| BackgroundEsophageal cancer occurs in the esophageal epithelium;it is a worldwide common malignant tumor in digestive system.The incidence of esophageal cancer has significant geographical and ethnic differences,there are mainly adenocarcinoma in Western countries,and squamous epithelial cancer accounts for more than 90%in Asian population,especially in the Chinese population.There are many very typical high incidence areas of esophageal cancer in the world.China's high incidence regions of esophageal cancer is particularly prominent by their clustering feature,many typical high incidence regions of esophageal cancer have been found since the 1970s,such as Feicheng County in Shandong Province,Ci County in Hebei Province,Linxian in Henan Province,Yangquan in Shanxi Province and other high-level incidence counties.In these different high-incidence areas,the temporal and spatial distribution of esophageal cancer have their own characteristics;that is,even in a relatively small area(county),the incidence of esophageal cancer also has a clear spatial structure and spatial heterogeneity,meaning the patient are influenced by both personal risk factors(such as diet,smoking,genetic,etc.)and ecological group risk factors(geological topography,hydrology,trace elements,environmental exposure,and even social and geographical factors in local areas,etc.).Therefore,research on the spatial epidemiological characteristics of esophageal cancer and its geographical risk factors on the scale of small spatial area,is important for prevention and reduction of esophageal cancer.Feicheng County in Shandong Province has been a typical high incidence region of esophageal cancer since 1970s.Many years of esophageal cancer morbidity and mortality monitoring data has been accumulated through the establishment of a detection system and cancer screening system.Feicheng County became a representative area of study on the spatial epidemiological characteristics of esophageal cancer and geographical risk factors.Over the years,a number of individual-level case-control studies have been conducted in the high incidence area of esophageal cancer.Although smoking(OR = 2.43),drinking(OR = 1.96)(OR =1.96),the family history of the cancer(OR = 1.47),the hot diet(OR = 5.732),the irregular diet(OR = 1.62),eating and eating(OR = 3.54),low protein intake(OR = 1.43),mildew food intake(OR=14.451)and low intake of vitamin C(OR = 1.75)has been found to be the risk factors associated with the incidence of esophageal cancer,but the attribution risk is low.This indicates that the cause of high incidence of esophageal cancer in addition to the above-mentioned individual exposure factors,there are still some unknown risk factors in local areas.Therefore,it is of great theoretical and practical significance to study the local geographical area of high incidence region of esophageal cancer,and to study the geographical risk factors leading to high incidence areas to further elucidate the causes of high incidence areas and formulate effective regional control measures.Based on the analysis above,this study takes the high incidence area of esophageal cancer in Feicheng County in Shandong Province as an example,and uses the information of the registration and registration system of tumor incidence and death in Feicheng County,then on the small spatial scale(with natural village as spatial geography unit),based on the 12-year cumulated incidence of esophageal cancer and cumulative mortality data,the spatial heterogeneity and spatial structural features of esophageal cancer were investigated by small-scale spatial epidemiology and spatial statistics.Then use GWR model to explore the high risk factors of esophageal cancer,such that laid the foundation for further study on the etiology of esophageal cancer epidemiology and provide the basis for the formulation of regional prevention and control measures.ContentsTaking the high incidence area of esophageal cancer in Feicheng as an example,the spatial structure and spatial heterogeneity of esophageal cancer in small area were elucidated by using spatial epidemiology and spatial statistics on the small area scale(natural village),then explore the geographical risk factors of esophageal cancer.The details are as the followings:1.Explore the long-term changes of incidence,death and disease burden of esophageal cancer(2001?2012),and study the effect of time factors on their long-term changes,hence provide evidence for further spatial epidemiological studies.2.The global Moran spatial autocorrelation method was used to test the existence of spatial structure(aggregation)in the pathogenesis and death of esophageal cancer,and to provide the basis for further spatial hotspot analysis.3.The spatial interpolation map of esophageal cancer incidence and death was drawn by spatial estimation method(Kriging interpolation),then the geographical gradient and variability were explored to clarify spatial trend and direction.4.The spatiotemporal scanning statistics were used to detect the incidence of esophageal cancer