Prospective cohort studies could be used, but they are relatively expensive due to the cost of recruiting many individuals who will never be infected, and the high staff cost of the reactive follow-up by medical personnel. A carefully designed prospective cluster study could provide a more efficient way of gathering key data to improve basic understanding of infectious disease transmission dynamics, although substantive problems related to space-time disease change remain unresolved [20]. In fact, most analytical methods used in outbreak detection studies are purely temporal [21-23], which means that these methods can be late at detecting outbreaks that start locally and are linked to serious multiple testing problems generating false signals [24]. Scan statistics methods attempting to resolve such issues are of rather limited usefulness since they make assumptions that are often unrealistic (e.g., a uniform population at risk or ad hoc probability models), or they require information that may be not easily obtainable (e.g., information about the geographical and temporal distribution of populations at risk). Some studies of disease outbreaks (e.g., those based on prospective space-time permutation scan statistics) consider separately purely spatial and purely temporal variations [24,25], which is a simplification of the natural fact that the disease propagates in a composite space-time domain affected by regional climate dynamics. Significant effort has been made by means of the Kulldorf method to improve the ability to find spatial outbreaks using univariate input. This includes our ongoing study to develop a new method to detect multiple clusters in a study area by constructing two or more clusters in the context of the alternative hypothesis. In fact, many of the above methods have not been designed to account for important associations between disease distribution and meteorological conditions
Given the difficulties of previous statistical studies as regards the handling of the high spatiotemporal data dimensionality and the rigorous representation of composite space-time disease variation, in this work we use the space-time BME-S method, which is a combination of the Bayesian Maximum Entropy (BME) theory and the Self-Organized Map (SOM) technique [26]. The BME-S avoids certain modeling simplifications and dimensionality problems of previous studies and offers a realistic framework for modeling and estimation of the disease distribution in a composite space-time domain. Using readily available and well-tested BME-S software, the present HFMD study provides valuable insight into the disease space-time structure and mechanisms in China and their relation to the meteorological attributes and indicators of the region. Otherwise said, the BME-S methodology considers disease propagation and outbreak detection as interdisciplinary problems, which require the integration of information bases from different fields, e.g., health, environmental and population sciences [27,28].