Early Population-Level Impact of Helicobacter pylori Eradication on Gastric Cancer Mortality in Japan: A Counterfactual Analysis of Short-Term Divergence

Early Population-Level Impact of Helicobacter pylori Eradication on Gastric Cancer Mortality in Japan: A Counterfactual Analysis of Short-Term Divergence | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Early Population-Level Impact of Helicobacter pylori Eradication on Gastric Cancer Mortality in Japan: A Counterfactual Analysis of Short-Term Divergence Akiko Kowada This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8750837/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Gastric cancer has historically been driven by long‑standing Helicobacter pylori infection. The nationwide expansion of H. pylori eradication therapy beginning in 2013 created a unique opportunity to evaluate its population‑level impact on gastric cancer mortality. However, compared with long-term effects, short‑term mortality trends following eradication are difficult to interpret because they reflect overlapping influences of ageing, cohort replacement, and cumulative infection history, all of which vary by year. This study aimed to provide a causal, population‑level assessment of the early impact of eradication during the first decade of nationwide implementation. Methods We applied a two‑layer analytic framework consisting of a counterfactual analysis comparing observed mortality during 2013–2021 with expected mortality had eradication uptake remained at pre‑2013 levels, combined with a structured, time‑dependent, multilayer state‑transition model. To estimate annual deaths prevented and the proportion of mortality reduction attributable to eradication, the model integrated age‑specific biological hazard, cumulative infection history, cohort‑specific H. pylori prevalence, and annual changes in eradication uptake. Results Observed gastric cancer mortality declined from 48,632 deaths in 2013 to 41,624 deaths in 2021, whereas counterfactual mortality declined more modestly, from 49,794 to 45,654 deaths. The divergence between observed and counterfactual mortality steadily widened from 1,162 deaths in 2013 to 4,030 deaths in 2021. Model‑based estimates indicated that eradication prevented 1,427 deaths during 2013–2021, with annual deaths prevented increasing from 17 in 2015 to 417 in 2021, particularly among adults aged 50–79, who showed the most pronounced early benefit reflecting cumulative infection history and real-world uptake patterns. Conclusions The early population‑level impact of H. pylori eradication has already contributed to a 10.4% reduction in gastric cancer mortality by 2021. These findings provide real‑world evidence of how primary prevention can shape short‑term national cancer trends. This provides a framework that may guide prevention strategies in high‑prevalence settings seeking to evaluate early implementation effects. Helicobacter pylori eradication gastric cancer mortality counterfactual analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Gastric cancer remains a major public health concern in Japan, where it continues to be the third leading cause of cancer‑related deaths [ 1 ]. Helicobacter pylori infection is the predominant etiologic factor [ 2 ], accounting for nearly all cases nationwide [ 3 ]. Although infection prevalence has declined across successive birth cohorts, Japan retains a unique epidemiologic structure in which older adults carry high lifetime exposure [ 4 ], shaping national gastric cancer trends for decades. In 2013, Japan became the first country to introduce nationwide insurance coverage for H. pylori eradication therapy for chronic gastritis [ 5 ]. This policy led to a rapid expansion of eradication uptake and created a rare opportunity to evaluate the early, population‑level impact of eradication in a real‑world setting (Figure S1 ). Previous modeling work has demonstrated the cumulative lifetime impact of H. pylori eradication on gastric cancer mortality [ 6 ] and identified the optimal age for population‑based implementation of eradication screening [ 7 ]. These findings highlight the importance of evaluating eradication strategies within a time‑dependent, cohort‑structured framework. However, interpreting short‑term mortality changes is challenging because observed trends reflect multiple overlapping forces, including ageing, cumulative infection history [ 8 ], cohort replacement [ 9 ], and evolving clinical practice [ 10 ], all of which vary by year. Conventional before–after comparisons or trend‑based analyses cannot disentangle these structural determinants and therefore cannot isolate the causal contribution of eradication [ 11 ]. A brief counterfactual analysis is therefore needed to quantify the short‑term divergence in gastric cancer deaths in the absence of eradication. To address this complexity, the present study employs a two‑layer analytic framework. First, a structured, time‑dependent multilayer model reconstructs etiologic incidence by integrating age‑specific biological hazard, duration‑related exposure, and cohort‑specific H. pylori prevalence. This modeling layer provides a biologically coherent representation of the causal pathway linking infection to gastric cancer. Second, a counterfactual analysis [ 12 ] compares observed mortality with an expected trajectory representing a scenario in which eradication uptake remained at pre‑2013 levels. This design enables a causal, population‑level assessment of the early impact of eradication during its initial decade of nationwide implementation. Using this combined modeling and counterfactual approach, the study aims to quantify the proportion of early reductions in gastric cancer mortality attributable to H. pylori eradication within the overall burden of gastric cancer deaths in Japan between 2013 and 2021. Clarifying these short‑term population‑level effects illustrates how primary prevention can begin to influence national cancer trends within a relatively brief period. Methods 2.1 Study Design and Overview We developed a structured, time-dependent multilayer model (Figure 1 )[ 12 , 13 ] to evaluate the population-level impact of Japan’s nationwide H. pylori eradication strategy implemented under the universal health insurance system. The analysis covered 2013–2021, corresponding to the period during which eradication uptake expanded rapidly following insurance coverage. Two scenarios were compared: the observed mortality reflecting real-world eradication uptake, and a counterfactual mortality trajectory representing expected mortality if eradication uptake had remained at pre-2013 levels. Comparing these scenarios isolates the contribution of eradication to short‑term changes in gastric cancer mortality while preserving etiologic coherence with the established biology and epidemiology of H. pylori –related carcinogenesis. 2.2 Model Structure 2.2.1 Multilayer incidence reconstruction To capture the structural determinants of gastric cancer risk, we reconstructed age-specific incidence using a multiplicative formulation integrating four components [ 8 , 9 ]: (1) Baseline incidence was defined as the gastric cancer incidence at age 40 in 2021, obtained from the national cancer registry [ 1 ]. This served as the reference scale. (2) Age-specific ageing factor was derived from 2021 incidence data to represent biological ageing effects independent of cohort exposure. (3) Duration-related historical exposure factor was estimated by comparing age-specific incidence in 2021 with incidence patterns from earlier high-burden periods. This factor captures cumulative historical exposure not explained by ageing alone. (4) Age- and cohort-specific H. pylori prevalence were obtained from a systematic review and meta-regression of 170,752 individuals [ 4 ]. These prevalence estimates were mapped to each age and calendar year. The final incidence formulation was: $$\:{\text{Incidence}}_{a,t}=\text{Baseline}\times\:{\text{Ageing}}_{a}\times\:{\text{Duration}}_{a}\times\:{\text{Prevalence}}_{a,t}$$ This formulation incorporates cumulative infection history by accounting for age, duration of infection, and cohort‑specific exposure. 