and the hot spots of esophageal cancer in the spatial dimension.Then,assess the stability of hotspot area in the spatial and temporal scale after the adjustment of temporal factors,so as to locate the high incidence hotspot areas.5.Though the inverse use of confounding triangular in epidemiology,using the method of exclusion in causal inference,treat the incidence rate of esophageal cancer as a dependent variable,the incidence of other tumors as an independent variable,establish the geographical weight regression model to clarify whether there is a common geographical high incidence area of malignant tumor in Feicheng county,indicate the specificity of hotspot area in Feicheng.6.Then take the incidence of esophageal cancer as dependent variables,the suspicious geographical risk factors(altitude,soil type,water quality test indicators,etc.)as independent variables,so that further explore the risk factors associated with the pathogenesis of esophageal cancer.Based on the analysis above,summarize the spatial epidemiological characteristics and geographical risk factors of high incidence area of esophageal cancer in Feicheng county.Methodology1.Construction of GIS Epidemiology Database of Esophageal Carcinoma in Feicheng.Based on the registration system of cancer incidence and death in Feicheng,the vector map of Feicheng was obtained from the vector map of Shandong Province by the "cutting" function of ArcMap,and the space-time coordinates of the i-th natural village are defined as(ui,vi,ti).The database of GIS epidemiology was established by linking the demographic data of each natural village,esophageal cancer registration information,other malignant tumor registration information,suspicious geographical risk factors(altitude,soil type,water quality)with the vector map above.2.The long-term trend of the incidence,death and disease burden of esophageal cancer in Feicheng County was analyzed by the method of descriptive epidemiological method.The time-dependent trend was tested by the Joinpoint regression analysis.The indicator of the disease burden was DALY calculated by the WHO recommended calculation method.3.The spatial autocorrelation coefficient Moran's I of cumulative incidence and cumulative mortality of esophageal carcinoma was calculated by global Moran spatial autocorrelation method,and the statistical significance was deduced by global Permutation test.4.Kriging spatial inter:polation method was used to predict the spatial morbidity,mortality and disease burden of esophageal carcinoma,then draw the contour,so as to show the trend of geographical variation and its spatial trend and direction.5.The spatial distribution and the aggregation area's exact location and risk of esophageal cancer incidence and mortality in the study area was analyzed by the Poisson distribution model in spatio-temporal scanning statistics.The statistical significance of the aggregation area was deduced by the likelihood ratio chi-square test.6.To investigate the spatial distribution pattern of esophageal cancer in Feicheng and its spatial hotspots,we compared the spatial distribution patterns of esophageal cancer with gastric cancer,liver cancer,colorectal cancer,lung cancer,leukemia,breast cancer,brain malignancy and other malignant tumors to explore whether they have spatial superposition effect with esophageal cancer.And then the GWR model yt =?0+(ui,vi)?jk=1?j(ui,vi)xij=?i was constructed between incidence variable(yi)of esophageal cancer and incidence(x1i,x2i,...,xki)of other malignant tumor by natural village as a unit.This model was to clarify whether there was a common high incidence area of malignant tumor in Feicheng and whether there was a specific region of high incidence of esophageal cancer.The parameter estimation of the GWR model was based on the local weighted least squares,and the AICc criterion was used to conduct the model selection.7.The GWR model of esophageal cancer incidence and suspicious geographic risk factors(altitude,soil type,water quality test indicators,etc.)was established to explore the association between geographical risk factors and esophageal cancer.All statistical analyzes were at significance level of 0.05.Results1.Descriptive epidemiological analysis showed that:1)The cumulative crude incidence and cumulative standardized age-specific incidence of esophageal cancer during 12 years was 95.40 per 100 thousand and 92.05 per 100 thousand,respectively;the results of Joinpoint test showed that the cumulative crude incidence(APC=4.34,P<0.0001)and cumulative standardized age-specific incidence(APC=2.35,P<0.0001)of esophageal cancer were time-dependent increasing trend,indicating that time factors had a certain impact on the incidence of esophageal cancer,but the total incidence was stable at a certain degree.2)The gender-specific incidence had significant differences;The cumulative crude incidence(129.58 per 100 thousand)and cumulative standardized age-specific incidence(127.16 per 100 thousand)of male were higher than female's(62.25 per 100 thousand,55.23 per 100 