Causal Association Between Green Space And Cancer Incidence

Background:Cancer is an important public health problem and the leading cause of death in most countries around the world.Along with rapid economic development,the social aging intensifies and the changes in prevalence of disease-related risk factors,the global cancer burden will continue to increase.Studies have shown that about 30 to 50 percent of cancers are attributed to modifiable risk factors.And primary prevention is the most effective way for cancer prevention.In addition to individual lifestyle-related factors,the impact of cumulative environmental exposure in living area on cancer incidence can’t be ignored,and health interventions about residential environment have shown to be more effective than those at the individual level.Therefore,it is necessary to explore the primary prevention measures related to the living environment.The implementation plan of cancer prevention and treatment in China also emphasizes the importance of healthy supportive environment construction.As an important indicator of ecological environment evaluation,green space is also one of the critical elements in urban planning.It plays a positive role in human physical and mental health through reducing pollution,increasing physical activity,promoting social contact and reducing stress.Studies have demonstrated the potential benefits of green space for cardiovascular disease,mental health,all-cause mortality and other health outcomes.Cancer shares many risk factors with other chronic diseases such as cardiovascular disease.Therefore,the health promotion approach of green space is likely to affect the occurrence and development of cancer.However,there were few researches on the relationship between green space and cancer incidence,with controversial conclusions.The causal relationship between green space and cancer needs to be further explored.Objective:Based on cancer registry data,study cohorts were established both at global scale and at small area scale and linked with normalized difference vegetation index(NDVI)deriving from satellite remote sensing data sources.On the basis of exploring the relationship between green space and cancer by correlation analysis,the possible confounding factors were then adjusted.Finally,causal correlation analysis was conducted to investigate the causal association between green space and cancer,and to provide reference for environment-related primary prevention of cancer.Methods:In the study based on global surveillance sites,the cities(regions)where the cancer surveillance sites are located were taken as the observation unit,and the incidence cohort was constructed based on the cancer registration data.NDVI data was extracted from 405 sites around the world by administrative area.Exposure was defined as average NDVI of 5 years before outcome.And cumulative risk(CR)of cancer was regarded as the outcome variable.Firstly,simple correlation analysis was used to explore the association between green space and cancer.Secondly,confounding factors such as longitude and latitude,altitude,temperature,air pressure and GDP per capita were adjusted in multiple linear regression.Finally,instrumental variable method and negative control exposure in time-series studies method(NCE-TS)were used for causal association analysis.And we conducted sensitivity analysis using NDVI of different exposure periods.In the small area study,the whole population of Pingyi county in Shandong province was taken as study subjects.Cancer registration data,electronic health records,and electronic medical records database were combined together according to ID number as the unique index to construct an incidence cohort.NDVI exposure was extracted based on the individual’s permanent address,and outcome was cancer during 2012 to 2015.We explored the association between green space and cancer using the generalized linear mixed model(GLMM)firstly,variables such as age,population density,spatial GDP and PM2.5 were included for adjusting.Finally,NCE-TS method was used to estimate the causal effect of green space on cancer.Results:1.Results of study based on global surveillance sites:(1)The average cumulative risk of cancer among men and women aged 0-74 in 405 regions was 26.85%and 19.90%,respectively.The highest cancer cumulative risk among men and women were trachea,bronchus,lung cancer(5.315%)and breast cancer(5.327%),respectively.