The Timing, the Treatment, the Question: Comparison of Epidemiologic Approaches to Minimize Immortal Time Bias in Real-World Data Using a Surgical Oncology

Background: Studies evaluating the effects of cancer treatments are prone to immortal time bias that, if unaddressed, can lead to treatments appearing more beneficial than they are.Methods: To demonstrate the impact of immortal time bias, we compared results across several analytic approaches (dichotomous exposure, dichotomous exposure excluding immortal time, time-varying exposure, landmark analysis, clone-censor-weight meth-od), using surgical resection among women with metastatic breast cancer as an example. All adult women diagnosed with incident metastatic breast cancer from 2013-2016 in the National Cancer Database were included. To quantify immortal time bias, we also conducted a simulation study where the "true" relationship between surgical resection and mortality was known.Results: 24,329 women (median age 61, IQR 51-71) were includ-ed, and 24% underwent surgical resection. The largest association between resection and mortality was observed when using a dichot-omized exposure [HR, 0.54; 95% confidence interval (CI), 0.51-0.57], followed by dichotomous with exclusion of immortal time (HR, 0.62; 95% CI, 0.59-0.65). Results from the time-varying exposure, land-mark, and clone-censor-weight method analyses were closer to the null (HR, 0.67-0.84). Results from the plasmode simulation found that the time-varying exposure, landmark, and clone-censor-weight method models all produced unbiased HRs (bias -0.003 to 0.016). Both standard dichotomous exposure (HR, 0.84; bias, -0.177) and dichotomous with exclusion of immortal time (HR, 0.93; bias, -0.074) produced meaningfully biased estimates. Conclusions: Researchers should use time-varying exposures with a treatment assessment window or the clone-censor-weight method when immortal time is present.Impact: Using methods that appropriately account for immortal time will improve evidence and decision-making from research using real-world data.