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While the End Tuberculosis (TB) Strategy has been implemented worldwide, the cause of the TB epidemic is multifactorial and not fully understood.
This study aims to investigate the risk factors of TB and incorporate these factors to forecast the incidence of TB infection across different age groups in Sichuan, China.
Correlation and linear regression analyses were conducted to assess the relationships between TB cases and ecological factors, including environmental, economic, and social factors, in Sichuan Province from 2006 to 2017. The transfer function-noise model was used to forecast trends, considering both time and multifactor effects.
From 2006 to 2017, Sichuan Province had a reported cumulative incidence rate of 1321.08 cases per 100,000 individuals in male patients and 583.04 cases per 100,000 individuals in female patients. There were significant sex differences in the distribution of cases among age groups (trend
The End TB Strategy in Sichuan should consider environmental, educational, medical, social, personal, and other conditions, and further substantial efforts are needed especially for male patients aged 0-24 years, female patients aged 0-14 years, and female patients older than 64 years.
Tuberculosis (TB) has been the leading cause of the global disease burden. Approximately 25% of the population worldwide are infected with
Most people (approximately 90%) develop the disease in adulthood, with men being more susceptible than women [
Furthermore, elucidating the trend of TB incidence with identified TB factors helps to assess the effectiveness of containing measurements that may aid policy maker decisions and public health practice. Therefore, our research aimed to identify these potential risk factors for TB in Southwest China using multiple regression and to predict the trend of TB incidence using a transfer function-noise (TFN) model [
We obtained data from China’s Geographic Information Center on Sichuan Province in 2009. The map of county-level administrative divisions included prefectures, counties, cities, and districts. In total, Sichuan Province has 21 cities or prefectures and 181 districts, counties, and cities, with a total of 1.4 million inhabitants.
Data were extracted from the 2006-2017 Statistical Yearbook of Sichuan Provincial Bureau of Statistics. All TB cases were grouped by sex and age. The age groups were as follows: children (aged 0-14 years), youths (aged 15-24 years), adults (aged 25-64 years), and older individuals (aged >64 years).
From the age-stratified population of the “Epidemic Information Network Direct Reporting System” from 2006 to 2017, we enrolled the subpopulation in Sichuan Province. All population data were for permanent residents, specific to county administrative divisions, and included population data by age and sex. Information on TB and HIV/AIDS was obtained from the TB Information Management System of the Chinese Disease Prevention and Control Information System and the Statistical Yearbook published by the Sichuan Provincial Bureau of Statistics. The incidence of TB was analyzed in different age groups.
The ecological analysis used data such as case reports, registered case data, and ecological information to explore the risk factors related to the prevalence of TB. Data on TB cases and the incidence rate of TB were collected per administrative division, sex, and age group. The variables for each model were chosen by auto-modeling.
The 128 ecological factors were all obtained from 12 years (2006-2017) of data. The transfer function model was fitted by the autoregressive integrated moving average (ARIMA) model by time series [
The expert modeler selected the optimal model from multiple fitted models, when the
Univariate analyses (Pearson correlation analysis) and multivariate analyses (regression analysis) were used to analyze the protective factors and risk factors for TB in Sichuan Province according to sex and age group (trend
The autocorrelation test of the residuals uses the Durbin-Watson (DW) test, with the following test statistic:
DW values occur in a range from 0 to 4 as follows: a DW value of 0 indicates complete positive autocorrelation, values between 0 and 1.5 indicate positive autocorrelation, values between 1.5 and 2.5 indicate no autocorrelation, values between 2.5 and 4 indicate negative autocorrelation, and a value of 4 indicates complete negative autocorrelation. In addition, the autocorrelation function and partial autocorrelation function show whether the data sequence reached a stable state. At the same time, the
Considering the effect of time and multiple factors, we used Panel regression, Poisson regression, and Lasso regression for the analysis; however, the data were not suitable for these regressions; for example, our study has a large number of factors to explore the relationship, so the Panel regression could not include all 128 factors and ID and time to fit. The pilot analyses revealed that the random effect model was better than the pool model and fixed effect model. For these reasons, we did not use other regression methods.
