A unified framework for assessing interaction effects among environmental exposures in epidemiologic studies: A case study on temperature, air pollution, and kidney-related conditions in New York state

There are various methods to assess interaction effects. However, current methods have limitations, and quantification of interaction effects is rarely performed. This study aimed to develop a unified quantitative framework for assessing interaction effects.We proposed a novel framework using log-linear models with a product term(s) across the exposures that generates parametric bi-variate association and interaction effect surfaces and allows flexible functional forms for exposures in the interaction term(s). In a case study, we assessed the interaction effects between temperature and air pollution (i.e., PM2.5, NO2, and O3) on risk for kidney-related conditions in New York State (2007-2016) using a case-crossover design with conditional logistic models. Our measures of exposure were the moving averages at lag 0-5 days for air pollution (linear) and daytime mean outdoor wet-bulb globe temperature (WBGT; using a natural cubic spline).We derived closed-form expressions for the magnitude of multiplicative interaction effects (the joint relative risk divided by the product of the two conditional relative risks) and their uncertainties. In the case study, we found a Bonferroni-corrected significant multiplicative interaction effect (IE) between outdoor WBGT at the 99th percentile (median as the reference) and (1) PM2.5 (per 5 μg/m3 increase, IE = 1.052; 95 % confidence interval [CI]: 1.019, 1.087) for acute kidney failure and (2) O3 (per 5 ppb increase; IE = 1.022; 95 % CI: 1.008, 1.036) for urolithiasis (the latter being inconclusive based on the sensitivity analysis).Our framework allows different functional forms of exposure variables in the interaction term, quantifies the magnitudes of entire-exposure-range (in addition to discrete exposure level) multiplicative interaction effects and their uncertainties in a categorical or continuous (linear or non-linear) manner, and harmonizes the two-way evaluation of effect modification. The case study underscores co-consideration of heat and air pollution when estimating health burden and designing heat/pollution alert systems.