2.2.2 Mortality Dynamics Counterfactual mortality trajectory To quantify the impact of eradication, we constructed a counterfactual trajectory [ 11 ] representing expected mortality if eradication uptake had not expanded after 2013. All other structural determinants such as ageing, duration, cohort effects, and case-fatality were held constant to isolate the effect of eradication. Annual mortality difference Annual mortality difference was defined as: $$\:{\text{Difference}}_{t}={\text{Mortality}}_{\text{counterfactual},t}-{\text{Mortality}}_{\text{observed},t}$$ This difference reflects the divergence between expected and observed mortality. Deaths prevented by eradication Deaths prevented were estimated by comparing two strategies within a structured state‑transition (Markov) model: (1) continuation of standard gastric cancer screening and (2) implementation of H. pylori eradication. This comparison yielded the reduction in gastric cancer mortality attributable to eradication. Proportion attributable to eradication The proportion of mortality reduction attributable to eradication was calculated as: where Difference represents the observed–counterfactual difference in deaths in year t, indicating the share explained by eradication (Figure 2 ). This modeling framework also enabled estimation of year-specific gastric cancer deaths prevented by eradication from 2013 to 2021. 2.3 Data inputs Age-specific mortality, population structure, and gastric cancer incidence were obtained from national cancer statistics [ 1 ] and vital statistics [ 14 ] (Table 1 ). Annual eradication counts were derived from published literature [ 15 ] and non-public regional datasets (Table 2 ). Model parameters related to screening adherence [ 16 ], endoscopy accuracy [ 17 ], eradication compliance [ 18 ], eradication success [ 18 ], and gastric cancer risk reduction with eradication [ 19 ] were obtained from published studies (Table 1 ). Table 1 Key parameters used in the model Variable Baseline value Reference Probabilities Proportion of gastric cancer cases attributable to H. pylori 0.98 3 Adherence rate of endoscopy after eradication (age ≥ 50) 0.20 Assumption Adherence rate to current gastric cancer screening (age ≥ 50) 0.44 16 Adherence rate to endoscopy among screened individuals 0.196 16 First-line eradication compliance rate 0.891 18 First-line eradication success rate 0.901 18 Second-line eradication compliance rate 0.901 18 Second-line eradication success rate 0.901 18 Gastric cancer risk reduction with eradication 0.54 19 Sensitivity of endoscopy 0.954 17 Specificity of endoscopy 0.888 17 Stage proportion of detected gastric cancer (screening) I: 0.898, II: 0.054, III: 0.020, IV: 0,028 20 Stage-specific 5-year survival rate (I-IV) 0.960, 0.692, 0.419, 0.063 20 Table 2 Annual differences between observed and counterfactual gastric cancer deaths and deaths prevented by H. pylori eradication, 2013–2021. Year Observed gastric cancer deaths (a) Counterfactual gastric cancer deaths (b) Difference in gastric cancer mortality (b-a) Deaths prevented by eradication (c) Attributable proportion (%) 2013 48,632 49,794 1,162 0 0 2014 47,904 49,717 1,813 0 0 2015 46,681 49,589 2,908 17 0.6 2016 45,546 49,310 3,764 47 1.3 2017 45,227 48,880 3,653 104 2.9 2018 44,192 48,300 4,108 194 4.7 2019 42,931 47,569 4,638 287 6.2 2020 42,319 46,687 4,368 361 8.3 2021 41,624 45,654 4,030 417 10.4 Total 405,056 435,500 30,444 1,427 4.7 Epidemiologic parameters related to gastric cancer progression were derived from national statistics [ 20 ] and from prior long‑term modeling work evaluating the cumulative lifetime impact of eradication on gastric cancer mortality [ 6 ]. Age-specific stage distributions for screened gastric cancer were incorporated using national cancer statistics [ 20 ], and are consistent with evidence showing that younger patients typically present with more advanced disease and aggressive tumor biology [ 21 , 22 ] (Table S1 ). All data sources were harmonized to produce internally consistent age- and year-specific inputs. All modeling analyses were conducted using TreeAge Pro 2025 (TreeAge Software, Williamstown, MA). Results 3.1 Trends in observed and counterfactual mortality Annual trends in the number of individuals undergoing H. pylori eradication are shown in Fig. 3 A, demonstrating a rapid increase following the introduction of insurance coverage in 2013, followed by a gradual decline and recent plateau. Observed gastric cancer mortality decreased steadily from 48,632 deaths in 2013 to 41,624 deaths in 2021 (Table 2 , Fig. 3 B). In contrast, the counterfactual mortality trajectory—representing expected mortality if eradication uptake had remained at pre-2013 levels—declined more slowly, from 49,794 deaths in 2013 to 45,654 deaths in 2021 (Table 2 , Fig. 3 B). The divergence between observed and counterfactual mortality widened consistently over time, increasing from 1,162 deaths in 2013 to 4,030 deaths in 2021 (Table 2 , Fig. 4 A). This widening gap reflects the cumulative impact of expanded eradication uptake on national mortality trends. 3.2 Annual deaths prevented by eradication Model-based estimates indicated that the number of gastric cancer deaths prevented by eradication increased gradually throughout the study period. Deaths prevented rose from 17 in 2015—when the earliest measurable effects of eradication became detectable—to 417 in 2021, with a cumulative total of 1,427 deaths prevented during 2013–2021 (Table 2 , Fig. 4 B). The largest annual reductions were observed among adults aged 50–79, consistent with both the age distribution of eradication uptake and the cohort-specific infection histories that shape gastric cancer risk (Figure 4 C). 3.3 Proportion of mortality reduction attributable to eradication The proportion of the observed–counterfactual mortality difference attributable to eradication increased steadily over time. This proportion rose from 0.6% in 2015 to 10.4% in 2021 (Table 2 , Fig. 4 D). This upward trend indicates that eradication has become an increasingly important contributor to Japan’s declining gastric cancer mortality, even within the relatively short nine-year period following nationwide insurance coverage. 3.4 Summary of early population-level impact Together, these findings demonstrate that: gastric cancer mortality in Japan is declining faster than expected under a no-expansion counterfactual eradication has already prevented more than 1,400 deaths the contribution of eradication is increasing each year the strongest effects are concentrated in middle-aged and older adults, reflecting cumulative infection history and real-world uptake patterns These results provide clear evidence that H. pylori eradication is already shaping national gastric cancer trends during the early phase of its implementation. Discussion 4.1 Interpretation of findings By integrating a structured incidence reconstruction with a counterfactual mortality trajectory, this study clarifies the early, population‑level impact of Japan’s nationwide H. pylori eradication strategy. Mortality declined more rapidly than expected beginning in 2015, and the divergence between observed and counterfactual mortality widened steadily through 2021. These findings indicate that eradication has already produced measurable reductions in gastric cancer deaths within the first decade of implementation, despite the long latency of gastric carcinogenesis. The strongest effects were observed among adults aged 50–79, reflecting both the age distribution of eradication uptake and the cumulative infection histories that shape gastric cancer risk. 4.2 Structural epidemiologic implications This study demonstrates the value of a two‑layer analytic framework that combines etiologic modeling with counterfactual evaluation. The multilayer incidence reconstruction captures the biological and historical determinants of gastric cancer risk—age‑specific hazard, duration‑related exposure, and cohort‑specific infection prevalence—providing a coherent representation of the causal pathway linking H. pylori infection to cancer. The counterfactual layer isolates the contribution of eradication from background trends driven by ageing, cohort replacement, and long‑term declines in infection prevalence. Together, these components enable a causal interpretation of short‑term mortality changes that cannot be achieved through conventional trend‑based or before–after analyses. 