thousand),and the difference was significant(z=4.8613,P<0.0001;z=5.3261,P<0.0001).3)The cumulative crude mortality rate and cumulative standardized age-specific mortality rate of esophageal cancer were 80.27 per 100 thousand and 78.19 mortality rate,respectively;The results of Joinpoint test showed that the cumulative crude mortality rate(APC= 1.17,P=0.0842)and cumulative standardized age-specific mortality rate(APC=-0.04,P=0.9506)of esophageal cancer were not significant time-dependent increasing trend.4)The cumulative crude mortality rate(108,65 per 100 thousand)and cumulative standardized age-specific mortality rate(108.03 per 100 thousand)of male were higher than female's(52.75 per 100 thousand,46.90 per 100 thousand),and the difference was significant(z=4.4001,P<0.0001;z=4.9112,P<0.0001).5)The DALY Rate of esophageal cancer was 8.10 per 1000 person years;The results of Joinpoint test showed that the DALY Rate was a significant time-dependent increasing trend;The DALY Rate of male was 11.50 per 1000 person years and female was 4.90 per 1000 person years;The burden of disease caused by esophageal cancer was mainly due to premature death,accounting for more than 90%of total burden of disease.6)The mean age of male who newly diagnosed as esophageal cancer was 62.00±10.00 years(median age of diagnosis was 62 years);The mean age of female was 66.00±10.00 years(median age of diagnosis was 67 years);High-risk population was mainly the elderly;the incidence began to rise rapidly after the age of 40,the elderly aged over 50 accounted for more than 75%of(?)the total number of patients;Pathological types of newly diagnosed patients with pathological esophageal were mainly squamous cell carcinoma,clinical TNM stage grade III and poorly differentiated.2.The analysis of Global Moran Spatial Autocorrelation showed that:1)The cumulative incidence of esophageal cancer during 12 years in Feicheng had significant spatial autocorrelation;The Moran's I of total incidence,male and female incidence were 0.3005?0.1964 and 0.2188,respectively;The P value of Permutation test were all less than 0.001;The Moran's I and the P value were statistically significant,indicating that the incidence of esophageal cancer had a clear spatial structure,and there might be the region with high incidence.2)The cumulative mortality rate of esophageal cancer during 12 years in Feicheng had significant spatial autocorrelation;The Moran's I of total mortality rate,male and female mortality rate were 0.2797?0.1733 and 0.223 8,respectively;The P value of Permutation test were all less than 0.001;The Moran's I and the P value were statistically significant,indicating that the incidence of esophageal cancer had a clear spatial structure,and there might be the region with high mortality.3.The results of Kriging spatial estimation are shown that:1)The cumulative incidence,cumulative mortality and disease burden of esophageal cancer increased gradually from town of Laocheng in the northeastern to the southwest,and reached the highest level in town of Sunbo in the southwest;The spatial distribution pattern with the low value area in the northeast and the high value area in the southwest was formed;The region from northwest to southeast appeared geographical boundaries of high-value and low-value areas,indicating that the cumulative incidence,cumulative mortality and disease burden of esophageal cancer in Feicheng showed significant variability and direction of geographical gradient,and the variability and directionality of geographical gradient of three indicators were consistent.2)The variability and direction of geographical gradient of cumulative incidence,cumulative mortality and disease burden were the same between male and female,indicating the variability and direction of geographical gradient had not gender-specific significant difference.4.The results of space scan statistics and space-time scan statistics by natural village as a unit was shown that:1)The results of spatial scanning for the cumulative incidence of esophageal cancer showed that there was the area with highest incidence of esophageal cancer contained 112 villages in Feicheng;The cumulative incidence was from 63.68 per 100 thousand to 273.05 per 100 thousand;the cluster area was located in the town of Sunbo,Anjiazhuang,Anlinzhan and Wenyang in the southwest;The relative risk was 1.5238;In addition,there were two secondary areas with higher incidence;The cumulative incidence rate were 53.75 per 100 thousand and 245.65 per 100 thousand,respectively;They located in the towns of Wangzhuang(including 26 villages with higher incidence)and Anlinzhan(including 14 villages with higher incidence);The relative risk were 1.5942 and 1.3839,respectively.The results of further space-time scan showed that the first cluster area was still stable in areas with high incidence such as the towns of Sunbo,Anzhuang and Wenyang.A total of 151 natural villages with high incidence were scanned,indicating that the time factor was not high influence on the high incidence of esophageal cancer.A