Cost-effectiveness Analysis of the Integrated Control Strategy for Schistosomiasis Japonica in Lake Region of China: a Jiangling Case Study

Background: Under the condition of low epidemic level and limited funding, it is urgent to carry out health economic evaluation on the integrated schistosomiasis control strategy currently implemented in lake region in order to rationally allocate and utilize health resources and maximize benets. The objective of this study is to provide reference for understanding the effectiveness of the integrated control strategy and adjusting prevention and control strategies or measures. Methods: The investment in schistosomiasis control and disability adjusted life years (cid:0) DALYs (cid:0) caused by schistosomiasis were calculated. Incremental cost-effectiveness ratio (ICER) was conducted through calculating the incremental cost of every additional case averted, the incremental cost of every additional DALY averted through implementation of the integrated schistosomiasis control at different control stages in Jiangling County. Results: The total expenditure for schistosomiasis control in Jiangling County from 2009 to 2019 was 607 million Chinese yuan (CNY). The average annual costs for schistosomiasis prevention and control in stages of morbidity control (2009-2012), transmission control (2013-2016), and transmission interruption (2017-2019) were 41.98 million CNY (cid:0) 90.19 million CNY and 26.06 million CNY respectively. The overall disease burden caused by schistosomiasis presented a downward trend. Meanwhile, the disease burden of advanced cases showed an upward trend with the DALY increased from 943.72 to1031.59 person-years. Most disease burden occurred in the age group over 45 years old (especially the elderly over 60 years old). Taking the morbidity control stage as an analysis control, incremental cost-effectiveness analysis (ICEA) showed that the cost increased by 8505.5 CNY and decreased by 2217.6 CNY respectively to avert one additional case in transmission control stage and transmission interruption stage respectively in Jiangling County. Correspondingly, to avert one additional DALY, the cost increased by 73937.6 CNY and decreased by 21508.6 CNY respectively. Conclusions: As the epidemic declines, the integrated prevention and control strategy is more cost-effective. Surveillance and management on elder population should be strengthened to avert higher diseases burden. transmission 41.98 90.19 million CNY and 26.06 the annual per capita investment in control of 123.08 CNY, 270.27 and 77.29 number of average annual resident population(341 100, 333 700, and 337 200 in corresponding periods). the large one-time investment projects, the overall investment in control high [30], but still reasonable from the population-based protection through prevention and control activities. investment in control after Jiangling reached the threshold of transmission interruption. rising prices of and labors gap


Background
The implementation of integrated prevention and control strategy focusing on the source of infection to interrupt the transmission of schistosomiasis had strongly accelerated the process of schistosomiasis control in People's Republic of China (P.R. China) [1]. Morbidity control (the infection rate of humans and livestock in epidemic villages < 5%) and transmission control (the infection rate of humans and livestock in epidemic villages < 1%) were reached nationwide in 2008 and 2015 respectively [2,3]. By the end of 2019, 95.3% of the epidemic counties in P.R. China had reached the threshold of transmission interruption or elimination according to the national standards [4]. The endemicity of schistosomiasis had dropped to the lowest level in history. At present, the key areas for schistosomiasis prevention and control in P.R. China are distributed along the middle and lower reaches of the Yangtze River, as well as the areas of Dongting Lake and Poyang Lake.
Under the condition of low epidemic level and limited funding, it is urgent to carry out health economic evaluation on the integrated schistosomiasis control strategy currently implemented in lake region in order to rationally allocate and utilize health resources and maximize bene ts. [5] The health economics evaluation refers to the evaluation and selection of alternatives by analyzing the economic effects (cost, effect or input, output) of health planning. [6] The methods used to evaluate the economic value of disease interventions mainly include cost-effectiveness analysis (CEA), cost-utility analysis (CUA), costbene t analysis (CBA) and cost-minimization analysis (CMA). CBA of schistosomiasis is relatively di cult because of the complexity of identifying and quantifying the health bene ts of schistosomiasis prevention and control [7,8]. In P.R. China, there have been several studies on the effectiveness of integrated prevention and control strategies for schistosomiasis, but there are few related to cost-effectiveness analyses [9].
As periodic assessment and analysis of resource utilization are conducive to the optimization of diseases prevention and control [10,11]. We evaluated the cost-effectiveness of the integrated control strategy for schistosomiasis taking Jiangling County as an example due to its heavy endemicity of schistosomiasis in history and well archived data and documents, thus to provide reference for understanding the effectiveness of the integrated control strategy and adjusting diseases prevention and control strategies or measures. elimination and control, toilets modi cation and integrated management in Jiangling County from 2009 to 2019 were collected [15][16][17][18]. The costs of case detection and treatment were composed of the annual costs of questionnaire survey, blood examination, stool examination, treatment against schistosomiasis, involving the costs of subsidies, diagnostic reagents and materials, drug, medical assistance for advanced cases of schistosomiasis and so on. The costs of snail control included the costs for conducting snails' survey and mollusciciding, involving the costs of subsidies, materials, drug and so on.
Health education expenses included the costs for conducting training courses for school students, village cadres and doctors, the costs for preparing and distributing the lea ets, setting the warning signs etc. As for integrated interventions, data re ecting the investment related to schistosomiasis control activities were collected from the departments of agriculture, forestry, water conservancy, transportation and land resources.

