| Part I.Nationwide multicenter epidemiological investigation of Helicobacter pylori familial infectionSection I-1.Establishment of National Helicobacter pylori Familial Infection Epidemiological Investigation databaseObjective:Helicobacter pylori（Hp）is a significant focus of gastric cancer prevention in China.The"Family Management Strategy"for Hp,a novel population management strategy proposed by Chinese scholars in 2022,has garnered considerable attention both domestically and internationally.However,epidemiological investigations of Hp at the family level have yet to be conducted,making it difficult to develop implementable Hp control strategies.To enhance the data on Hp familial infections and further demonstrate the underlying mechanisms of the"family management strategy,"this study conducted a large-scale epidemiological survey of Hp family infections covering 29 provinces.Methods:This study employed a multicenter,cross-sectional design,from September2021 to December 2021,enrolling community participants at the household level across various provinces nationwide.Following the acquisition of informed consent from patients,demographic data,household hygiene habits,and family medical history were collected face-to-face.The Hp infection status was determined based on the 13C urea breath test.An Hp-infected family was defined as a family with at least one Hp-infected member;the Hp familial infection rate was defined as the proportion of Hp-infected families among all households.Results:A total of 36029 participants from 17041 households were enrolled.Following the exclusion criteria,this studies ultimately included 10735 households（31098participants）.The average age of the participants was 43.49 years,with 12646 individuals infected with Hp（35.20%）,3781 children and adolescents（12.16%）,and 13477 males（43.34%）.The average family size was 2.90,with an average of 1.02 Hp-infected individuals per household.The familial infection rate was 71.13%（7636/10735）.Among these households,28.87%（3099/10735）had no infections,14.01%（1504/10735）had all members infected with Hp,and the remaining 57.12%（6132/10735）had both infected and non-infected members.Across the 29 provinces,the Hp familial infection rates ranged from50.27%to 85.06%,with 26 provinces exceeding 60%and 20 provinces surpassing 70%.Particularly severe infections were observed in five provinces:Qinghai,Hainan,Gansu,Jiangsu,and Liaoning,where familial infection rates exceeded 80%.Conclusions:In China,a significant number of households are infected by Hp,with the family infection rate surpassing anticipated levels and notably exceeding individual infection rates as well as rates among children.Provinces such as Qinghai,Hainan,and Gansu are identified as high-infection areas for Hp in China.Section I-2.Expansion of Helicobacter pylori "Family Management Strategy" in the Search for Infected IndividualsObjective: The familial clustering of Helicobacter pylori（Hp）serves as a crucial theoretical foundation for the "Family Management Strategy",yet this characteristic still lacks large-scale empirical data.This section aims to investigate the distribution status of Hp-infected individuals within households and,based on this exploration,to examine whether conducting Hp testing by reaching out to the family members of individuals who tested positive could enhance the screening efficiency for Hp infection.Method: This study was based on the aforementioned epidemiological survey cohort.Utilizing a goodness-of-fit test for binomial distribution,we analyzed the familial clustering of Hp infection in China and across provinces.By calculating the Intraclass Correlation Coefficient（ICC）,we quantified the degree of familial clustering of Hp infection nationwide and in each province.Computer simulations were employed to assess the efficiency of conducting Hp screening around Hp-positive individuals.Results: The number of households with different numbers of infected individuals did not follow a binomial distribution（χ2 = 21.643,P < 0.001）.This suggested that there were differences in the infection probabilities among individuals from different households,indicating a familial clustering distribution of Hp infection in China.The highest levels of familial clustering were observed in Shanghai（KAPPA = 0.289）and Beijing（KAPPA = 0.150）.Furthermore,compared to random sampling in the population,conducting Hp testing on family members of Hp-positive individuals could increase the efficiency of identifying Hp infections by 11.99%.This approach could have detected an additional 851 Hp infections when conducting 