We included all reported cases of TB during 2006-2017; these data possibly contain information and selection bias. The TFN model is a multivariate time series analysis method that can be seen as a combination of the ARIMA model and a multiple regression model. We used SPSS 23.0 (IBM Corp) and ArcGis Map 10.6 (ESRI Inc) to create spatiotemporal scans and to conduct the analyses that predicted TB trends by sex and age. The three main steps were as follows: model identification, parameter estimation, and model testing. For the calculation of the
Data collection of TB was required by the Law of the People’s Republic of China on Prevention and Treatment of Infectious Diseases. The ethics approval in this study was granted by the Ethics Committee of Sichuan Center for Disease Control and Prevention (SCCDCIRB2022-001).
From 2006 to 2017, Sichuan Province reported 548,584 cases of pulmonary TB in male patients, with a reported cumulative incidence rate of 1321.08 cases per 100,000 individuals (average 110.09 cases/100,000 individuals), and 235,149 cases of pulmonary TB in female patients, with a reported cumulative incidence rate of 583.04 cases per 100,000 individuals (average 48.59 cases/100,000 individuals). Thus, there were approximately 2.33 times more cases in male patients than in female patients. The reported cumulative incidence of TB in Sichuan Province from 2006 to 2017 was 961.71 cases per 100,000 individuals (average 80.14 cases/100,000 individuals). These TB cases mainly occurred in individuals aged 15-64 years, which accounted for 82.02% (n=642,808) of the total cases.
As shown in
TB cases in Sichuan Province of China during 2006-2017. TB: tuberculosis.
TB incidence rate in Sichuan Province of China during 2006-2017. TB: tuberculosis.
The incidence of male and female TB in Sichuan Province of China during 2006-2017(1/100,000). TB: tuberculosis.
Across the four age groups, there were significant associations between TB incidence and the environmental and socioeconomic effects in five aspects, including other diseases as well as health resources; economic and social factors; pollutant, forestry, and meteorology variables; population structure, marriage, and habit variables; and educational investment and education level (all
As shown in
In addition, in those aged 0-14 years, the factors affecting the risk of TB were as follows: the number of families with the urban minimum living standard guarantee, average wind speed, number of patients with invasive pulmonary TB discharged, number of people with the rural minimum living standard guarantee, total health expenditure as a percentage of regional gross domestic product (GDP), and being a single man. These factors reduced the risk of TB. The incidence of TB in those aged 15-24 years, sex ratio, number of forest fires, and regular exercise rate of adults increased the risk of TB in children (
In those aged 15-24 years, the incidence of TB in those aged 0-14 years, total illiteracy rate, number of infectious disease hospitals, enrollment number (secondary school and above), exposure to secondhand smoke among nonsmokers (%), fraction of married men (%), number of forest fires, and number of junior high school boys (%) increased the risk of TB (
In those aged 25-64 years, the number of hospitals, number of health workers in infectious disease hospitals, TB rate in those aged ≥65 years, daylight duration, and male life expectancy decreased the risk of TB (
Finally, in the group of people older than 64 years, the risk of TB was increased by the following factors: the rate of TB cases in female patients, cumulative precipitation over 24 hours (8 PM to 8 PM), rate of TB in those aged 25-64 years, total health expenditure as a percentage of regional GDP, number of families with the rural minimum living standard guarantee, rate of TB in patients aged 15-24 years, and civil medical assistance. The risk of TB decreased with the amount of daily morning and evening exercise and the number of people with the urban minimum living standard guarantee and in women who were married (
Multivariate analysis of tuberculosis (TB) incidence by age group (individuals aged 0-14, 15-24, 25-64, or ≥65 years) in Sichuan Province.