4.3 Policy relevance Japan’s experience provides real‑world evidence that population‑based H. pylori eradication can produce detectable mortality reductions within a relatively short timeframe. The alignment between eradication volume, early mortality reductions, and modeled deaths prevented supports the continued expansion of eradication as a primary prevention strategy. These findings are particularly relevant for high‑prevalence countries where gastric cancer remains a major cause of cancer mortality. As younger cohorts with lower infection prevalence gradually replace older, high‑risk cohorts, the relative contribution of eradication to national mortality trends may increase further. Integrating eradication with risk‑based screening strategies may accelerate progress toward reducing gastric cancer burden. 4.4 Comparison with conventional modeling and forecasting approaches Unlike conventional natural history models that rely on unobservable transition parameters, the present framework reconstructs incidence directly from etiologic determinants. This etiology‑based approach avoids assumptions about latent disease states and provides a transparent representation of the causal structure underlying gastric cancer risk. Forecasting‑based approaches, including ARIMA and interrupted time‑series regression [ 23 ], are valuable for projecting future trends but cannot isolate the causal impact of specific policy actions because they extrapolate past patterns without reconstructing counterfactual disease dynamics. In contrast, the combined modeling and counterfactual design used here quantifies the short‑term mortality reduction attributable specifically to real‑world eradication efforts. 4.5 Strengths and limitations Strengths of this study include the use of a counterfactual framework aligned with real‑world policy structures, incidence reconstruction based on etiologic determinants, integration of age‑specific case fatality and eradication uptake, and quantification of both deaths prevented and the proportion of mortality decline attributable to eradication. Limitations include reliance on published case‑fatality estimates, assumptions regarding the stability of background risk factors in the counterfactual scenario, and the focus on short‑term effects without projecting long‑term outcomes. Temporal changes in non– H. pylori risk factors were not explicitly modeled, although their short‑term influence is unlikely to materially affect the estimates relative to the impact of eradication. 4.6 Implications This structured counterfactual analysis demonstrates that population‑based H. pylori eradication can produce measurable reductions in gastric cancer mortality within a decade. The findings highlight the importance of integrating real‑world implementation patterns, etiologic determinants, and causal evaluation frameworks when assessing primary prevention strategies. More broadly, this study provides a complementary perspective to global analyses by emphasizing the role of historical implementation context and short‑term dynamics in shaping national cancer trends. Conclusion This study provides clear evidence that population‑based H. pylori eradication has already contributed to measurable reductions in gastric cancer mortality in Japan. By combining a structured etiologic modeling framework with a counterfactual evaluation of expected mortality in the absence of expanded eradication, the analysis clarifies how eradication is shaping national mortality trends during the early phase of its implementation. These findings demonstrate that primary prevention can yield detectable population‑level benefits within a decade, even for a cancer with a long natural history. Japan’s experience offers real‑world evidence of how systematic eradication can alter short‑term national cancer trajectories and provides a framework for evaluating early implementation effects in high‑prevalence settings. Declarations Acknowledgments None. Funding information None. Conflicts of interest statement The author declares no conflict of interest. Author contributions A.K. contributed to the study concept and design, data acquisition and analysis, interpretation of the data, accepted responsibility for the integrity of the research process and findings, and approved the final manuscript. Funding : This research received no specific grant from any funding agency in the public, commercial, or not‑for‑profit sectors. Conflict of Interest: The author declares no conflicts of interest. Ethics Statement: This study used publicly available, aggregated national statistics and did not involve human subjects; therefore, ethical approval was not required. Author Contributions: The author conceptualized the study, developed the model, conducted the analysis, validated the model, interpreted the results, drafted the manuscript, and revised the final version. References Cancer Information Service, National Cancer Center, Japan. Cancer registry and statistics. Available at: https://ganjoho.jp/reg_stat/statistics/stat/cancer/5_stomach.html. 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Sensitivity of endoscopic screening for gastric cancer by the incidence method. Int J Cancer . 2013;133:653–659. https://doi.org/10.1002/ijc.28065 Mori H, Suzuki H, Omata F, et al. Current status of first- and second-line Helicobacter pylori eradication therapy in the metropolitan area: a multicenter study with a large number of patients. Ther Adv Gastroenterol . 2019;12:1756284819858511. https://doi.org/10.1177/1756284819858511 Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut. 2020;69:2113–2121. https://doi.org/10.1136/gutjnl-2020-320839 National Cancer Center Japan. Cancer statistics in Japan 2025. Foundation for Promotion of Cancer Research; 2025. Available at: https://ganjoho.jp/public/qa_links/report/statistics/2025_en.html. Accessed January 30, 2026. Cheng L, Chen S, Wu W, Zhuang Q, et al. Gastric cancer in young patients: a separate entity with aggressive features and poor prognosis. 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Supplementary Files Supplementarymaterial.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 07 Apr, 2026 Reviews received at journal 14 Mar, 2026 Reviewers agreed at journal 12 Mar, 2026 Reviews received at journal 09 Mar, 2026 Reviewers agreed at journal 09 Mar, 2026 Reviewers invited by journal 24 Feb, 2026 Editor assigned by journal 05 Feb, 2026 Submission checks completed at journal 05 Feb, 2026 First submitted to journal 31 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8750837","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":597058582,"identity":"0ac09753-87c9-4cdc-b1de-b01a7d0fa2b6","order_by":0,"name":"Akiko Kowada","email":"data:image/png;base64,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","orcid":"","institution":"Kitasato University Graduate School of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Kowada","suffix":""}],"badges":[],"createdAt":"2026-01-31 15:08:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8750837/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8750837/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104399002,"identity":"3b6ff521-61d1-41fb-b3df-1b4d66601600","added_by":"auto","created_at":"2026-03-11 12:04:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":201019,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical pathway and outcomes of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eHelicobacter pylori \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003einfection and eradication.