parent–offspring pairing between 1.08 (95% CI: 1.06, 1.10; mother–son) and 1.23 (95% CI: 1.16, 1.29; father–daughter). Conclusion Both methods supported a causal role of higher BMI increasing mortality, although caution is required regarding the immediate causal interpretation of these exact values. Evidence of instrument invalidity from measured covariates was limited for the OAI method and minimal for the PGMR method. The methods are complementary for interrogating the average putative causal effects because the biases are expected to differ between them.

中文翻译：

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英国生物银行体重指数和死亡率的代际工具变量分析比较


背景 越来越多的人的体重指数 (BMI) 被归类为超重或肥胖，但已发表的研究对于这是否有益于健康存在分歧。我们应用并评估了两种代际工具变量方法，以估计 BMI 对死亡人数众多的队列（英国生物银行参与者的父母）死亡率的平均因果效应。方法 在 Cox 回归模型中，使用“后代作为工具”(OAI) 估计的后代 BMI 以及“代理基因型孟德尔随机化”(PGMR) 估计中的后代 BMI 相关遗传变异来测量父母 BMI。结果 对 233 361 名英国生物银行参与者的父母进行了完整病例分析，获得了完整的表型、基因型和协变量数据。 PGMR 方法表明，较高的 BMI 会增加死亡率，母亲每公斤/平方米的风险比为 1.02（95% CI：1.01，1.04），父亲每公斤/平方米的风险比为 1.04（95% CI：1.02，1.05）。 OAI 方法给出的估计值要高得多，根据亲子配对的不同，估计值在 1.08（95% CI：1.06，1.10；母子）和 1.23（95% CI：1.16，1.29；父女）之间变化。结论 两种方法都支持较高的 BMI 增加死亡率的因果作用，尽管对这些确切值的直接因果解释需要谨慎。对于 OAI 方法，来自测量协变量的仪器无效性证据有限，而对于 PGMR 方法则极少。这些方法对于询问平均假定因果效应是互补的，因为预计它们之间的偏差会有所不同。