(2)Simple correlation analysis showed that NDVI was negatively correlated with all-site cancer risk in women but not men,with Pearson’s correlation coefficients of-0.22(P<0.001)and-0.072(P=0.149),respectively.And for site-specific cancer,NDVI was in negative correlation with 13 site-specific cancer such as prostate cancer and colorectal cancer in men,and 14 types of cancer such as breast cancer and colorectal cancer in women.(3)After adjusting for latitude,longitude,altitude,temperature,air pressure and GDP per capita,multiple linear regression showed that NDVI was negatively correlated with 10 types of cancer in males.For every 0.01 increase in NDVI,CR decreased from 0.0121%in testicular cancer to 0.2432%in colorectal cancer.There was a negative association with 6 types of cancer in women,with CR reductions ranging from 0.0124%(nasopharyngeal cancer)to 0.2692%(thyroid cancer)for every 0.01 increase in NDVI.(4)Results of instrumental variable analysis showed that NDVI had a protective effect on all-site cancer(β=-5.0189,P=0.042)and 5 types of site-specific cancer including lung cancer in men.While in women,there was a protective effect on nasopharyngeal and pancreatic cancer.And the causal association with cancers in other site-specific and all-site cancer was not statistically significant.(5)In men,the NCE-TS analysis showed that NDVI had a protective effect on all-site cancer,each 0.01 increase in 5-year NDVI was associated with an average 1.1553%reduction in caner cumulative risk(95%CI:-2.2767%～-0.0340%,P=0.043).For site-specific cancers,5year average NDVI was in protective association with 8 types of cancers,and the highest effect estimation occurred in trachea,bronchi and lung cancer(-0.6830%,95%CI:-0.9966%～0.3693%),and following was colorectal and anal cancer(-0.3764%,95%CI:-0.6166%～0.1363%).In addition,the protective effect estimation for pancreatic,laryngeal,testicular and leukaemia was estimated at less than 0.1%.The causal association between NDVI and the cumulative risk of all-sites cancer was not statistically significant in women.But it had a protective effect against colorectal and anal cancer,trachea,bronchial and lung cancer,skin melanoma,breast cancer and bladder cancer,with the highest protective effect on breast cancer(-0.4162%,95%CI:-0.8218%～-0.0107%).2.Results from the small area study:(1)A total of 917,450 participants were included,with an average age of 39.40 years,of whom 51.03%were males.A total of 9157 cancer cases were reported,with a cumulative incidence of 9.98‰ from 2012 to 2015 in Pingyi county.(2)After adjusting for age,population density,PM2.5 and spatial GDP,results of generalized linear mixed model showed that NDVI had a protective effect on the incidence of cancer.For every 0.01 increase in NDVI,OR of all-site cancer in male was 0.9067(95%CI:0.9045～0.9088).For site-specific cancers,the OR values varied from 0.8064(thyroid cancer,95%CI:0.8039-0.8090)to 0.8972(gastric cancer,95%CI:0.8921-0.9024).While in women,the OR of all-site cancer was 0.8991(95%CI:0.8962～0.9019).For site-specific cancers,NDVI had the highest effect on thyroid cancer(OR=0.7477,95%CI:0.7141～0.7829),followed by cervical cancer(OR=0.8305,95%CI:0.8297～0.8313),and lung cancer was the lowest(OR=0.8879,95%CI:0.8820～0.8938).(3)Results of NCE-TS analysis showed that high-level NDVI had a protective effect on all types of cancer,and could reduce the causal absolute risk(AR)of all-site cancer incidence in men and women by 3.243%(95%CI:-3.400%～-3.092%)and 2.031%(95%CI:-2.147%～1.917%),respectively.For 9 types of site-specific cancer,the absolute risk of lung cancer decreased most whether in men or women.And the causal AR was-0.972%(95%CI:-1.051%-0.887%)and-0.455%(95%CI:-0.515%～-0.399%),respectively.Conclusion:1.In association analysis,NDVI showed a protective effect on most cancers,and this protective association persisted after adjusting covariates.After eliminating the influence of confounding factors by NCE-TS,there was a causal association between green space and cancer incidence,showing a protective trend for all-site and most site-specific cancers.2.At global scale,green space showed a protective trend for most cancers,but the causal association for several cancers was not significant.While in small area study,the measurement error of population exposure was reduced,and the protective causal association between NDVI and cancer was more significant.3.The protective effect of green space on cancer may vary with the length of exposure period.4.This study provides environmental epidemiological evidence for the primary prevention of cancer in residential environment,and attention should be paid to green space which is an important ecological factor.