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Streptococcus pneumoniae is an opportunistic pathogen that, while usually carried asymptomatically, can cause severe invasive diseases like meningitis and bacteremic pneumonia. A central goal in S. pneumoniae public health management is to identify which serotypes (immunologically distinct strains) pose the most risk of invasive disease. The most common invasiveness metrics use cross-sectional data (i.e., invasive odds ratios (IOR)), or longitudinal data (i.e., attack rates (AR)). To assess the reliability of these metrics we developed an epidemiological model of carriage and invasive disease. Our mathematical analyses illustrate qualitative failures with the IOR metric (e.g., IOR can decline with increasing invasiveness parameters). Fitting the model to both longitudinal and cross-sectional data, our analysis supports previous work indicating that invasion risk is maximal at or near time of colonization. This pattern of early invasive disease risk leads to substantial (up to 5-fold) biases when estimating underlying differences in invasiveness from IOR metrics, due to the impact of carriage duration on IOR. Together, these results raise serious concerns with the IOR metric as a basis for public health decision-making and lend support for multiple alternate metrics including AR., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier B.V.)

Bacterial infections are becoming an increasing problem worldwide and there is a need for a deeper understanding of how bacteria turn pathogenic. Here, we suggest that one answer may be found by taking into account the localization of the bacteria, both at an anatomical level and at a microenvironment level. Both commensals and traditional pathogens alter their interaction with the human host depending on the local surroundings--turning either more or less virulent. These localization effects could derive from the characteristics of different anatomical sites but also from local differences within a microenvironment. In order to understand the adaptive functions of bacterial virulence factors, we need to study the bacteria in the environments where they have evolved.