17492 Hp tests.Conclusion: The distribution of Hp infection shows a familial clustering pattern in China,particularly pronounced in Beijing and Shanghai,providing a data foundation for the "family management strategy" of Hp.Focusing on Hp-positive individuals and conducting Hp testing at the family level can efficiently screen for infected individuals within the population,thereby expanding the application of the "family management strategy".Section I-3.Analysis of Family and Individual Risk Factors for Helicobacter pylori InfectionObjective: Currently,clinical practices regarding Helicobacter pylori（Hp）infection primarily focus on individual care within communities.However,there has been recent discussion suggesting that implementing Hp "family management strategies" may be a more effective approach to controlling infections.Nevertheless,the risk factors and transmission patterns of Hp infection based on families are still unclear.This section aims to investigate the socio-economic and hygiene habits characteristics of clustered Hp families to achieve preventive Hp management at the family level.Method: This study was based on the aforementioned epidemiological survey cohort.Chi-square tests or Fisher’s exact probability tests were used to examine unordered categorical variables,while logistic regression was employed to explore the risk factors for Hp infection.In the univariate analysis,all variables with P < 0.10 were included in the multivariate logistic regression analysis（stepwise method,sls=0.10,sle=0.05）.Odds ratios（OR）and 95% confidence intervals（CI）were calculated to investigate the association between risk factors and Hp infection.A significance level of P < 0.05 was considered statistically significant.Results: From a household infection perspective,independent risk factors for Hp infection included residing in high prevalence areas such as the Northwest region（OR = 1.83,95% CI: 1.57-2.13,P < 0.001）,Northeast region（OR = 1.50,95% CI: 1.25-1.80,P < 0.001）,and South China region（OR = 1.51,95% CI: 1.27-1.79,P < 0.001）,as well as having a larger family size（e.g.,compared to households with two members,households with three members had an OR = 1.97,95% CI: 1.76-2.21,P < 0.001）.From an individual perspective,independent risk factors for Hp infection included living with Hp-infected family members（OR = 1.52,95% CI: 1.43-1.62,P < 0.001）,being male（OR = 1.14,95% CI: 1.08-1.21,P < 0.001）,being married（OR = 1.31,95% CI: 1.18-1.45,P < 0.001）.Protective factors included being younger in age（OR = 0.57,95% CI: 0.46-0.70,P < 0.001）and having a higher level of education（OR = 0.85,95% CI: 0.79-0.91,P < 0.001）.Paternal infection（OR = 1.68,95% CI: 1.08-2.61,P = 0.020）and maternal infection（OR = 1.70,95% CI: 1.10-2.63,P = 0.017）were independent risk factors for children’s Hp infection.Additionally,households that used communal spoons and chopsticks during meals had a lower Hp infection rate（P = 0.034）.Conclusion: Hp infection is influenced by multiple factors at different levels.Exposure to infected family members may be a primary driver of Hp transmission within households,with communal dining likely serving as a specific pathway for Hp transmission within families.Fathers and mothers emerge as the primary sources of Hp infection in children.Section I-4.Investigation on the Helicobacter pylori Infection in Gastric Cancer FamiliesObjective: This study aims to conduct a detailed investigation on the Helicobacter pylori（Hp）infection status among gastric cancer patients and their family members in Shanghai,China.A comparison will be made with data from a national community Hp survey to elucidate the differences in infection rates between gastric cancer patients,their family members,and the general community residents.Method: This survey utilized a single-center,cross-sectional design from September 2023 to March 2024 to investigate the Hp familial infection rate in gastric cancer patient families and the Hp infection status of cohabiting members on a household basis.Members of families with histologically confirmed gastric adenocarcinoma patients from the past five years at the hospital were included.The 13 C urea breath test was used to detect Hp infection status in general family members,and Helicobacter pylori stool antigen test was used to detect Hp infection status in patients who underwent subtotal gastrectomy.Hp infected families were defined as those containing at least one Hp-infected individual,and the Hp familial infection rate was defined as the proportion of Hp infected families among all households.Results: A total of 675 