No abstract

Background: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist.Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk.Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80–2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68–0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy.Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.

The FAMILY Cohort is a longitudinal study of health, happiness and family harmony (the '3Hs') at individual, household and neighbourhood levels in Hong Kong. Using a family living in the same household as the sampling unit, the study (n = 20 279 households and 46 001 participants) consists of a composite sample from several sources, including: a population-representative random core sample (n = 8115 households and 19 533 participants); the first-degree relatives of this sample (n = 4658 households and 11 063 participants); and oversampling in three new towns (n = 2891 households and 7645 participants) and in three population subgroups with anticipated changes in family dynamics (n = 909 households and 2160 participants). Two household visits and five telephone- or web-based follow-ups were conducted over 2009-14. Data collected include socio-demographics, anthropometrics, lifestyle and behavioural factors, measures of social capital, and standardized instruments assessing the 3Hs. We also intend to collect biomaterials in future. The analytical plan includes multilevel inter-relations of the 3Hs for individuals, households, extended families and neighbourhoods. With Hong Kong's recent history of socioeconomic development, the FAMILY Cohort is therefore relevant to global urban populations currently experiencing similarly rapid economic growth. The FAMILY Cohort is currently set up as a supported access resource.