Data management and statistical analyses
Data collected was entered and descriptive analysis was conducted by Microsoft Excel 2016 software.
The Disability Adjusted Life Years (DALY) was used to quantify the burden of disease, which was calculated with the life quality method based on disability weight (DW) got from cases' life quality assessment. [19] The formula was listed as follows [20]: DALYA=YLD+YLL, YLDprev x =ΣPx*DWx, YLL= N*L Where YLD is the years lived with disability, YLL is the years of life lost, YLDprev x is the years lived with disability based on prevalence (prev is the abbreviation of prevalence, x is the grouping variable), Px is the number of cases in the reference population at a speci c time. DWx is the disability weight of health outcomes. The DW of different age groups of advanced schistosomiasis cases was calculated as the following criteria: 30-44 years old (0.378), 45-59 years old (0.399), over 60 years old (0.510) [21]. The DW of different age groups of chronic cases of schistosomiasis was standardized as the follows: 5-14 years old (0.095), 15-44 years old (0.159), 45-59 years old (0.207), over 60 years old (0.246) [22]. N is the number of deaths in different age groups and genders; L is the life loss value of each age group, that is, the life expectancy value corresponding to the death age point in the standard life table.
For incremental cost-effectiveness analysis (ICEA), the discount formula of the current year was calculated according to formula : Cn' =Cn/(1+r)n [23], where Cn' is the discounted cost ; Cn is the actual cost of each year; r is the discount rate, often using the current bank's regular interest rate; n is the year. Incremental cost-effectiveness ratio (ICER) was used as the effect indicator [24][25][26], that was, the incremental cost for each additional case averted and the incremental cost for each additional DALY averted.  The overall disease burden caused by schistosomiasis presented a downward trend with DALYs decreased from 3178.38 person-years in 2009 to 1497.42 person-years in 2019. Calculating the disease burden by the types of schistosomiasis cases, the DALYs of chronic cases of schistosomiasis presented a downward trend (2234.66 ~ 465.83 person-years), while that of advanced cases showed an upward trend (943.72 ~ 1031.59 person-years) with a small peak in 2017. In addition, the variation trend in total DALYs of schistosomiasis was consistent with that of chronic cases before 2013, but shifted to be consistent with that of advanced cases after 2013. (Fig. 1 (Fig. 2).

ICEA of integrated schistosomiasis control
Taking the morbidity control stage as an analysis control, ICEA based on the number of schistosomiasis cases showed that the costs increased by 8505.5 CNY and decreased by 2217.6 CNY respectively to avert one additional case in transmission control stage and transmission interruption stage respectively in Jiangling County ( Table 3). The integrated control strategy was more cost-effective in transmission interruption stage. Taking the morbidity control stage as an analysis control, ICEA based on the DALY showed that the cost increased by 73937.6 CNY and decreased by 21508.6 CNY respectively to avert one additional DALY in transmission control stage and transmission interruption stage respectively in Jiangling County ( Table 4). The integrated control strategy was more cost-effective in transmission interruption stage.