Model and variables | B (95% CI) | |||
|
||||
|
(constant) | –8.259 (–8.269 to –8.249) | –10626.577 (11) | <.001 |
|
TB rate in those aged 15-24 years | 1.01E-01 (0.101 to 0.101) | 14772.916 (11) | <.001 |
|
Sex ratio | 8.387 (8.379 to 8.394) | 14578.003 (11) | <.001 |
|
Number of forest fires | 0.001 (0.001 to 0.001) | 3593.154 (11) | <.001 |
|
Number of families with the minimum living standard guarantee in urban areas (households) | –7.438E-07 (0 to 0) | –2011.933 (11) | <.001 |
|
Average wind speed | –0.005 (–0.005 to –0.005) | –1576.859 (11) | <.001 |
|
Number of patients with invasive TB discharged | –1.505E-05 (0 to 0) | –4259.893 (11) | <.001 |
|
Number of people with the minimum living standard guarantee in rural areas (person) | –1.41E-07 (0 to 0) | –1813.338 (11) | <.001 |
|
Regular exercise rate | 1.82 (1.8 to 1.839) | 1199.617 (11) | .001 |
|
Total health expenditure as a percentage of regional GDPa (%) | –0.007 (–0.008 to –0.007) | –377.144 (11) | .002 |
|
Unmarried men (%) | –0.001 (–0.001 to –0.001) | –105.253 (11) | .006 |
|
||||
|
(constant) | –2541.142 (–2542.913 to –2539.371) | –18234.07 (11) | <.001 |
|
TB rate in those aged 0-14 years | 6.227 (6.226 to 6.228) | 82051.414 (11) | <.001 |
|
Total illiteracy rate (%) | 1.789 (1.788 to 1.789) | 27895.184 (11) | <.001 |
|
Average pressure at each measuring station | 0.307 (0.307 to 0.307) | 18170.576 (11) | <.001 |
|
Number of infectious disease hospitals | 0.854 (0.853 to 0.854) | 20744.736 (11) | <.001 |
|
Enrollment number (secondary school and above) | 0.000004396 (0 to 0) | 13489.017 (11) | <.001 |
|
Exposure to secondhand smoke among nonsmokers (%) | 0.094 (0.094 to 0.094) | 11336.041 (11) | <.001 |
|
Male illiteracy rate (%) | –0.617 (–0.618 to –0.615) | –5377.636 (11) | <.001 |
|
Married men (%) | 0.083 (0.083 to 0.083) | 3963.885 (11) | <.001 |
|
Number of forest fires | 0.001 (0.001 to 0.001) | 895.709 (11) | .001 |
|
Junior high school boys (%) | 0.004 (0.004 to 0.005) | 128.503 (11) | .005 |
|
||||
|
(constant) | 10.268 (10.218 to 10.317) | 2642.64 (11) | <.001 |
|
TB rate | 1.123 (1.123 to 1.123) | 99793.924 (11) | <.001 |
|
Number of hospitals | –0.009 (–0.009 to –0.009) | –54131.67 (11) | <.001 |
|
Number of health workers in infectious disease hospitals | –0.006 (–0.006 to –0.006) | –32021.619 (11) | <.001 |
|
TB rate in those aged >64 years | –0.048 (–0.048 to –0.048) | –26994.198 (11) | <.001 |
|
Daylight duration | –0.178 (–0.178 to –0.178) | –14248.119 (11) | <.001 |
|
Life expectancy | 0.421 (0.418 to 0.424) | 1887.559 (11) | <.001 |
|
Diabetes mortality rate (1/100,000) | 0.117 (0.116 to 0.117) | 4809.176 (11) | <.001 |
|
Total expenditure per person in urban residents (¥) | 0.00002666 (0 to 0) | 915.623 (11) | .001 |
|
Number of public health workers per 1000 people | 0.062 (0.06 to 0.065) | 356.061 (11) | .002 |
|
Male life expectancy | –0.032 (–0.034 to –0.029) | –171.099 (11) | .004 |
|
||||
|
(constant) | –28.128 (–28.41 to –27.846) | –1266.037 (11) | .001 |
|
TB rate in women | 2.98E+00 (2.979 to 2.98) | 70646.596 (11) | <.001 |
|
Amount of daily morning and evening exercise | –5.24E-05 (0 to 0) | –29473.402 (11) | <.001 |
|
Cumulative precipitation in 24 hours (8 PM to 8 PM) | 0.985 (0.985 to 0.985) | 44529.735 (11) | <.001 |
