A descriptive analysis of the Spatio-temporal distribution of intestinal infectious diseases in China

Background Intestinal infectious diseases (IIDs) have caused numerous deaths worldwide, particularly among children. In China, eight IIDs are listed as notifiable infectious diseases, including cholera, poliomyelitis, dysentery, typhoid and paratyphoid (TAP), viral Hepatitis A, viral Hepatitis E, hand-foot-mouth disease (HFMD) and other infectious diarrhoeal diseases (OIDDs). The aim of the study is to analyse the spatio-temporal distribution of IIDs from 2006 to 2016. Methods Data on the incidence of IIDs from 2006 to 2016 were collected from the public health science data centre issued by the Chinese Center for Disease Control and Prevention. This study applied seasonal decomposition analysis, spatial autocorrelation analysis and space-time scan analysis. Plots and maps were constructed to visualize the spatio-temporal distribution of IIDs. Results Regarding temporal analysis, the incidence of HFMD and Hepatitis E showed a distinct increasing trend, while the incidence of TAP, dysentery, and Hepatitis A presented decreasing trends over the last decade. The incidence of OIID remained steady. Summer is the season with the greatest number of cases of different IIDs. Regarding the spatial distribution, approximately all p values for the global Moran’s I from 2006 to 2016 were less than 0.05, indicating that the incidences of the epidemics were unevenly distributed throughout the country. The high-risk areas for HFMD and OIDD were located in the Beijing-Tianjin-Tangshan (BTT) region and south China. The high-risk areas for TAP were located in some parts of southwest China. A higher incidence rates for dysentery and Hepatitis A were observed in the BTT region and some west provincial units. The high-risk areas for Hepatitis E were the BTT region and the Yangtze River Delta area. Conclusions Based on our temporal and spatial analysis of IIDs, we identified the high-risk periods and clusters of regions for the diseases. HFMD and OIDD exhibited high incidence rates, which reflected the negligence of Class C diseases by the government. At the same time, the incidence rate of Hepatitis E gradually surpassed Hepatitis A. The authorities should pay more attention to Class C diseases and Hepatitis E. Regardless of the various distribution patterns of IIDs, disease-specific, location-specific, and disease-combined interventions should be established. Electronic supplementary material The online version of this article (10.1186/s12879-019-4400-x) contains supplementary material, which is available to authorized users.