households with previously diagnosed gastric adenocarcinoma patients were recruited via phone calls.59 gastric cancer families participated in the information registration.Ultimately,104 subjects from 39 families were included in the analysis.The mean age of the enrolled subjects was 51.88 years.Among the 38 gastric cancer patients in the study,28.94%（11/38）reported a history of gastric cancer in first-degree relatives,with 5.26%（2/38）reporting a history in two first-degree relatives and 2.63%（1/38）reporting a history in three first-degree relatives.In Shanghai gastric cancer families,the proportion of low-income families（annual household income < 100,000 RMB）was significantly higher than that in community families（71.05% > 36.41%,P < 0.001）.Additionally,the proportion of gastric cancer families drinking tap water was significantly higher than that in community families（13.16% > 2.76%,P < 0.001）,while the proportion of families regularly disinfecting utensils was significantly lower than that in community families（23.68% < 41.01%,P < 0.001）,and the proportion of families practicing separate meal consumption was significantly lower than that in community families（23.68% > 41.01%,P < 0.001）.The Hp familial infection rate in gastric cancer families was 68.42%,whereas it was only 53.92% in community families.The Hp infection rate among gastric cancer patients in Shanghai was 44.74%,31.73% among family members of gastric cancer patients,and 31.80% among general community residents.Conclusion: The Hp familial infection rate in gastric cancer families may be higher than that in general community families,and these families also exhibit disadvantages in terms of economic status and hygiene habits compared to the general community families.Part II.Application Value Evaluation of the Stepwise Gastric Cancer Screening Strategy: A Prospective,Large Cohort Clinical StudySection II-1.Establishment of a Large-Scale Stepwise Gastric Cancer Screening ProgramObjective: Detection and eradication of Helicobacter pylori（Hp）are primary in preventing gastric cancer（GC）,while secondary prevention involves early detection,diagnosis,and treatment of patients.However,China lacks a mature,feasible,and efficient GC screening model.Hp is a recognized carcinogen for GC and a key indicator in screening.Our team developed a novel pre-screening tool based on serum Hp antibodies,gastric pepsinogen,gastrin-17,age,and gender.Yet,large-scale clinical validation of this tool for GC screening is needed.This study aims to evaluate the effectiveness of a sequential screening model using serological pre-screening tools in real-world settings.Method: This study employed a multicenter,prospective research design conducted from May 4,2022,to November 30,2023,across 26 provinces in China.The screening scenarios included opportunistic screening conducted at hospital outpatient departments（hospital-based screening）,organized screening through community setting（communitybased screening）,and screening conducted during annual medical examinations in workplaces and factories（Physical exam screening）,collectively forming the screening group.Participants identified as moderate to high risk during pre-screening were recommended for a second-stage endoscopic examination,while low-risk individuals underwent endoscopy based on voluntary participation.Concurrently,an additional 136 centers were selected to prospectively collect the endoscopic diagnostic results of consecutive individuals undergoing endoscopy in real clinical settings,excluding those undergoing re-examination or repeat diagnosis to form the control group,reflecting the current status of GC diagnosis in China.The GC detection rate,early diagnosis rate,and other diagnostic indicators between the screening group and the control group were compared using chi-square tests or Fisher’s exact probability method.Results: A total of 144262 participants in the screening group underwent pre-screening tool assessment,and after excluding criteria,106088 participants were included in the analysis.Among them,4715 individuals（4.4%）were classified as high risk,30264（28.5%）as moderate risk,and 71089（67%）as low risk based on pre-screening.The stepwise screening strategy saved 67% of endoscopic resources compared to universal endoscopy.Among moderate and high-risk individuals,33.3%（11660/34979）underwent the recommended endoscopic examination（endoscopic compliance rate of 33.3%）,leading to the detection of 253 GC cases（GC detection rate of 2.2%）,including 151 cases of earlystage（early diagnosis rate of 59.7%）.In the control group,27764 qualified