|
TB rate in those aged 25-64 years | 1.391 (1.39 to 1.392) | 15700.111 (11) | <.001 |
|
Number of people with the urban minimum living standard guarantee (person) | –0.00001256 (0 to 0) | –3962.971 (11) | <.001 |
|
Total health expenditure as a percentage of regional GDP (%) | 1.51 (1.506 to 1.513) | 5632.666 (11) | <.001 |
|
Number of families with the rural minimum living standard guarantee (households) | 0.000001464 (0 to 0) | 1182.888 (11) | .001 |
|
TB rate in women aged 15-24 years | 0.132 (0.13 to 0.133) | 1161.821 (11) | .001 |
|
Married women (%) | –0.192 (–0.196 to –0.189) | –676.252 (11) | .001 |
|
Civil medical assistance (times used) | 1.04E-09 (0 to 0) | 44.526 (11) | .01 |
aGDP: gross domestic product.
In addition, the TFN model predicted that in 2035, the incidence of TB in male patients aged 0-14, 15-24, 25-64, and ≥65 years per 100,000 individuals would be 4.00, 377.08, 0.00, and –54.00, respectively (
Moreover, the TFN results showed that the incidence of TB among female patients aged 0-14, 15-24, 25-64, and ≥65 years per 100,000 individuals in 2018 was 3.00, unpredictable, 42.00, and 65.00, respectively. However, in 2035, these rates were predicted to increase, and TB incidence among female patients aged 0-14 years was predicted to be higher than among women aged ≥65 years, which might also exhibit an upward trend (
The transfer function-noise model predicts the trend of age-specific incidence rates (male/female: aged 0-14, 15-24, 25-64, and ≥65 years). LCL: lower confidence limit; UCL: upper confidence limit.
The TFN model was used to fit the number and incidence rate of TB cases reported in Sichuan Province during 2006-2017, establish and judge the models, and predict TB incidence in Sichuan Province during 2018-2035. The TFN model was fitted for different groups to determine the TB incidence. The
The TFN models used female and male data separately in the multivariate models, and the total of all cases was 783,735. From 2006 to 2017, Sichuan Province reported 548,585 cases of pulmonary TB in male patients, with a reported incidence rate of 11 cases per 100,000 individuals, and 235,150 cases of pulmonary TB in female patients, with a reported cumulative incidence rate of 4.85 cases per 100,000 individuals. There were 12-year observations per model at the population level. For each model, using stepwise regression methods, 10 well-fitting models were established (a better
Additionally, we adjusted the variables of the data to be standardizing variables, and the result did not change. The findings also show that the data trend is relatively stable after multiple data processing, such as splitting or logarithmic processing. Both the destandardized and standardized results and indicators showed that the models were the same.
The TFN model, number and incidence rate of TB cases, autocorrelation function, and partial autocorrelation function showed that the data sequence reached a stable state, and the effect of white noise was eliminated (
Transfer function-noise model: tuberculosis and incidence rate of ACF and PACF in the whole population. ACF: autocorrelation function; PACF: partial autocorrelation function.