Background
Intestinal infectious diseases (IIDs), also known as infectious enteric diseases, are transmitted via the faecal-oral route through contaminated food, water, or fomites. The main symptoms of intestinal infectious diseases include nausea, vomiting, fever, headache, limb pain, abdominal pain, loss of appetite, systemic poisoning, diarrhoea, and other gastrointestinal symptoms, which may lead to death if not treated promptly. IIDs have posed public health threats and resulted in severe social and economic burdens due to the high incidence and morbidity rates, particularly in young children [1][2][3]. Several large, severe global disease outbreaks have been associated with IIDs, such as the outbreaks of HFMD in east and southeast Asia in the early twenty-first century [4], the constantly high burden of cholera that persists in many African countries, and the cholera outbreaks with active cholera transmission in many sub-Saharan African countries [5]. According to the sustainable development goals (SDG), we should combat hepatitis, water-borne diseases and other communicable diseases. IIDs represent a significant obstacle to achieving SDG [6].
The Chinese government enacted the Law of the People's Republic of China on the Prevention and Treatment of Infectious Diseases and regularly reports cases of notifiable diseases to effectively monitor and control infectious diseases. All reported infectious diseases are divided into Classes A, B and C in terms of severity, which is shown in Additional file 1. In China, IIDs are one of the main types of infectious diseases, presenting the characters of a high morbidity rate and low mortality rate [7]. Eight IIDs are listed in the law, including cholera, poliomyelitis, dysentery, typhoid and paratyphoid (TAP), viral Hepatitis A, viral Hepatitis E, hand-foot-mouth disease (HFMD) and other infectious intestinal diseases (OIIDs). Among these diseases, cholera and poliomyelitis have been almost completely eradicated. In contrast, according to the data reported by the Chinese CDC in 2017, viral Hepatitis A, viral Hepatitis E, and dysentery are among the top five most severe diseases in Class B. At the same time, HFMD and OIDDs were the most severe diseases in class C. The status of intestinal infectious diseases requires further attention.
Previous studies have investigated the epidemiology of different intestinal infectious diseases. First, temporal analysis of different intestinal infectious diseases was conducted. The initial efforts in conducting a temporal analysis investigated the temporal variations in the incidence rates of different diseases in different age groups and areas. For example, Tian et al. analysed the temporal characteristics of HFMD and the relationship between meteorological factors and the incidence of HFMD in Beijing, China. May to July is the period with peak HFMD incidence each year in Beijing [8]. Xiao (1,1)] to predict the trend in the incidence of typhoid using data collected from Wuhan City in China from 2004 to 2015 [10]. Liu et al. forecasted the incidence of bacillary dysentery diseases by applying the seasonal trend model based on the moving average method, which forecast the incidence of Hepatitis A in 2015 [11]. Ming et al. investigated the seasonal signals and long-term trends in a series of 10 IGS sites in China [12]. Xing et al. conducted a study examining the epidemiological characteristics in China from 2008 to 2012, emphasizing seasonal patterns among people at different ages [13]. Temporal analyses of infectious diseases have allowed researchers to develop a wide range of research methods, namely, time series analysis and seasonal analysis. However, temporal analysis failed to reflect the overall circumstances of infectious intestinal diseases.
On the other hand, the academic world gradually began to realize the importance of performing spatial analysis of infectious diseases. Zhang et al. conducted a space-time scan analysis of HFMD in Liaocheng City in China from 2007 to 2011 at the town level [14]. The distribution of the identified cluster was described in the article. Zheng et al. mapped the incidence rate and coefficient of determinants of HFMD to present and identify the most severely affected areas and the most influential determinants [15]. As shown in the study by Wang et al., the typhoid prevalence is spatially clustered and exhibits a gradually decreasing trend [16]. According to Ma et al., bacillary dysentery is not equally distributed across Sichuan Province in China [17]. Nie et al. used a spatial correlation analysis to explore the associations between selected factors and bacillary dysentery in Guangxi Province in China [18]. The spatial analysis visually displayed the discrepancies among different regions, which would be able to present additional results if combined with the temporal analysis.
In conclusion, temporal and spatial analyses are useful. Previous studies have focused on the epidemiological characteristics of different IIDs. However, a comprehensive study analysing the spatial and temporal distributions of all reported IIDs in China is lacking. Second, an overall introduction to IIDs in China to researchers in other countries is unavailable. Therefore, this study will collect data on the basic IIDs and populations, use seasonal decomposition analyses to explore the temporal epidemiology, and perform spatial autocorrelation analysis and space-time scan analysis to explore the spatial epidemiology.

Study setting and data resources
Among the eight IIDs, cholera and poliomyelitis have been almost completely eradicated. The number of deaths related to cholera and poliomyelitis since 2004 were 2180 and 0, respectively, indicating that the two diseases were less emergent. At the same time, according to the Chinese classification of viral hepatitis, the Hepatitis A and E should be analysed separately [19]. Overall, this study analyses the spatiotemporal distribution of six intestinal infectious diseases, namely, dysentery, typhoid and paratyphoid (TAP), viral Hepatitis A, viral Hepatitis E, hand-foot-mouth disease (HFMD) and other infectious intestinal diseases (OIID). To better demonstrate the trends of incidence of IIDs, we analysed these diseases from 2006 to 2016, which represents two equal periods: 2006-2011 and 2011-2016.
The data were collected from public health science data centre issued by Chinese Center for Diseases Control and Prevention (China CDC) [20]. The sorted data are presented in Additional file 2 and Additional file 3. Additional file 2 displays the number of cases of IIDs. Additional file 3 displays the number of cases of IIDs by month and the morbidity of IIDs by month. Intestinal infectious diseases are strictly monitored by the Chinese CDC. The centre aims to integrate the scattered data distributed by governments, universities, research institutes and scientists.

Temporal analysis method Seasonal decomposition analysis
The seasonal decomposition analysis was based on the seasonal trend decomposition using Loess (STL), which incorporates three components: trend, seasonal, and remainder or residual [21]. Advantages of the method include its simplicity and speed of computation, the robustness of results, and flexibility in the period of the seasonal component [22].
In the present study, IIDs were analysed by performing a seasonal decomposition of the time series. This assay employed Holt-Winters filtering and Ljung-Box test to define the structure (additive or multiplicative) and seasonality (stationary or non-stationary). Using an additive model, the IID results were compiled by summing three components: where Z t represents the monthly incidence rates of the diseases, M t represents the trend, S t symbolizes the seasonal variation, and R t denotes the remainder.
The result of seasonal decomposition analysis is displayed in a figure with the time from 2006 to 2016 on the horizontal axis and the incidence rate on the vertical axis.