endoscopy data were included in the analysis,revealing 223 GC cases and 60 cases of early-stage.The GC detection rate（2.2% > 0.8%,P < 0.001）and early diagnosis rate in the screening group were significantly higher than those in the control group（59.7% > 26.9%,P < 0.001）.As the prescreening score increased,the GC detection rate and endoscopic compliance also increased.Conclusion: Implementing a stepwise GC screening program in China can significantly reduce the utilization of gastroscopy resources,markedly increase GC detection rates and early diagnosis rates,thereby enhancing GC screening efficiency.Section II-2.Comparative effectiveness and health economic evaluation of stepwise gastric cancer screening under different settingsObjective: Large-scale screening practices for cancers such as liver cancer,breast cancer,and prostate cancer have shown that the screening setting significantly influences the final outcomes.However,there is a serious lack of relevant research in gastric cancer（GC）screening.This study aims to analyze the characteristics of different screening settings such as hospital-based screening,community-based screening,and physical examination-based screening,and their impact on screening outcomes.Furthermore,we use tools from health economics to evaluate the cost-effectiveness parameters of GC screening under these three scenarios.The ultimate goal is to determine the optimal screening setting for GC screening in China,thereby supporting the advancement of GC screening initiatives in the country.Methods: This study was based on the aforementioned stepwise GC screening cohort.The chi-square test or,when appropriate,Fisher’s exact test was employed to compare the compliance rate of gastroscopy,GC detection rate,and rate of early diagnosis among different screening settings.A health economic model was constructed,and the costs and benefits were discounted using the present value function.Cost-effectiveness analysis（CEA）,cost-benefit analysis（CBA）,and cost-utility analysis（CUA）were conducted.Univariate sensitivity analysis was utilized to explore the key factors influencing the health economic outcomes of stepwise GC screening.Results: Participants recruited from community settings were more likely to be classified as low-risk during pre-screening compared to those recruited from hospitals（community vs.outpatient: 75% > 63.4%,P < 0.001;community vs.physical examination: 75% > 66.9%,P < 0.001）.Conversely,participants recruited from hospital outpatient settings had a significantly higher proportion of intermediate and high-risk individuals during prescreening（P < 0.001）.The compliance rate for gastroscopy among hospital participants was significantly higher than that of community participants（41.0% > 32.2%,P < 0.001）and physical examination participants（41.0% > 20.5%,P < 0.001）.Furthermore,the GC detection rate among hospital participants was significantly higher than that of community participants（2.6% > 0.9%,P < 0.001）and physical examination participants（2.6% > 1.6%,P = 0.007）.In terms of GC early diagnosis,the rates were higher in community（77.8%）and physical examination（77.1%）settings compared to the hospital setting（55.0%）.Health economic analysis indicated that an average investment of 177,000 RMB was required to detect one case of early cancer through screening,resulting in savings of 193,000 RMB in medical insurance costs and an additional indirect benefit of 88,000 RMB.The cost-benefit ratio（cost: benefit）was 1:3.8.The health economic benefits were highest in the hospital setting,where every 1 RMB invested yielded 5.8 RMB in returns.Sensitivity analysis suggested that factors related to the screening setting played a dominant role in the final health economic outcomes of Stepwise Gastric Cancer Screening.Conclusion: The choice of screening setting has a significant impact on the final screening outcomes.Screening in hospital settings demonstrates advantages in terms of gastroscopy compliance rate and GC detection rate,while community-based screening excels in GC early diagnosis.Conducting stepwise screening in settings such as hospitals,communities,and physical examination centers aligns with health economic principles.The utilization of pre-screening tools can enhance subjects’ compliance with gastroscopy,thereby increasing health economic benefits.Section II-3.Comparison of gastric cancer pre-screening toolsObjective: This study aims to systematically retrieve similar pre-screening tools developed based on Helicobacter pylori（Hp）and other gastric cancer（GC）related indicators.Leveraging the extensive GC