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis diagram illustrates the progression and treatment outcomes associated with \u003cem\u003eH. pylori\u003c/em\u003e infection and its potential link to gastric cancer. Infection may persist or be successfully eradicated through therapy. Persistent infection increases the risk of gastric cancer, which may lead to death or post‑treatment remission. Successful eradication reduces—but does not eliminate—cancer risk. Arrows indicate possible transitions between health states, including recurrence after remission. Colors represent distinct clinical phases: blue for natural history, green for intervention, red for cancer progression, light blue for remission, and grey for death.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8750837/v1/22db928870b62fedd1502c2e.png"},{"id":103606911,"identity":"10617e54-7263-4e72-8697-c560aee4e670","added_by":"auto","created_at":"2026-02-27 15:01:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":178194,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eConceptual framework for observed and counterfactual gastric cancer deaths and the estimated contribution of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eH. pylori \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eeradication.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eObserved gastric cancer deaths (2013–2021) were compared with counterfactual deaths projected from mortality trends calibrated to national statistics from 1999–2012. The mortality difference (b − a) represents the annual gap between expected and observed deaths in the absence of increased eradication uptake. Deaths prevented by eradication (c), estimated using a multilayer incidence model, and the attributable proportion (c / [b − a]) quantify the contribution of \u003cem\u003eH. pylori\u003c/em\u003e eradication to reductions in gastric cancer mortality.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8750837/v1/42f083d9396a851cd1c1572f.png"},{"id":103606912,"identity":"9b38280c-2a66-4efe-bd22-e2ba142e4fbb","added_by":"auto","created_at":"2026-02-27 15:01:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":300152,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA. Annual number of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eH. pylori \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eeradications in Japan, 2013–2021.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing the introduction of national insurance coverage for chronic gastritis in 2013, eradication uptake increased sharply, followed by a gradual decline, a marked drop during the COVID‑19 pandemic, and a subsequent plateau.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB. Annual trends in observed and counterfactual gastric cancer deaths, 2013–2021.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCounterfactual deaths were projected from mortality trends prior to widespread eradication uptake (1999–2012), with internal consistency checks confirming the stability of pre‑intervention trends. The divergence between observed and counterfactual deaths indicates that mortality trends after 2013 did not follow the pre‑2013 trajectory.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8750837/v1/ae55ce65737d0bae97d98e57.png"},{"id":103606914,"identity":"9549514c-70d2-42d6-9b52-56c47f9b3f65","added_by":"auto","created_at":"2026-02-27 15:01:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":517196,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA. Annual difference between expected and observed gastric cancer deaths.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe annual difference represents the reduction in gastric cancer deaths each year, calculated as the number of deaths expected under the counterfactual scenario minus the number of deaths actually observed.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB. Annual deaths prevented by \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eH. pylori \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eeradication.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrevented deaths represent the portion of the annual mortality difference attributable to \u003cem\u003eH. pylori\u003c/em\u003e eradication.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC. Age distribution of individuals undergoing\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e H. pylori\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e eradication between 2013 and 2021.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe majority of eradication uptake occurred among adults aged 60–79 years, consistent with the observed concentration of gastric cancer mortality reductions in this age group.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD. Annual attributable proportion of gastric cancer deaths due to \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eH. pylori\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eeradication.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe attributable proportion represents the share of the annual mortality difference explained by \u003cem\u003eH. pylori\u003c/em\u003e eradication, calculated as eradication‑attributable deaths divided by the annual mortality difference between expected and observed gastric cancer deaths.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8750837/v1/c915be43e4ec473b24e90e6b.png"},{"id":104407689,"identity":"8000ef51-0535-4dac-b6d4-2ca85a77ecf2","added_by":"auto","created_at":"2026-03-11 12:39:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2281548,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8750837/v1/2471dea9-293c-46e4-8c49-d4910970c373.pdf"},{"id":103606915,"identity":"c33ba501-f38f-4d07-9ed8-cd74ea9c7713","added_by":"auto","created_at":"2026-02-27 15:01:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":215705,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8750837/v1/72ec98e4eecc8f9efb6e6876.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early Population-Level Impact of Helicobacter pylori Eradication on Gastric Cancer Mortality in Japan: A Counterfactual Analysis of Short-Term Divergence","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastric cancer remains a major public health concern in Japan, where it continues to be the third leading cause of cancer‑related deaths [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. \u003cem\u003eHelicobacter pylori\u003c/em\u003e infection is the predominant etiologic factor [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], accounting for nearly all cases nationwide [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although infection prevalence has declined across successive birth cohorts, Japan retains a unique epidemiologic structure in which older adults carry high lifetime exposure [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], shaping national gastric cancer trends for decades.\u003c/p\u003e \u003cp\u003eIn 2013, Japan became the first country to introduce nationwide insurance coverage for \u003cem\u003eH. pylori\u003c/em\u003e eradication therapy for chronic gastritis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This policy led to a rapid expansion of eradication uptake and created a rare opportunity to evaluate the early, population‑level impact of eradication in a real‑world setting (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Previous modeling work has demonstrated the cumulative lifetime impact of \u003cem\u003eH. pylori\u003c/em\u003e eradication on gastric cancer mortality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and identified the optimal age for population‑based implementation of eradication screening [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These findings highlight the importance of evaluating eradication strategies within a time‑dependent, cohort‑structured framework. However, interpreting short‑term mortality changes is challenging because observed trends reflect multiple overlapping forces, including ageing, cumulative infection history [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], cohort replacement [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and evolving clinical practice [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], all of which vary by year. Conventional before\u0026ndash;after comparisons or trend‑based analyses cannot disentangle these structural determinants and therefore cannot isolate the causal contribution of eradication [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A brief counterfactual analysis is therefore needed to quantify the short‑term divergence in gastric cancer deaths in the absence of eradication.