We found that the total illiteracy rate and average pressure at each measuring station (in individuals aged 15-24 years) were risk factors for TB incidence overall. Factors that protected against TB incidence were the number of families with the minimum living standard guarantee in urban areas, average wind speed, number of patients with invasive TB discharged, number of people with the minimum living standard guarantee in rural areas, total health expenditure as a percentage of regional GDP, being a single man (aged 0-14), number of hospitals, number of health workers in infectious disease hospitals (for those aged 25-64 years), amount of daily morning and evening exercises, number of people with the urban minimum living standard guarantee, and being a married woman (aged ≥65 years). The noise transfer-function model predicts that until 2035, the incidence of TB in male patients aged 0-14 and 15-24 years will increase, while in female patients aged 0-14 and ≥65 years, the incidence will increase rapidly.
To our knowledge, this is the most comprehensive ecological correlation and time series trend forecast analyses to investigate the associations of ecological factors with TB epidemic and the secular trend of TB incidence. The ecological correlation analyses demonstrated an overall limited influence of the environmental and socioeconomic effects and prediction on the TB epidemic. Incorporating these environmental and socioeconomic conditions into time series trend forecast models found that the TB incidence rate will continue to increase among male patients aged 0-24 years, female patients aged 0-14 years, and female patients older than 64 years, which should be considered as targeted populations to end the TB epidemic before 2035.
Compared with the worldwide rate and those for high-income countries, TB incidence in rural areas of Sichuan Province was very high, which was supported by a significant increase risk of TB infection among farmers compared with individuals with other occupations and in clustering areas of ethnic minorities in western and northeastern Sichuan [
Additionally, in China, the highest TB burden was found in those aged >70 years, the same as our findings that they had the peak TB incidence [
Of note, the risk factors for TB incidence varied across different ages. For children aged 0-14 years, we found that the proportion reflected by the total health expenditure divided by the regional GDP was associated with a decrease in the incidence of TB, while an inverse association was observed in the population older than 64 years. In-depth investigations need to reveal its role in TB incidence. In addition, a decrease in the number of forest fires led to a decrease in TB incidence. This finding was in line with those of Chen et al [
For female individuals older than 64 years, daily morning and evening exercise, the number of people with the urban minimum living standard guarantee, and marriage (for women) may reduce the incidence of TB. Married women who do not require assistance for extreme poverty may have better nutrition and better health well-being [
Moreover, our findings did not support the protective role of neonatal BCG vaccination in TB incidence across all age groups. Notably, delivering the neonatal BCG vaccination displayed a negative correlation with TB incidence across all age groups, principally in line with previous findings [
This study also has several limitations. First, we did not take into account determinations of genetic predisposition, treatments, treatment efficacy, and other ecological factors due to limited data availability. Second, all data in this study was obtained from Sichuan Province, and the results were subject to the inherent limitations of an ecological study; thus, principal findings may not be generalizable. Prospectively, further long-term cohort studies with large sample sizes as well as randomized controlled experimental studies are needed to determine the causal relationships.
In conclusion, our study identifies a series of environmental and socioeconomic conditions associated with TB incidence through the most comprehensive ecological analyses. Incorporating these TB factors into the TFN model clarifies that male individuals aged 0-24 years, female individuals aged 0-14 years, and female individuals older than 64 years are barriers to the End TB Strategy in Sichuan, and provides new insights into TB prevention and control strategies.
Supplementary material.
autoregressive integrated moving average
Durbin-Watson
gross domestic product
tuberculosis
transfer function-noise
We appreciated Professor Jianwei Zhao and Professor Chuang Chen for help with the study design and writing, and Professor Shujuan Yang, Professor Fangfang Zeng, and Dr Sui Zhu for revising the manuscript.
All data used in the analysis of this manuscript are freely available by contacting the corresponding author. Data are available in a public open access repository, available on reasonable request.
RL and WW designed the study and searched the publications. WW and LX analyzed the data and wrote the Methods section. JW wrote the Results section and checked all the data. ZZ and WZ wrote the Discussion section. All authors were responsible for data synthesis and have read and approved the manuscript.
None declared.