14West Nile virus (WNV) has consistently been reported to be associated with human cases of 15 illness in the region near Chicago, Illinois. However, the number of reported cases of human 16 illness varies across years, with intermittent outbreaks. Several dynamic factors, including 17 temperature, rainfall, and infection status of vector mosquito populations, are responsible for 18 much of these observed variations. However, local landscape structure and human 19 demographic characteristics also play a key role. The geographic and temporal scales used to 20 analyze such complex data affect the observed associations. Here, we used spatial and 21 statistical modeling approaches to investigate the factors that drive the outcome of WNV 22 human illness on fine temporal and spatial scales. Our approach included multi-level 23 modeling of long-term weekly data from 2005 to 2016, with weekly measures of mosquito 24 infection, human illness and weather combined with more stable landscape and demographic 25 factors on the geographical scale of 1000m hexagons. We found that hot weather conditions, 26 warm winters, and higher MIR in earlier weeks increased the probability of an area of having 27 a WNV human case. Higher population and the proportion of urban light intensity in an area 28 also increased the probability of observing a WNV human case. A higher proportion of open 29 water sources, percentage of grass land, deciduous forests, and housing built post 1990 30 decreased the probability of having a WNV case. Additionally, we found that cumulative 31 positive mosquito pools up to 31 weeks can strongly predict the total annual human WNV 32 cases in the Chicago region. This study helped us to improve our understanding of the fine-33 scale drivers of spatiotemporal variability of human WNV cases.34 35 Introduction 36 West Nile virus (WNV), a mosquito-borne zoonotic disease, was first identified in the 37 United States in the summer of 1999 in New York City [1].The mosquitoes of several Culex 38 species are the primary enzootic and bridge vectors for the transmission of WNV, and several 39 bird species are known to contribute in the amplification of the virus [2-4]. Since its first 40 successful invasion in New York, WNV quickly adapted to the local populations of Culex 41 vector mosquitoes and avian populations and rapidly spread throughout the conterminous 42 United States [5,6]. The first major WNV outbreak in the United States was observed in 43 2002, when more than 4,150 human cases and 284 deaths attributable to WNV infection were 44 reported to the CDC from 40 states compared to only 149 cases and 19 deaths from 10 states 45 cumulatively during the three years from 1999 to 2001 [7]. This stirred a prompt public 46 health response from federal, state, and local public health agencies and led to the 47 establishment of a more robust surveillance of mosquitoes and birds to monitor and control 48 the spread of WNV [8]. 49 Public health surveillance for West Nile virus (WNV) involves collection and testing 50 of Cul...