\u003c/p\u003e \u003cp\u003eTo address this complexity, the present study employs a two‑layer analytic framework. First, a structured, time‑dependent multilayer model reconstructs etiologic incidence by integrating age‑specific biological hazard, duration‑related exposure, and cohort‑specific \u003cem\u003eH. pylori\u003c/em\u003e prevalence. This modeling layer provides a biologically coherent representation of the causal pathway linking infection to gastric cancer. Second, a counterfactual analysis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] compares observed mortality with an expected trajectory representing a scenario in which eradication uptake remained at pre‑2013 levels. This design enables a causal, population‑level assessment of the early impact of eradication during its initial decade of nationwide implementation.\u003c/p\u003e \u003cp\u003eUsing this combined modeling and counterfactual approach, the study aims to quantify the proportion of early reductions in gastric cancer mortality attributable to \u003cem\u003eH. pylori\u003c/em\u003e eradication within the overall burden of gastric cancer deaths in Japan between 2013 and 2021. Clarifying these short‑term population‑level effects illustrates how primary prevention can begin to influence national cancer trends within a relatively brief period.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Study Design and Overview\u003c/h2\u003e\n \u003cp\u003eWe developed a structured, time-dependent multilayer model (Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e)[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e] to evaluate the population-level impact of Japan\u0026rsquo;s nationwide \u003cem\u003eH. pylori\u003c/em\u003e eradication strategy implemented under the universal health insurance system. The analysis covered 2013\u0026ndash;2021, corresponding to the period during which eradication uptake expanded rapidly following insurance coverage. Two scenarios were compared: the observed mortality reflecting real-world eradication uptake, and a counterfactual mortality trajectory representing expected mortality if eradication uptake had remained at pre-2013 levels. Comparing these scenarios isolates the contribution of eradication to short‑term changes in gastric cancer mortality while preserving etiologic coherence with the established biology and epidemiology of \u003cem\u003eH. pylori\u003c/em\u003e\u0026ndash;related carcinogenesis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Model Structure\u003c/h2\u003e\n \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.1 Multilayer incidence reconstruction\u003c/h2\u003e\n \u003cp\u003eTo capture the structural determinants of gastric cancer risk, we reconstructed age-specific incidence using a multiplicative formulation integrating four components [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]: (1) Baseline incidence was defined as the gastric cancer incidence at age 40 in 2021, obtained from the national cancer registry [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. This served as the reference scale. (2) Age-specific ageing factor was derived from 2021 incidence data to represent biological ageing effects independent of cohort exposure. (3) Duration-related historical exposure factor was estimated by comparing age-specific incidence in 2021 with incidence patterns from earlier high-burden periods. This factor captures cumulative historical exposure not explained by ageing alone. (4) Age- and cohort-specific \u003cem\u003eH. pylori\u003c/em\u003e prevalence were obtained from a systematic review and meta-regression of 170,752 individuals [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. These prevalence estimates were mapped to each age and calendar year.\u003c/p\u003e\n \u003cp\u003eThe final incidence formulation was:\u003c/p\u003e\n \u003cdiv id=\"Equa\" class=\"Equation\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e$$\\:{\\text{Incidence}}_{a,t}=\\text{Baseline}\\times\\:{\\text{Ageing}}_{a}\\times\\:{\\text{Duration}}_{a}\\times\\:{\\text{Prevalence}}_{a,t}$$\u003c/div\u003e\n \u003c/div\u003e\n \u003cp\u003eThis formulation incorporates cumulative infection history by accounting for age, duration of infection, and cohort‑specific exposure.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2.2 Mortality Dynamics\u003c/h2\u003e\n \u003cp\u003e\u003cstrong\u003eCounterfactual mortality trajectory\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eTo quantify the impact of eradication, we constructed a counterfactual trajectory [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e] representing expected mortality if eradication uptake had not expanded after 2013. All other structural determinants such as ageing, duration, cohort effects, and case-fatality were held constant to isolate the effect of eradication.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAnnual mortality difference\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAnnual mortality difference was defined as:\u003c/p\u003e\n \u003cdiv id=\"Equb\" class=\"Equation\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e$$\\:{\\text{Difference}}_{t}={\\text{Mortality}}_{\\text{counterfactual},t}-{\\text{Mortality}}_{\\text{observed},t}$$\u003c/div\u003e\n \u003c/div\u003e\n \u003cp\u003eThis difference reflects the divergence between expected and observed mortality.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDeaths prevented by eradication\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eDeaths prevented were estimated by comparing two strategies within a structured state‑transition (Markov) model: (1) continuation of standard gastric cancer screening and (2) implementation of \u003cem\u003eH. pylori\u003c/em\u003e eradication. This comparison yielded the reduction in gastric cancer mortality attributable to eradication.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eProportion attributable to eradication\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe proportion of mortality reduction attributable to eradication was calculated as:\u003c/p\u003e\n \u003cdiv id=\"Equc\" class=\"Equation\"\u003e\n \u003cdiv class=\"mathdisplay\" id=\"FileID_Equc\" name=\"EquationSource\"\u003e\u003cimg src=\"https://myfiles.space/user_files/58895_8739fc6c57c1c19a/58895_custom_files/img1772203814.png\" width=\"470\" height=\"108\"\u003e\u003c/div\u003e\n \u003c/div\u003e\n \u003cp\u003ewhere Difference represents the observed\u0026ndash;counterfactual difference in deaths in year t, indicating the share explained by eradication (Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). This modeling framework also enabled estimation of year-specific gastric cancer deaths prevented by eradication from 2013 to 2021.