Estimating the influence of body mass index (BMI) on mortality using offspring BMI as an instrumental variable

OBJECTIVE: High body mass index (BMI) is an important predictor of mortality but estimating underlying causality is hampered by confounding and pre-existing disease. Here we use information from the offspring to approximate parental BMIs, with an aim to avoid biased estimation of mortality risk caused by reverse causality. METHODS: The analyses were based on information on 9 674 offspring-mother, and 9 096 offspring-father pairs obtained from the 1958 British birth cohort. Parental BMI - mortality associations were analysed using conventional methods, and using offspring BMI as a proxy, or instrument, for their parents’ BMI. RESULTS: In the conventional analysis, associations between parental BMI and all-cause mortality were U-shaped (P(curvature) <0.001), while offspring BMI had linear associations with parental mortality (P(trend)<0.001, P(curvature)>0.46). Curvature was particularly pronounced for mortality from respiratory diseases and from lung cancer. Instrumental variable analyses suggested a positive association between BMI and mortality from all causes [Mothers: HR per SD of BMI 1.43 (95% CI 1.21 to 1.69). Fathers: HR 1.17, (1.00 to 1.36)] and from coronary heart disease [Mothers: HR 1.65 (1.15 to 2.36). Fathers: HR 1.51, (1.17 to 1.97)]. These were larger than HR from the equivalent conventional analyses, despite some attenuation by adjustment for social indicators and smoking. CONCLUSIONS: Analyses using offspring BMI as a proxy for parental BMI suggest that the apparent adverse consequences of low BMI are considerably overestimated and adverse consequences of overweight are underestimated in conventional epidemiological studies.