Spatial analysis method Spatial autocorrelation analysis
The concept of spatial autocorrelation was proposed by Tobler in the first geography law [23]: "Everything is related to everything else, but nearest things are more related than distant things." Moran's I was the tool used to measure spatial autocorrelation and consists of two types: global Moran's I and local Moran's I. Global Moran's I measures the general spatial autocorrelation and the spatial distribution of research object. Local Moran's I reflects the local spatial autocorrelation and the cluster regions. In the present study, spatial autocorrelation was applied to analyse the IIDs. Global Moran's I shows the overall cluster level and distribution of IIDs; local Moran's I reveals the specific cluster regions and cluster categories and the hotspots of IIDs [24].
Global Moran's I is an index ranging from − 1 to 1. When the index was distributed around − 1, the overall spatial distribution displayed the dissimilarity, indicating that high cluster regions bordered on low cluster regions. When the index was approximately 0, a distinct spatial cluster was not observed in the studied regions. When the index was close to 1, the overall spatial distribution revealed the similarity, indicating that the same cluster category was bounded on another cluster category. The following equation was used to calculate the global autocorrelation: where n denotes the number of observed values, x i represents the incidence rate in province I, x j represents the incidence rate in province j, x indicates the mean value, and w ij represents a spatial weight matrix of systematic binomial distribution, which represents neighbouring relations between geographical units with n representing the total number of those units . In the present study, the data were based on regions. The value for w ij is 1 if province i and province j are adjacent. Otherwise, the value is 0. Local Moran's I avoids the weaknesses of global spatial autocorrelation by analysing the spatial autocorrelation of certain characters in local regions. The range and explanation for the local Moran's I was same as the global index. The cluster results obtained from local Moran's I were classified into four types: high-high cluster (HH, which indicated that the high cluster areas were surrounded by other high cluster areas), high-low cluster (HL, which indicated that the high cluster areas were surrounded by low cluster areas), low-high cluster (LH), and low-low (LL) cluster. The clusters were visualized using LISA cluster maps. The following equation was used to calculate local Moran's I: where y i represents the incidence rate in province I, y j represents the incidence rate in province j, y indicates the mean value. [25] In the present study, we analysed a long period to investigate the incidence rates of different IIDs. The years 2006, 2011, 2016 were selected to show the long-term changes.

Space-time scan analysis
Space-time scan statistics were introduced by Kulldorff [26]. The space-time scan statistic based on the discrete Poisson model was applied to detect the space-time cluster of IID cases in high-risk or low-risk regions in China [27]. The shape of space-time scanning windows is cylindrical with the geographic units and the height associated with time [28]. The null hypothesis presumed that the window area and outside areas have the same relative risk (RR) of incidence. The difference in the incidence inside and outside the windows was evaluated by calculating the log likelihood ratio (LLR): where C denotes the total number of cases, c represents the number of observed cases inside the window, and n represents the number of expected cases inside the window [19]. The space-time analysis was applied to identify the clusters according to the LLR value, including the most likely cluster, secondary cluster 1, secondary cluster 2, secondary cluster 3, and secondary cluster 4, as well as the cluster time. Statistical significance was evaluated using a Monte Carlo simulation with 99,999 replicates and a significance level of 0.05. For the other parameters, the maximum radius of the circular base was set to 50% of the total population at risk and the maximum height of the cylinder was set to 50% of the total study period.
The method is sensitive to user-controlled parameter choices. A reliability analysis was conducted to determine the sensitivity and consistency of the results. Multiple scans with different maximum sizes ranging from 50 to 1% of the population were conducted. Reliability was measured using the following equation: where R i denotes the reliability of different provincial units, S indicates the number of scans, and C i represents the number of high-risk areas in these scans. The range of reliability is from 0 to 1 points, where 1 indicates that all scans report a place as high risk and 0 indicates no scan reports [29].
The reliability results were visualized by constructing a map (Additional file 4 and Additional file 5).

Software tools
The seasonal decomposition analysis were visualized using Microsoft Excel (version 2013, Microsoft Corp, Redmond, WA, USA). The seasonal decomposition analysis was performed using IBM SPSS Statistics (version 22, IBM, Armonk, NY, USA). GeoDa (version 1.8.61, GitHub, San Francisco, CA, USA) was employed to attain the global Moran's I and local Moran's I hierarchical maps, and LISA cluster maps, and space-time scan maps were obtained using ArcGIS (version 10.0, ESRI Inc., Redlands, CA, USA). The space-time scan was analysed using SatScan (version 9.5, Kulldorff and Information Management Services, Inc., Boston, MA, USA).