screening data established in the first section,a comparative analysis of models’ diagnostic performance will be conducted to identify the most suitable pre-screening tool for the Chinese population regarding GC screening.Methods: Based on the above screening data,the predictive efficacy of the retrieval models was evaluated using the bootstrap method.The area under the curve,sensitivity,specificity,accuracy,positive predictive value,negative predictive value,positive likelihood ratio,negative likelihood ratio,and Brier score of different models in the data were utilized to evaluate the model discrimination,and the results of R2,Hosmer-Lemeshow test,calibration curve,and slope of calibration curve of different models were utilized to evaluate the model calibration.Results: A total of 9 models,including the new GC screening scale method,ABC method,ABC method（Chinese version）,new ABC method,Chan’s model,Cho’s model,Tu’s model,Ji’s model,and De Re’s model,were finally included in the external validation.Regardless of whether the final goal of screening was set as gastric cancer or early gastric cancer,the differentiation of the new gastric cancer screening scale reached the highest among similar models,with the areas under the curve of 0.73 and 0.70,respectively,and the statistical test suggested that the area under the curve of the new gastric cancer screening scale was significantly better than that of the other models（P < 0.05）.In the comparison of calibration results,Ji model-strategy A,Ji model-strategy B,ABC method（Chinese version）and the new gastric cancer screening scale had relative advantages.Conclusion: The "New Gastric Cancer Screening Scale" has the relative advantage of discrimination in multiple scenarios,good generalizability,and the performance is ahead of similar models,which is suitable to be used in large-scale promotion in China.Section II-4.Meta-Analysis of Screening Outcomes in Global Gastroscopy Surveillance Projects and a Comparative Analysis with Stepwise ScreeningObjective: Gastric endoscopy remains the current international mainstream method for gastric cancer（GC）screening and has been implemented in some high-risk areas for GC.This study aims to analyze whether stepwise GC screening,as compared to the mainstream gastric endoscopy method,offers advantages in terms of GC detection rates and early diagnosis outcomes.Method: Using key terms such as "gastric cancer," "endoscopy," "gastroscopy," "screening," "detection," and "diagnosis," a systematic search of domestic and international GC screening reports was conducted in four databases,namely Pub Med,Embase,Web of Science,and Scopus.Following data extraction and quality assessment,gastric endoscopy compliance rates,GC detection rates,GC early diagnosis rates,and other key screening indicators of gastric endoscopy programs were comprehensively calculated.These findings were then compared with the data obtained from the previous stepwise screening analysis.Results: Literature search identified a total of 82676 studies.After removing 45318 duplicate studies and 7,745 non-original articles,we reviewed the titles and abstracts of 29,613 studies,with 90 studies ultimately included for data analysis.The overall gastric endoscopy compliance rate for global endoscopy programs was 46.94%（95% CI: 41.35-52.53%）,with China exhibiting a relatively lower compliance rate of 39.68%（95% CI: 31.84-47.52%）.The global GC detection rate was 0.62%（95% CI: 0.46-0.80%）,while in China,it was 0.51%（95% CI: 0.33-0.74%）.The global GC early diagnosis rate was 61.41%（95% CI: 51.42-71.40%）,with China at 51.35%（95% CI: 36.33-66.37%）.The GC detection rate of the stepwise screening method was 2.2%,higher than the global level of gastric endoscopy and higher than that in China.The early gastric cancer diagnosis rate of the stepwise screening method was 59.7%,close to the global level of gastric endoscopy and higher than that in China.The gastric endoscopy compliance rate of the stepwise screening method was 33.3%,slightly lower than the global level of gastric endoscopy and similar to that in China.Conclusion: In the previous gastric endoscopy screening programs conducted in China,the effectiveness of GC screening lags behind that of developed countries such as Japan and South Korea.Compared to traditional gastric endoscopy,the stepwise screening method demonstrates a higher GC detection rate and comparable early GC diagnosis.This method shows potential for rapidly improving GC screening levels in China,thereby reducing the burden of GC. |
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