Davey Smith George, Sterne Jonathan A C, Fraser Abigail, Tynelius Per, Lawlor Debbie A, Rasmussen Finn
Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, BS8 2BN.
BMJ. 2009 Dec 22;339:b5043. doi: 10.1136/bmj.b5043.
To obtain valid estimates of the association between body mass index (BMI) and mortality by using offspring BMI as an instrumental variable for own BMI.
Cohort study based on record linkage, with 50 years of follow-up for mortality. Associations of offspring BMI with all cause and cause specific maternal and paternal mortality were estimated as hazard ratios per standard deviation of offspring BMI.
A large intergenerational prospective population based database covering the general population of Sweden.
More than one million Swedish parent-son pairs.
The final dataset analysed contained information on 1 018 012 mother-son pairs (122 677 maternal deaths) and 1 004 617 father-son pairs (242 126 paternal deaths). For some causes of death, the patterns of associations between offspring BMI and mortality were similar to those seen for own BMI and mortality in previous studies. Parental mortality from diabetes, coronary heart disease, and kidney cancer had the strongest positive associations with offspring BMI (for example, hazard ratio (HR) for coronary heart disease per standard deviation increase in offspring BMI for mothers 1.15, 95% CI 1.14 to 1.17 and for fathers 1.10, 1.09 to 1.11). However, in contrast to the inverse association of own BMI with lung cancer and respiratory disease mortality seen in other studies, there was a positive association between offspring BMI and lung cancer mortality in mothers (1.12, 1.09 to 1.15) and fathers (1.03, 1.02 to 1.05) and between offspring BMI and respiratory mortality in mothers (1.05, 1.02 to 1.08) and fathers (1.02, 1.00 to 1.04). Associations of own BMI and offspring BMI with all cause, cardiovascular disease related, and non-cardiovascular disease related mortality were compared in a subset of father-son pairs (n=72 815). When offspring BMI was used as an instrumental variable for paternal BMI, the causal association between BMI and paternal cardiovascular disease mortality (HR per standard deviation of BMI 1.82, 95% CI 1.17 to 2.83) was stronger than that indicated by the directly observed association between own BMI and cardiovascular disease mortality (1.45, 1.31 to 1.61).
Use of offspring BMI as a predictor of own BMI, a technique that avoids problems of reverse causality, suggests that positive associations of BMI with all cause and cardiovascular mortality may be underestimated in conventional observational studies. Use of offspring BMI instead of own BMI in analyses of respiratory disease and lung cancer mortality, for which previous studies have reported consistent and strong inverse associations with own BMI, suggests that such studies have overstated the apparent adverse consequences of lower BMI with respect to these outcomes.
通过将子代体重指数（BMI）作为自身BMI的工具变量，来获得BMI与死亡率之间关联的有效估计值。
基于记录链接的队列研究，对死亡率进行50年随访。子代BMI与全因及特定病因的母亲和父亲死亡率的关联以子代BMI每标准差的风险比来估计。
一个覆盖瑞典普通人群的大型代际前瞻性人群数据库。
超过100万瑞典父子对。
最终分析的数据集包含1018012对母子对（122677例母亲死亡）和1004617对父子对（242126例父亲死亡）的信息。对于某些死因，子代BMI与死亡率之间的关联模式与先前研究中自身BMI与死亡率的关联模式相似。糖尿病、冠心病和肾癌导致的父母死亡率与子代BMI的正相关性最强（例如，母亲子代BMI每增加一个标准差，冠心病的风险比（HR）为1.15，95%CI为1.14至1.17；父亲为1.10，1.09至1.11）。然而，与其他研究中自身BMI与肺癌和呼吸系统疾病死亡率的负相关不同，母亲（1.12，1.09至1.15）和父亲（1.03，1.02至1.05）的子代BMI与肺癌死亡率之间以及母亲（1.05，1.02至1.08）和父亲（1.02，1.00至1.04）的子代BMI与呼吸系统死亡率之间存在正相关。在一部分父子对（n = 72815）中比较了自身BMI和子代BMI与全因、心血管疾病相关和非心血管疾病相关死亡率的关联。当子代BMI用作父亲BMI的工具变量时，BMI与父亲心血管疾病死亡率之间的因果关联（BMI每标准差的HR为1.82，95%CI为1.17至2.83）比自身BMI与心血管疾病死亡率之间直接观察到的关联（1.45，1.31至1.61）更强。
使用子代BMI作为自身BMI的预测指标，这一避免了反向因果关系问题的技术表明，在传统观察性研究中，BMI与全因和心血管死亡率的正相关可能被低估。在分析呼吸系统疾病和肺癌死亡率时，用子代BMI代替自身BMI，而先前研究报告自身BMI与这些疾病死亡率存在一致且强烈的负相关，这表明此类研究夸大了较低BMI对这些结局的明显不良影响。