The prevalence of IIDs
We listed all IIDs reported in each provincial unit in China from 2006 to 2016. Table 1 presents a descriptive analysis of 6 selected IIDs, including the average, maximum and minimum incidence from 2006 to 2016. All provincial units were divided into east, central and west China.
According to the descriptive summary, HFMD was the most severe disease, with an average incidence of 105.46. OIDD ranked second with an average incidence of 69.52 from 2006 to 2016. The third most common disease was dysentery, with an average incidence of 24.75. Regarding the region, east China had the highest incidence rates for HFMD, OIDD and Hepatitis E. The west area was the area with the greatest number of TAP, dysentery and Hepatitis A cases.

Seasonal decomposition analysis
The seasonal decomposition plots contain four parts, the raw data, remainder, seasonal variation, and trend. The raw data represent the original incidence rate of certain diseases. The remainder represents the irregularity of data. Seasonal variation exists when the rangeability is greater than 0.2. The trend symbolizes the long-term variation in the data. The seasonality and variation in the trends in monthly data were distinguished from the remainder or residual using a decomposition analysis. Figure 1 shows the results of the decomposition analysis for all IIDs. Regarding the seasonal variation, the incidence rates of HFMD and dysentery were high in summer. Higher incidence rates for OIDD and Hepatitis A were observed in summer and autumn. Hepatitis E showed a high rate in spring. A distinct seasonal variation in the incidence of TAP was not observed. Regarding the trend, the HFMD, OIDD and Hepatitis E displayed increasing trends, and the other diseases showed decreasing trends. Based on the remainder, a 12-month stochastic variance was displayed.

Spatial autocorrelation analysis
The spatial autocorrelation analysis was divided into global spatial autocorrelation and local spatial autocorrelation. The former was considered to represent geographical  -difference in whole areas, while the latter was regarded as the difference at the regional cluster level.
Global spatial autocorrelation Table 2 shows the results from the global spatial autocorrelation analysis and significance test. In terms of the significance, all Moran's I values for dysentery and Hepatitis E reached the significance threshold, while of the values for OIDD, TAP, and Hepatitis A achieved results, with one insignificant index each. HFMD had five significant indexes. In the global spatial autocorrelation analysis, Moran's I for HFMD ranged from 0.0039 to 0.3812 throughout the 11 years without an obvious increasing or decreasing trend, suggesting that the disease Local spatial autocorrelation analysis Beijing and Shanghai were the areas with the highest incidence rates, while the areas with the lowest rates included Xizang, Qinghai, Yunnan, and Guangxi, among others. Figure 3 displays the spatial clusters of all IIDs, reflecting the regional variation from 2006 to 2016. The hot spot for HFMD is located in Guangdong, while cold spots were detected in some areas of the central and west provinces, such as Sichuan, Chongqing, Hubei, Guizhou, and Jiangxi. In 2016, the hot spots shifted to adjacent provinces, Guizhou and Jiangxi; new cold spots shifted to areas in the north province, such as Gansu, Jilin, Xinjiang, and Inner Mongolia.
For OIDD, the HH cluster feature was observed in BTT areas, while Heilongjiang and Jilin in northwest China showed the LL cluster feature in 2006. Throughout the ensuing 10 years, Jilin and Hebei were no longer present in the original hot spots and cold spots. Jiangxi showed the HH cluster character as well.
For TAP, HH cluster character was witnessed in Yunnan, Jiangxi, and Guizhou throughout the 10-year period, while Xizang, Sichuan, Neimenggu and Xinjiang showed the character of a cold spot.
In terms of dysentery, Inner Mongolia, Beijing, and Tianjin were located in HH cluster areas, while the LH cluster was located in Hebei. Guangxi and Guangdong contained the LL cluster. In 2011 and 2016, the cluster characters presented the same trends. Beijing, Tianjin, and Hebei were the HH cluster areas, while the LL cluster was located in Guangdong. Hebei experienced a change from a cold spot to a hot spot.
For Hepatitis A, the HH cluster character was present in west China, including Xinjiang, Gansu, Qinghai, Xizang, Sichuan, and Chongqing, throughout the 10-year period, while the LL cluster character was located in the BTT area, Jiangsu and Guangdong. Xizang was a hot spot in 2006 and 2016, but was a cold spot in 2011.
The hot spots for Hepatitis E were mainly concentrated in the BTT area and Yangtze River Delta area, while cold spots were located in areas of west China, Jiangxi and Hubei.

