Abstract
Studies have shown that accounting for time-varying confounding through time-dependent Cox proportional hazards models may provide biased estimates of the causal effect of treatment when the confounder is also a mediator. We explore 2 alternative approaches to addressing this problem while examining the association between vitamin D supplementation initiated after breast cancer diagnosis and all-cause mortality. Women aged 50–80 years were identified in the National Cancer Registry Ireland (n = 5,417) between 2001 and 2011. Vitamin D use was identified from linked prescription data (n = 2,570). We sought to account for the time-varying nature of vitamin D use and time-varying confounding by bisphosphonate use using 1) marginal structural models (MSMs) and 2) G-estimation of structural nested accelerated failure-time models (SNAFTMs). Using standard adjusted Cox proportional hazards models, we found a reduction in all-cause mortality in de novo vitamin D users compared with nonusers (hazard ratio (HR) = 0.84, 95% confidence interval (CI): 0.73, 0.99). Additional adjustment for vitamin D and bisphosphonate use in the previous month reduced the hazard ratio (HR = 0.45, 95% CI: 0.33, 0.63). Results derived from MSMs (HR = 0.44, 95% CI: 0.32, 0.61) and SNAFTMs (HR = 0.45, 95% CI: 0.34, 0.52) were similar. Utilizing MSMs and SNAFTMs to account for time-varying bisphosphonate use did not alter conclusions in this example.
Cox proportional hazards models with left truncation and time-varying coefficient: Application of age at event as outcome in cohort studies