Discussion
The transmission of schistosomiasis is affected by biological, natural and social factors, thus determining that the control of schistosomiasis is a systematic social project, involving many departments, such as agriculture, forestry, water conservancy, land resources etc. Although the integrated control strategy focusing on the source of infection to block the transmission of schistosomiasis has been implemented in P. R. China more than ten years, it's relatively di cult to carry out a systematic health economic evaluation on the integrated control strategy. The economic evaluation indices of schistosomiasis control measures reported in previous studies were mainly the costs for reducing the infection rate of S. japonicum in residents, livestock, snails, or the costs for reducing the integrated impact index of schistosomiasis. [27][28][29] However, in current situation, the majority of schistosomiasis cases are advanced cases in P.R. China, featured with a long process of pathological changes and neglected impacts on residents' health. Thus previous evaluation indices were no longer applicable. In our study, the CEA of the integrated control strategy for schistosomiasis was conducted through calculating the indices of DALY and ICER, taking Jiangling County as an example, to explore the burden of schistosomiasis on population more scienti cally and comprehensively.
The analysis of schistosomiasis investment in different periods in Jiangling County found that the average annual costs of schistosomiasis prevention and control in stages of morbidity control, transmission control and transmission interruption were 41.98 million CNY, 90.19 million CNY and 26.06 CNY respectively, equivalent to the annual per capita investment in schistosomiasis control of 123.08 CNY, 270.27 CNY and 77.29 CNY respectively, if considering the number of average annual resident population(341 100, 333 700, and 337 200 in corresponding periods). Due to the large one-time investment in environmental improvement projects, the overall investment in schistosomiasis control was relatively high [30], but still reasonable from the perspective of population-based protection through prevention and control activities. The study showed that the investment in schistosomiasis control decreased signi cantly after Jiangling reached the threshold of transmission interruption. The rising prices of materials and labors may further deepen the gap between investment and actual demand of schistosomiasis control.
Because there has been no acute schistosomiasis cases in Jiangling County since 2009, the disease burden only included the DALYs of chronic and advanced schistosomiasis in this study. The DALYs of chronic schistosomiasis was mainly based on YLD caused by schistosomiasis rather than YLL [31]. In addition, we took the mean value (0.177) as the DW of a few cases as their age information missed in this study. Our study found that the overall disease burden caused by schistosomiasis presented a downward trend. To the opposite, the disease burden of advanced cases showed an upward trend, which can be explained by that YLL of advanced cases increased from 377.40 person-years in 2009 to 535.06 person-years in 2019. Also a small peak was presented in 2017 because 137 advanced cases were dead in that year (137 died cases), resulting in a larger YLL. In addition, the current YLD of schistosomiasis in Jiangling County mainly distributed in the age group of 60 years and over, followed by the age group of 45-59 years. The aging trend of cases was obvious, which was consistent with existing researches [32,33]. With the improvement of treatment quality and strengthening of medical assistance for advanced cases in P.R. China, the life expectancy of advanced cases will extend. As aging is an important factor affecting life quality and disease burden, it is necessary to strengthen dynamic monitoring and management of the elder age group through regular follow-up and healthy education. Early detection of advanced cases and timely interventions when the disease progression was found, are required to avert further deterioration leading to more disease burden.
Taking the morbidity control stage as an analysis control, the ICEA of the integrated prevention and control strategy for schistosomiasis in Jiangling County showed that the costs increased by 8505.5 CNY and decreased by 2217.6 CNY respectively to avert one additional case in transmission control stage and transmission interruption stage respectively. Correspondingly, to avert one additional DALY, the costs increased by 73937.6 CNY and decreased by 21508.6 CNY respectively. These results all indicated that the strategy in the transmission interruption stage was the most cost-effective. Although the investment was relatively high in early stage, the disease burden decreased signi cantly due to the implementation of this strategy. As the endemicity of schistosomiasis declines, this strategy is more cost-effective. Therefore, multiple section collaboration and resource integration should be strengthened further and investments in the schistosomiasis integrated prevention and control should be continued to facilitate the elimination of schistosomiasis.
There are some limitations of our study. First, being a retrospective research, a few data are missing because of the large time span. In this paper, the mean substitution was used to deal with the missing value, which may lead to a possible error with the real value, but it's unavoidable. Second, the investment in human resources and xed equipment, are not included in the cost calculation due to its complicity of de nition, which may impact on the ndings. It is suggested to strengthen the recording and archiving of relevant data in the future in order to improve the quality of similar research thus to better guide on-site prevention and control.

Conclusions
Although the investment was relatively high in early stage of schistosomiasis control, the disease burden decreased signi cantly due to the implementation of the integrated prevention and control strategy. As the epidemic declines, this strategy is more cost-effective. Thus, multiple section collaboration and resource integration should be strengthened further and investments in the schistosomiasis integrated prevention and control should be continued to facilitate the elimination of schistosomiasis. In addition, the current disease burden of schistosomiasis mainly distributed in the elder age group. Early detection of advanced cases and timely interventions when the disease progression was found, are required to avert further deterioration leading to more disease burden.