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Data inputs\u003c/h2\u003e\n \u003cp\u003eAge-specific mortality, population structure, and gastric cancer incidence were obtained from national cancer statistics [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e] and vital statistics [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e] (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Annual eradication counts were derived from published literature [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e] and non-public regional datasets (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Model parameters related to screening adherence [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e], endoscopy accuracy [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e], eradication compliance [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e], eradication success [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e], and gastric cancer risk reduction with eradication [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e] were obtained from published studies (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eKey parameters used in the model\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eProbabilities\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProportion of gastric cancer cases attributable to \u003cem\u003eH. pylori\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdherence rate of endoscopy after eradication (age\u0026thinsp;\u0026ge;\u0026thinsp;50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAssumption\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdherence rate to current gastric cancer screening (age\u0026thinsp;\u0026ge;\u0026thinsp;50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdherence rate to endoscopy among screened individuals\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.196\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst-line eradication compliance rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.891\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst-line eradication success rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.901\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond-line eradication compliance rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.901\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecond-line eradication success rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.901\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastric cancer risk reduction with eradication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSensitivity of endoscopy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpecificity of endoscopy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage proportion of detected gastric cancer (screening)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI: 0.898, II: 0.054, III: 0.020, IV: 0,028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage-specific 5-year survival rate (I-IV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.960, 0.692, 0.419, 0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAnnual differences between observed and counterfactual gastric cancer deaths and deaths prevented by \u003cem\u003eH. pylori\u003c/em\u003e eradication, 2013\u0026ndash;2021.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYear\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eObserved gastric cancer deaths (a)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCounterfactual gastric cancer deaths (b)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDifference in gastric cancer mortality (b-a)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDeaths prevented by eradication (c)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAttributable proportion (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48,632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49,794\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1,162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47,904\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49,717\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1,813\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46,681\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49,589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2,908\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45,546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e49,310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3,764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45,227\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48,880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3,653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44,192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48,300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4,108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42,931\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47,569\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4,638\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42,319\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46,687\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4,368\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e361\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41,624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45,654\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4,030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e417\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e405,056\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e435,500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30,444\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1,427\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eEpidemiologic parameters related to gastric cancer progression were derived from national statistics [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e] and from prior long‑term modeling work evaluating the cumulative lifetime impact of eradication on gastric cancer mortality [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. Age-specific stage distributions for screened gastric cancer were incorporated using national cancer statistics [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e], and are consistent with evidence showing that younger patients typically present with more advanced disease and aggressive tumor biology [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e] (Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eAll data sources were harmonized to produce internally consistent age- and year-specific inputs. All modeling analyses were conducted using TreeAge Pro 2025 (TreeAge Software, Williamstown, MA).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Trends in observed and counterfactual mortality\u003c/h2\u003e \u003cp\u003eAnnual trends in the number of individuals undergoing \u003cem\u003eH. pylori\u003c/em\u003e eradication are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, demonstrating a rapid increase following the introduction of insurance coverage in 2013, followed by a gradual decline and recent plateau. Observed gastric cancer mortality decreased steadily from 48,632 deaths in 2013 to 41,624 deaths in 2021 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn contrast, the counterfactual mortality trajectory\u0026mdash;representing expected mortality if eradication uptake had remained at pre-2013 levels\u0026mdash;declined more slowly, from 49,794 deaths in 2013 to 45,654 deaths in 2021 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eThe divergence between observed and counterfactual mortality widened consistently over time, increasing from 1,162 deaths in 2013 to 4,030 deaths in 2021 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). This widening gap reflects the cumulative impact of expanded eradication uptake on national mortality trends.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Annual deaths prevented by eradication\u003c/h2\u003e \u003cp\u003eModel-based estimates indicated that the number of gastric cancer deaths prevented by eradication increased gradually throughout the study period. Deaths prevented rose from 17 in 2015\u0026mdash;when the earliest measurable effects of eradication became detectable\u0026mdash;to 417 in 2021, with a cumulative total of 1,427 deaths prevented during 2013\u0026ndash;2021 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eThe largest annual reductions were observed among adults aged 50\u0026ndash;79, consistent with both the age distribution of eradication uptake and the cohort-specific infection histories that shape gastric cancer risk (Figure \u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003eC).