time-related secondary cluster area(a part villages in towns of Hutun and Wanggua in 2008)might be related to the time order of intervention work like screening.2)The results of spatial scanning for the cumulative mortality rate of esophageal cancer showed that there was the area with highest mortality rate of esophageal cancer contained 95 villages in Feicheng County;The cumulative mortality rate was from 54.36 per 100 thousand to 266.33 per 100 thousand;the cluster area was located in the town of Sunbo,Anjiazhuang,and Wenyang in the southwest;The relative risk was 1.5799;In addition,there were two secondary areas with higher mortality rate;The cumulative mortality rate were from 64.47 per 100 thousand to 183.27 per 100 thousand;They located in the towns of Wangzhuang(including 19 villages with higher mortality rate)and Wenyang(including 3 villages with higher mortality rate),respectively;The relative risk were 1.4237 and 1.8164,respectively.3)In the first cluster area,89 natural villages,which coincided between morbidity and mortality,accounted for 79.46%of natural villages(112)with high morbidity and mortality.The results of the time-space scan statistics of mortality was consistent with the results of the simple space scan statistics,indicating that the spatial hot spot of mortality rate was also stable.The above results show that in the small area of Feicheng,there were fixed natural villages with high incidence mortality rate of esophageal cancer.These villages with high incidence mortality rate were gathered in the southwest towns of Sunbo,Anzhuang,Wenyang and Wangzhuang.And number of patients(3009)and deaths(2188)in those villages accounted 35.69%and 30.84%for the total number(8431 and 7094)caused by esophageal cancer.5.To investigate the spatial distribution pattern of esophageal cancer in Feicheng and its spatial hotspots,we compared the spatial distribution patterns of esophageal cancer with gastric cancer,liver cancer,colorectal cancer,lung cancer,leukemia,breast cancer,brain malignancy and other malignant tumors.The results showed that the geometric gradient of esophageal cancer,spatial distribution pattern and hot spot distribution were different from other tumors,had no effect of space superposition,and was specific.In addition,the cumulative number of patients with esophageal cancer during 12 years accounted for 34.21%of the total number of patients with tumors,as the absolute superiority,indicating that there were specific geographical risk factors associated with esophageal cancer.The GWR regression model based on the inverse principle of epidemiological hybrid triangle and the principle of extrapolation of causal inference showed that:1)The geographical area where had significant association between esophageal cancer and gastric cancer was only located in town of Anjiazhuang,and it also was one hotspot of esophageal cancer.The geographical risk factors have homogeneity between them;But many areas of non-hotspot coincidence suggested that esophageal cancer and gastric cancer had their own specific geographical risk areas,although both belong to the upper gastrointestinal cancer.2)The areas where had significant correlation between esophageal and colorectal cancer did not coincide with the hotspots of esophageal cancer,indicating that geographical risk factors of esophageal cancer were significantly different from colorectal cancer,even if both belong to the digestive tumors.3)The areas where had significant correlation between esophageal and hepatocellular cancer did not coincide with the hotspots of esophageal cancer,indicating that geographical risk factors of esophageal cancer were significantly different from hepatocellular cancer,which also belonged to the digestive tumors.4)The incidence of esophageal cancer was 2.23 times higher than that of lung cancer in Feicheng.The incidence of lung cancer was the first highest in Shandong Province but the third in Feicheng,and was no significant area in Feicheng.It indicated that geographical risk factors had no related in the incidence of lung cancer.The geographical risk factors of esophageal cancer were different from lung cancer.5)leukemia,breast cancer,brain tumors and other tumors had the lower incidence.Their incidences were about 12.68%of esophageal cancer's or even lower.The areas related with hotspots of esophageal cancer were not found.In summary,there were specific high incidence areas of esophageal cancer in Feicheng,and the hotspots were not homogeneous with other tumors.There were the specific geographical risk factors of esophageal cancer in Feicheng which was the real hotspot of esophageal cancer.6.The results of the GWR analysis carried out bythe incidence of esophageal cancer as a dependent variable,the suspicious geographical risk factors collected(such as geological topography,water quality,etc.)as the independent variables were shown that:The Radj2 fitted by model was 32.3%,which was significantly higher than the Radj2(14.4%)of the global general least squares regression.It indicated that the geographical