Big data, observational research and p-value: a recipe for false positive findings? A study of simulated and real prospective cohorts

Background: An increasing number of observational studies combine large sample sizes with low participation rates, which could lead to standard inference failing to control the false discovery rate. We investigated if the “empirical calibration of p-value” method (EPCV), reliant on negative controls, can preserve type-I error in the context of survival analysis. Methods. Simulated cohort studies with 50% participation rate and two different selection bias mechanisms, and a real-life application on predictors of cancer mortality using data from four population-based cohorts in Northern Italy (n=6976 men and women aged 25-74 years at baseline and 17 years of median follow-up). Results: Type-I error for the standard Cox model was above the 5% nominal level in 15 out of 16 simulated settings; for n=10,000, the chances of a null association with hazard ratio=1.05 having a p-value<0.05 were 42.5%. Conversely, EPCV with 10 negative controls preserved the 5% nominal level in all the simulation settings, reducing bias in the point estimate by 80-90% when its main assumption was verified. In the real case, 15 out of 21 (71%) blood markers with no association with cancer mortality according to literature had a p-value<0.05 in age- and gender-adjusted Cox models. After calibration, only 1 (4.8%) remained statistically significant. Conclusions. In the analyses of large observational studies prone to selection bias, the use of empirical distribution to calibrate p-values can substantially reduce the number of trivial results needing further screening for relevance and external validity