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Proportion of mortality reduction attributable to eradication\u003c/h2\u003e \u003cp\u003eThe proportion of the observed\u0026ndash;counterfactual mortality difference attributable to eradication increased steadily over time. This proportion rose from 0.6% in 2015 to 10.4% in 2021 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003eThis upward trend indicates that eradication has become an increasingly important contributor to Japan\u0026rsquo;s declining gastric cancer mortality, even within the relatively short nine-year period following nationwide insurance coverage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Summary of early population-level impact\u003c/h2\u003e \u003cp\u003eTogether, these findings demonstrate that:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003egastric cancer mortality in Japan is declining faster than expected under a no-expansion counterfactual\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eeradication has already prevented more than 1,400 deaths\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ethe contribution of eradication is increasing each year\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ethe strongest effects are concentrated in middle-aged and older adults, reflecting cumulative infection history and real-world uptake patterns\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThese results provide clear evidence that \u003cem\u003eH. pylori\u003c/em\u003e eradication is already shaping national gastric cancer trends during the early phase of its implementation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Interpretation of findings\u003c/h2\u003e \u003cp\u003eBy integrating a structured incidence reconstruction with a counterfactual mortality trajectory, this study clarifies the early, population‑level impact of Japan\u0026rsquo;s nationwide \u003cem\u003eH. pylori\u003c/em\u003e eradication strategy. Mortality declined more rapidly than expected beginning in 2015, and the divergence between observed and counterfactual mortality widened steadily through 2021. These findings indicate that eradication has already produced measurable reductions in gastric cancer deaths within the first decade of implementation, despite the long latency of gastric carcinogenesis. The strongest effects were observed among adults aged 50\u0026ndash;79, reflecting both the age distribution of eradication uptake and the cumulative infection histories that shape gastric cancer risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Structural epidemiologic implications\u003c/h2\u003e \u003cp\u003eThis study demonstrates the value of a two‑layer analytic framework that combines etiologic modeling with counterfactual evaluation. The multilayer incidence reconstruction captures the biological and historical determinants of gastric cancer risk\u0026mdash;age‑specific hazard, duration‑related exposure, and cohort‑specific infection prevalence\u0026mdash;providing a coherent representation of the causal pathway linking \u003cem\u003eH. pylori\u003c/em\u003e infection to cancer. The counterfactual layer isolates the contribution of eradication from background trends driven by ageing, cohort replacement, and long‑term declines in infection prevalence. Together, these components enable a causal interpretation of short‑term mortality changes that cannot be achieved through conventional trend‑based or before\u0026ndash;after analyses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Policy relevance\u003c/h2\u003e \u003cp\u003eJapan\u0026rsquo;s experience provides real‑world evidence that population‑based \u003cem\u003eH. pylori\u003c/em\u003e eradication can produce detectable mortality reductions within a relatively short timeframe. The alignment between eradication volume, early mortality reductions, and modeled deaths prevented supports the continued expansion of eradication as a primary prevention strategy. These findings are particularly relevant for high‑prevalence countries where gastric cancer remains a major cause of cancer mortality. As younger cohorts with lower infection prevalence gradually replace older, high‑risk cohorts, the relative contribution of eradication to national mortality trends may increase further. Integrating eradication with risk‑based screening strategies may accelerate progress toward reducing gastric cancer burden.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Comparison with conventional modeling and forecasting approaches\u003c/h2\u003e \u003cp\u003eUnlike conventional natural history models that rely on unobservable transition parameters, the present framework reconstructs incidence directly from etiologic determinants. This etiology‑based approach avoids assumptions about latent disease states and provides a transparent representation of the causal structure underlying gastric cancer risk. Forecasting‑based approaches, including ARIMA and interrupted time‑series regression [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], are valuable for projecting future trends but cannot isolate the causal impact of specific policy actions because they extrapolate past patterns without reconstructing counterfactual disease dynamics. In contrast, the combined modeling and counterfactual design used here quantifies the short‑term mortality reduction attributable specifically to real‑world eradication efforts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Strengths and limitations\u003c/h2\u003e \u003cp\u003eStrengths of this study include the use of a counterfactual framework aligned with real‑world policy structures, incidence reconstruction based on etiologic determinants, integration of age‑specific case fatality and eradication uptake, and quantification of both deaths prevented and the proportion of mortality decline attributable to eradication. Limitations include reliance on published case‑fatality estimates, assumptions regarding the stability of background risk factors in the counterfactual scenario, and the focus on short‑term effects without projecting long‑term outcomes. Temporal changes in non\u0026ndash;\u003cem\u003eH. pylori\u003c/em\u003e risk factors were not explicitly modeled, although their short‑term influence is unlikely to materially affect the estimates relative to the impact of eradication.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.6 Implications\u003c/h2\u003e \u003cp\u003eThis structured counterfactual analysis demonstrates that population‑based \u003cem\u003eH. pylori\u003c/em\u003e eradication can produce measurable reductions in gastric cancer mortality within a decade. The findings highlight the importance of integrating real‑world implementation patterns, etiologic determinants, and causal evaluation frameworks when assessing primary prevention strategies. More broadly, this study provides a complementary perspective to global analyses by emphasizing the role of historical implementation context and short‑term dynamics in shaping national cancer trends.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides clear evidence that population‑based \u003cem\u003eH. pylori\u003c/em\u003e eradication has already contributed to measurable reductions in gastric cancer mortality in Japan. By combining a structured etiologic modeling framework with a counterfactual evaluation of expected mortality in the absence of expanded eradication, the analysis clarifies how eradication is shaping national mortality trends during the early phase of its implementation. These findings demonstrate that primary prevention can yield detectable population‑level benefits within a decade, even for a cancer with a long natural history. Japan\u0026rsquo;s experience offers real‑world evidence of how systematic eradication can alter short‑term national cancer trajectories and provides a framework for evaluating early implementation effects in high‑prevalence settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e \u003cstrong\u003estatement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declares no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eA.K. contributed to the study concept and design, data acquisition and analysis, interpretation of the data, accepted responsibility for the integrity of the research process and findings, and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This research received no specific grant from any funding agency in the public, commercial, or not‑for‑profit sectors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003c/strong\u003e The author declares no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement: \u003c/strong\u003eThis study used publicly available, aggregated national statistics and did not involve human subjects; therefore, ethical approval was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e The author conceptualized the study, developed the model, conducted the analysis, validated the model, interpreted the results, drafted the manuscript, and revised the final version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCancer Information Service, National Cancer Center, Japan. Cancer registry and statistics. Available at: https://ganjoho.jp/reg_stat/statistics/stat/cancer/5_stomach.html. Accessed January 30, 2026.