risk factors of esophageal cancer had obvious spatial heterogeneity and spatial structural characteristics.As shown in the spatial distribution of part Radj2,its geometric variation gradient and regions with high goodness-of-fit were consistent with the geographic variation gradient and hotspots of esophageal cancer.It indicated that the 25-38%of spatial variability of esophageal cancer can be explained by the geographic risk factors as known in the model(nitrate nitrogen,sulfate,Chloride,pH,oxygen consumption in drinking water,altitude and soil composition),but there were also many unknown risk factors for esophageal cancer.At the same time,the spatial distribution of P values of variables in the model showed that the nitrate nitrogen,sulfate,chloride and PH in the water and altitude were consistent with the hotspots of esophageal cancer,indicating that those factors were the geographic risk factors of areas with high incidence of esophageal cancer.But only the 29.5%of spatial variability of esophageal cancer be explained.Those factors were not the main geographical environmental risk factors leading to hotspots of esophageal cancer.Conclusion1.The cumulative incidence of esophageal cancer was 95.40/100 000 during 12 years,the cumulative mortality was 80.27/100 000,and the incidence and mortalityof esophageal cancer accounted for 34.21%and 35.91%for all cancers respectively,then the corresponding disease burden was 71956 life years,they all rank the first position among all caners;2.The incidence and mortality of esophageal carcinoma in Feicheng have obvious spatial autocorrelation,showing significant spatial structure and spatial variability.3.The incidence,death and disease burden of esophageal cancer in Feicheng showed obvious geographical gradient variability and directionality:they increased from the northeast to the southwest,then reached the peak at Sunbezhen town in the southwest,forming the spatial distribution pattern that low value area in the northeast and the high-value region in the southwest.The geographical boundaries exist between low value area in the northeast and the high-value region in the southwest.4.In the small area of Feicheng,the spatial positions of high incidence and mortality of esophageal cancer are fixed.They are clustered in Sun Bozhen Town,Anzhuang Town,Wenyang Town and Wangzhuang Town in the southwest of Feicheng County,the incidence(3009 cases)and death(2188 cases)in these areas accounted for 35.69%and 30.84%of the total number of incidences(8431 cases)and total deaths(7094 cases)respectively.5.There are specific high incidence areas of esophageal cancer in Feicheng County,and the hotspot areas do not have homogeneity with other cancers.It shows that there are obvious geographical risk factors for esophageal cancer in Feicheng County,which is a real incidence area of esophageal cancer.6.Nitrate nitrogen,sulphate,chloride and pH value in drinking water together with altitude are the geographical risk factors leading to high incidence of esophageal cancer.However,these risk factors can only But they can only explain the spatial variability of esophageal cancer incidence of 1/3,there are still 2/3 of the geographical risk factors are not identified..Innovations and limitations of this studyThe innovations of this study:1.This study takes the high incidence area of esophageal cancer in Feicheng County as an example,then described the spatial epidemiological features on the small spatial scale,hence provided evidence for exploringgeographical risk factors of regional esophageal cancer.2.Though the inverse use of confounding triangular in Epidemiology,using the method of exclusion in causal inference,establish the GWR model of esophageal cancer with all other cancers,indicating the specificity of hotspot area in Feicheng,and the hotspot areas do not have homogeneity with other cancers.It also shows that there are obvious geographical risk factors for esophageal cancer in Feicheng County,which is a real incidence area of esophageal cancer.3.This study crudely proved that nitrate nitrogen,sulphate,chloride and PH value in drinking water together with altitude are the geographical risk factors leading to high incidence of esophageal cancer.However,these risk factors can only limitedly explain the spatial variability of the incidence of esophageal cancer,hence further exploring more specific geographical risk factors for esophageal cancer is needed.The limitations of this study:The three innovative conclusions above were obtained only at the ecological level,and the causality conclusions of the geographical risk factors based on the rigorous analysis of epidemiological design(case-control study,cohort study)and experimental epidemiology were lacking;further studies will design the dual case control study under the guidance of the spatial analysisabove,then use the high-throughput environmental exposure group method,analyze the essential cause of high incidence of esophageal cancer in Feicheng County. |
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