Space-time scan analysis
Space-time scan analysis was used to explore the cluster likelihood, the level of which was classified as the most  likely cluster, secondary cluster, 2nd secondary cluster, 3rd secondary cluster and 4th secondary cluster. This study analysed IIDs in China from 2006 to 2016. Fig. 4 and Table 3

Discussion
Studies of the epidemiology of different intestinal infectious diseases, particularly the temporal and spatial distributions, have played an important role in preventing infections prevention. However, previous studies have neglected to analyse the correlation between the temporal and spatial analyses. A systematic spatio-temporal analysis of IIDs has not been conducted in China. This study supplements data from other related research in the area of infectious intestinal diseases by performing a temporal analysis and spatial analysis and determining the correlation between them. The evidence provided insights into potential solutions to diminish the diseases.
On one hand, we would like to compare the temporal analyses of the six intestinal infectious diseases. According to the incidence rates recorded from 2006 to 2016, the temporal trends differed. Regarding the absolute incidence of cases, the incidence of HFMD was higher than the other IIDs, and it gradually became a wide-spread disease, which is consistent with the results from the study by Zhang [30]. Then, dysentery and OIDD were less severe diseases. Hepatitis A, Hepatitis E and TAP were the least severe diseases, according to the incidence rates. Regarding the trend, the incidence rates of HFMD and Hepatitis E showed a distinct increasing trend, consistent with the results from the study by Zhu. As the epidemic of Hepatitis A was controlled, the percentage of Hepatitis E cases among patients with viral hepatitis and among patients with IIDs has increased. The mortality rate of Hepatitis E has increased among infectious diseases [31]. The trend in the incidence of OIDD was almost unchangeable. Dysentery and TAP displayed obvious decreasing trends. The analysis of dysentery filled the research gap in the study by Xie et al., which showed a decreasing trend in the incidence of dysentery from 2005 to 2010 [32]. The results for TAP were similar to the findings reported by Liu [33], which showed a decreasing trend. The improvement in sanitation facilities and the reduction in food and water pollution likely contributed to the decreasing trend in the incidence rates of these diseases. Hepatitis A exhibited a slight increasing trend in the first 2 years, followed by a decreasing trend. This result was similar to the findings reported by Zhu [19]. In conclusion, class B diseases were prevented with high efficiency. Class C diseases experienced a higher incidence rate and gradually increasing trend. Regarding the seasonal changes, the incidence of HFMD and dysentery peaked in the summer, Hepatitis E exhibited a high-incidence season in spring, OIDD peaked in summer and a smaller peak in autumn, the peak incidence of Hepatitis A occurred in summer and spring, and a distinct peak for TAP was not observed. Previous studies have revealed an association between the IIDs and seasons [16,[34][35][36][37]. The occurrence of intestinal infectious diseases is related to climatic factors, such as the sunshine duration, temperature and humidity, as well as the quality of food and drinking water [38]. Due to the high temperature and humidity in summer, which are conducive to bacterial reproduction, food and water are easily contaminated. At the same time, the human immune system is relatively weak due to higher bodily exertion in summer. In conclusion, summer is the season with the highest incidence rates for IIDs and should receive closer attention.
On the other hand, the high-risk areas for different IIDs were mainly located in the Beijing-Tianjin-Tangshan (BTT) region, Yangtze River Delta, south and west China. The former two sites are developed areas with extensive urbanization, which attract larger mobile populations characterized by low immune systems, poor living environments and living conditions, and poor health and knowledge of epidemic prevention measures. The hot spots for HFMD, OIDD, dysentery and Hepatitis E are located in the BTT region and Yangtze River Delta [39]. South China is located closer to the equator with a subtropical monsoon and tropical monsoon climate, which are characterized by high humidity, temperature, rainfall, and wind speed. IIDs are strongly correlated with the climatic character of south China [40], which is a high-risk area for HFMD, OIDD, and TAP. The high-risk areas for TAP were located in southwest China (Yunnan, Guizhou, and Guangxi), which are also the most likely cluster areas and HH cluster areas. The main reasons are that southwest China borders Southeast Asia (Vietnam, Laos, and Myanmar), which has a high-risk population due to low sanitation. Moreover, the population of southwest China has a medical history of TAP and very poor climatic, geographical (Karst landform) and sanitation conditions.