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A key issue in infectious disease epidemiology is to identify and predict geographic sites of epidemic establishment that contribute to onward spread, especially in the context of invasion waves of emerging pathogens. Conventional wisdom suggests that these sites are likely to be in densely-populated, well-connected areas. For pandemic influenza, however, epidemiological data have not been available at a fine enough geographic resolution to test this assumption. Here, we make use of fine-scale influenza-like illness incidence data derived from electronic medical claims records gathered from 834 3-digit ZIP (postal) codes across the US to identify the key geographic establishment sites, or "hubs", of the autumn wave of the 2009 A/H1N1pdm influenza pandemic in the United States. A mechanistic spatial transmission model is fit to epidemic onset times inferred from the data. Hubs are identified by tracing the most probable transmission routes back to a likely first establishment site. Four hubs are identified: two in the southeastern US, one in the central valley of California, and one in the midwestern US. According to the model, 75% of the 834 observed ZIP-level outbreaks in the US were seeded by these four hubs or their epidemiological descendants. Counter-intuitively, the pandemic hubs do not coincide with large and well-connected cities, indicating that factors beyond population density and travel volume are necessary to explain the establishment sites of the major autumn wave of the pandemic. Geographic regions are identified where infection can be statistically traced back to a hub, providing a testable prediction of the outbreak's phylogeography. Our method therefore provides an important way forward to reconcile spatial diffusion patterns inferred from epidemiological surveillance data and pathogen sequence data., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Influenza epidemics vary in intensity from year to year, driven by climatic conditions and by viral antigenic evolution. However, important spatial variation remains unexplained. Here we show predictable differences in influenza incidence among cities, driven by population size and structure. Weekly incidence data from 603 cities in the United States reveal that epidemics in smaller cities are focused on shorter periods of the influenza season, whereas in larger cities, incidence is more diffuse. Base transmission potential estimated from city-level incidence data is positively correlated with population size and with spatiotemporal organization in population density, indicating a milder response to climate forcing in metropolises. This suggests that urban centers incubate critical chains of transmission outside of peak climatic conditions, altering the spatiotemporal geometry of herd immunity., (Copyright © 2018, American Association for the Advancement of Science.)