Test for Comparing the Associations of Multiple Exposures With a Common Outcome.

Introduction: With advancement of medicine, alternative exposures or interventions are emerging with respect to a common outcome, and there are needs to formally test the difference in the associations of multiple exposures.

Methods: The paper proposes a duplication method-based multivariate Wald test in the Cox proportional hazard regression model to test the difference in the associations of multiple exposures with a same outcome. This method applies to continuous or categorical exposures. For illustration, the method was applied to compare the associations between alignment to 2 different dietary patterns (Alternative Healthy Eating Index-2010 and reversed empirical dietary inflammatory pattern), either as continuous or quartile exposures, and incident chronic diseases, defined as a composite of cardiovascular disease, cancer, and diabetes, in the Health Professional Follow-up Study. Relevant sample codes in R that implement the proposed approach are provided. The present analysis was conducted in 2024.

Results: With a median follow-up of 22 years, there were a total of 14,427 chronic disease incidences among N=43,185 men included in the Health Professional Follow-up Study analysis. The hazard ratios (HRs) (95% CI) per increment from the 10th to the 90th percentile for incident chronic disease were 0.83 (0.79, 0.87) for Alternative Healthy Eating Index-2010 and 0.76 (0.73, 0.80) for reversed empirical dietary inflammatory pattern. Although the 95% CIs were overlapped for each exposure, the proposed test was well powered to detect the difference (p=0.005).

Conclusions: The proposed duplication-method-based approach offers a flexible, formal statistical test for heterogeneity in the associations of multiple exposures with the common outcome with minimal assumptions.