Exploratory study of factors associated with human brucellosis in mainland China based on time-series-cross-section data from 2005 to 2016

Objective Many studies focused on reasons behind the increasing incidence and the spread of human brucellosis in mainland China, yet most of them lacked comprehensive consideration with quantitative evidence. Hence, this study aimed to further investigate the epidemic mechanism and associated factors of human brucellosis in China so as to provide suggestions on more effective countermeasures. Methods Data of human brucellosis incidence and some associated factors in economy, animal husbandry, transportation and health were collected at provincial level from 2005-2016. Time series plot and cluster analysis were first used to visualize incidence levels and categorize provinces based on their incidence level and epidemic trend of human brucellosis. Furthermore, according to the characteristics of data, the dynamic panel data model in combination with supervised principal component analysis was proposed to explore the effects of associated factors on human brucellosis. Results ① The incidence rate of human brucellosis has increased threefold (from 1.41 in 2005 to 4.22 in 2016) in mainland China. Incidence rates in the north have always been higher than those in the south, but the latter also experienced an upward trend especially in the recent five years. ② The 31 provinces of mainland China were categorized into three clusters, and each cluster had its own characteristics of incidence level and epidemic trend. ③ Public health expenditure and rural medical expenditure proportion were potential protective factors of human brucellosis, with attribute risks of −0.74 and −1.04 respectively. Other factors (such as amount of sheep, total length of highways, etc.) exhibited relatively trivial effects. Conclusions The epidemic status of human brucellosis has changed in both spatial and temporal dimensions in recent years. Apart from those traditional control measures, more attention should be paid to the improvement of medical healthcare especially in rural areas in order to strengthen the control effect.


Introduction
Brucellosis is a highly contagious zoonotic disease mainly caused by unpasteurized 51 milk or undercooked meat products from infected animals. Direct contacts with ill 52 animals can also cause brucellosis infection. On a global scale, brucellosis was and 53 still is an important zoonosis across the world [1][2][3]. In China [4], it has been listed as forth. In terms of the expansion of involved areas, some studies [11] assumed that 75 people's increasing opportunities to contact infected animals directly or indirectly in 76 recent years might be the reason. In the study of Jiang et al [12], it was found that the 77 Northern and Southern brucella strains shared the same MLVA-16 genotype, which 78 somehow verified another popular speculation that the epidemic in southern area was 79 partly caused by the import of infected animals from other areas. Therefore, it could 80 be summarized that the development of husbandry and trading was the most 81 commonly accepted explanation for human brucellosis epidemics in recent years. 82 Although current studies were instructive and illuminating for the prevention and  This is a preliminary study targeted at the temporal-spatial characteristics of human 107 brucellosis prevalence and the joint influence of different associated factors in 108 mainland China in the last decade (2005 to 2016). We aimed to reveal the spatial and 109 temporal characteristics of human brucellosis prevalence and explore the effects of its 110 associated factors in a comprehensive and quantitative way, which would provide 111 more valid evidence for making sophisticated and specific strategies for the 112 prevention and control of human brucellosis in China and the rest of the world.

Number of cattle cattle_num
The number of cattle kept by all units and urban residents.
Mutton production (Ten thousand tons)

mutton_prod
The weight of mutton that was butchered in that year in the whole society.
Beef production (Ten thousand tons)

beef_prod
The weight of beef that was butchered in that year in the whole society.
, , -1 , , where n represented the province, t the year (n and t were both sequentially 148 numbered), y n , t the human brucellosis incidence rate of the n-th province in the t-th 149 year, and y n , t-1 referred to that in the past year. In addition, x n , t was the value of the year t and μ n,t the random effect of the n-th province in the t-th year. Specifically, the 152 regression coefficient γ measured the relative risk of factor x on the human brucellosis 153 incidence, which was the parameter of interest in this study.
(2), referred to the value of the r principal component in  and Heilongjiang belonged to Cluster 2 and the remaining provinces were included in 212 Cluster 3 (Fig 2). Through reviews of previous studies [6], a similar partition was 213 observed, which helped to testify the rationality of our clustering.    According to Table 2, brucellosis t-1 , health 1

317
(2) The interpretation of results

318
The estimated results in Table 2  Human brucellosis is one of the few infectious diseases whose incidence rates still 336 keep increasing nowadays in mainland China [20]. Though previous studies have tried 337 to explore its epidemic patterns and associated factors, this study contributed to the 338 prevention of human brucellosis in a more novel and more explicit way: it not only 339 considered both temporal and spatial patterns of human brucellosis across mainland 340 China, but also comprehensively revealed the multiple relations between human 341 brucellosis and its potential associated factors. Therefore, the results of this study 342 could supply the following new knowledge and implications for the prevention and 343 control work in this field.

344
Firstly, apart from the traditional recognition that human brucellosis incidence rates 345 in northern China were much higher than those in southern area, this study further 346 analysed and compared the temporal and spatial epidemic characteristics of various 347 areas. Specifically, according to both the incidence level and epidemic trend, all 348 provinces of mainland China were classified into three clusters, i.e., Cluster 1 with the 349 highest incidence rate all year round, Cluster 2 with rather high incidence rates but 350 lower than that of Cluster 1 and lastly, Cluster 3 whose incidence rates were at a 351 comparatively low level.

372
(2) The exploratory analysis in this paper contributed to clarify the potential effects 373 of associated factors on human brucellosis in a more comprehensive way. It helped 21 374 update and deepen the understanding of epidemic mechanism as well as locate the key 375 areas of controlling human brucellosis more precisely. Here are some brief 376 discussions on some factors involved.

377
① Historical impact According to the analysis, there existed a statistically 378 significant influence of the human brucellosis incidence rate in the previous year (lag, 379 brucellosis 1) on the current incidence rate, which might be explained by the latency 380 and invasiveness of brucella [22].  human brucellosis [19], but no supporting result was found in this study. This  can also affect their medical expenditure [26], current priority could be given to 427 increase the health care subsidy of residents in these areas in order to achieve the goal 428 of improving the medical expenditure proportion to control human brucellosis.