A more thorough understanding of the effect of environmental factors on seasonal IPD incidence could offer significant insight into pathogenesis, improve disease forecasting, and help determine the likely direction of pneumococcal disease incidence in the face of global climate change [16] . Our objective was to investigate how environmental factors influence IPD occurrence in Philadelphia County. We used both traditional analytic methods (i.e., Poisson regression with seasonal smoothers) and a novel case-crossover method to examine the effects of acute weather fluctuations on IPD occurrence. Both methods reduce confounding by environmental, behavioural, and infectious influences that might otherwise distort the observed magnitude of environmental effects on disease risk.