\u003c/li\u003e\n\u003cli\u003eIARC Helicobacter Working Group. Population-based \u003cem\u003eHelicobacter pylori\u003c/em\u003e screen-and-treat strategies for gastric cancer prevention: Guidance on implementation. IARC Working Group Report No. 12. Lyon, France: International Agency for Research on Cancer; 2025.\u003c/li\u003e\n\u003cli\u003eMatsuo T, Ito M, Takata S, et al. Low prevalence of \u003cem\u003eHelicobacter pylori\u003c/em\u003e-negative gastric cancer among Japanese. \u003cem\u003eHelicobacter\u003c/em\u003e. 2011;16:415\u0026ndash;419. https://doi.org/10.1111/j.1523-5378.2011.00889.x\u003c/li\u003e\n\u003cli\u003eWang C, Nishiyama T, Kikuchi S, et al. Changing trends in the prevalence of \u003cem\u003eH. pylori\u003c/em\u003e infection in Japan (1908\u0026ndash;2003): a systematic review and meta-regression analysis of 170,752 individuals. \u003cem\u003eSci Rep\u003c/em\u003e. 2017;7:15491.https://doi.org/\u003cu\u003e10.1038/s41598-017-15490-7\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eAsaka M, Kato M, Sakamoto N. Roadmap to eliminate gastric cancer with \u003cem\u003eHelicobacter pylori\u003c/em\u003e eradication and consecutive surveillance in Japan. \u003cem\u003eJ Gastroenterol\u003c/em\u003e. 2014;49(1):1\u0026ndash;8. https://doi.org/10.1007/s00535-013-0897-8\u003c/li\u003e\n\u003cli\u003eKowada A, Asaka M. Economic and health impacts of introducing \u003cem\u003eHelicobacter pylori\u003c/em\u003e eradication strategy into national gastric cancer policy in Japan: a cost-effectiveness analysis. \u003cem\u003eHelicobacter\u003c/em\u003e. 2021;26:e12837. https://doi.org/10.1111/hel.12837\u003c/li\u003e\n\u003cli\u003eKowada A. Cost-Effectiveness of Population-Based Helicobacter pylori Screening With Eradication for Optimal Age of Implementation. Helicobacter. 2024;29(4):e13120. https://doi.org/10.1111/hel.13120\u003c/li\u003e\n\u003cli\u003eAnderson RM, May RM. \u003cem\u003eInfectious Diseases of Humans: Dynamics and Control\u003c/em\u003e. Oxford: Oxford University Press; 1991.\u003c/li\u003e\n\u003cli\u003eClayton D, Schifflers E. Models for temporal variation in cancer rates. I: Age\u0026ndash;period\u0026ndash;cohort models. \u003cem\u003eStat Med\u003c/em\u003e. 1987;6(4):449\u0026ndash;467.\u003c/li\u003e\n\u003cli\u003eCutler DM, McClellan M. Is technological change in medicine worth it? \u003cem\u003eHealth Aff (Millwood)\u003c/em\u003e. 2001;20(5):11\u0026ndash;29.\u003c/li\u003e\n\u003cli\u003eRothman KJ, Greenland S, Lash TL. \u003cem\u003eModern Epidemiology\u003c/em\u003e. 3rd ed. Philadelphia: Lippincott Williams \u0026amp; Wilkins; 2008.\u003c/li\u003e\n\u003cli\u003eHern\u0026aacute;n MA, Robins JM. \u003cem\u003eCausal Inference: What If\u003c/em\u003e. Boca Raton: Chapman \u0026amp; Hall/CRC; 2020.\u003c/li\u003e\n\u003cli\u003eMoolgavkar SH, Holford TR, Levy DT, et al. Impact of reduced tobacco smoking on lung cancer mortality in the United States during 1975\u0026ndash;2000. \u003cem\u003eRisk Anal\u003c/em\u003e. 2009;29:483\u0026ndash;497. https://doi.org/10.1111/j.1539-6924.2008.01179.x\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare, Japan. Vital statistics. Available at: https://www.mhlw.go.jp/english/database/db-hw/vs01.html. Accessed January 30, 2026.\u003c/li\u003e\n\u003cli\u003eHowden CW, Cook EE, Swallow E, et al. Real-world outcomes associated with vonoprazan-based versus proton pump inhibitor-based therapy for Helicobacter pylori infection in Japan. Therap Adv Gastroenterol. 2023;16:17562848231168714. https://doi.org/10.1177/17562848231168714\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. Prefectural cancer screening rate 2022. National life foundation survey. Available at: https://www.mhlw.go.jp/toukei/saikin/hw/k-tyosa/k-tyosa22/index.html. Accessed January 30, 2026.\u003c/li\u003e\n\u003cli\u003eHamashima C, Okamoto M, Shabana M, et al. Sensitivity of endoscopic screening for gastric cancer by the incidence method. \u003cem\u003eInt J Cancer\u003c/em\u003e. 2013;133:653\u0026ndash;659. https://doi.org/10.1002/ijc.28065\u003c/li\u003e\n\u003cli\u003eMori H, Suzuki H, Omata F, et al. Current status of first- and second-line \u003cem\u003eHelicobacter pylori\u003c/em\u003e eradication therapy in the metropolitan area: a multicenter study with a large number of patients. \u003cem\u003eTher Adv Gastroenterol\u003c/em\u003e. 2019;12:1756284819858511. https://doi.org/10.1177/1756284819858511\u003c/li\u003e\n\u003cli\u003eFord AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut. 2020;69:2113\u0026ndash;2121. https://doi.org/10.1136/gutjnl-2020-320839\u003c/li\u003e\n\u003cli\u003eNational Cancer Center Japan. Cancer statistics in Japan 2025. Foundation for Promotion of Cancer Research; 2025. Available at: https://ganjoho.jp/public/qa_links/report/statistics/2025_en.html. Accessed January 30, 2026.\u003c/li\u003e\n\u003cli\u003eCheng L, Chen S, Wu W, Zhuang Q, et al. Gastric cancer in young patients: a separate entity with aggressive features and poor prognosis. J Cancer Res Clin Oncol. 2020;146:2937\u0026ndash;2947. https://doi.org/10.1007/s00432-020-03268-w\u003c/li\u003e\n\u003cli\u003eGuan WL, Yuan LP, Yan XL, et al. More attention should be paid to adult gastric cancer patients younger than 35 years old: extremely poor prognosis was found. J Cancer. 2019;10:472\u0026ndash;478. https://doi.org/10.7150/jca.27517\u003c/li\u003e\n\u003cli\u003eBernal JL, Cummins S, Gasparrini A. Interrupted time series regression for the evaluation of public health interventions. \u003cem\u003eInt J Epidemiol\u003c/em\u003e. 2017;46(1):348\u0026ndash;355. https://doi.org/10.1093/ije/dyw098\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"population-health-metrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pohm","sideBox":"Learn more about [Population Health Metrics](http://pophealthmetrics.biomedcentral.com/)","snPcode":"12963","submissionUrl":"https://submission.nature.com/new-submission/12963/3","title":"Population Health Metrics","twitterHandle":"@PHMjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Helicobacter pylori, eradication, gastric cancer, mortality, counterfactual analysis","lastPublishedDoi":"10.21203/rs.3.rs-8750837/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8750837/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGastric cancer has historically been driven by long‑standing \u003cem\u003eHelicobacter pylori\u003c/em\u003e infection. The nationwide expansion of \u003cem\u003eH. pylori\u003c/em\u003e eradication therapy beginning in 2013 created a unique opportunity to evaluate its population‑level impact on gastric cancer mortality. However, compared with long-term effects, short‑term mortality trends following eradication are difficult to interpret because they reflect overlapping influences of ageing, cohort replacement, and cumulative infection history, all of which vary by year. This study aimed to provide a causal, population‑level assessment of the early impact of eradication during the first decade of nationwide implementation.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe applied a two‑layer analytic framework consisting of a counterfactual analysis comparing observed mortality during 2013\u0026ndash;2021 with expected mortality had eradication uptake remained at pre‑2013 levels, combined with a structured, time‑dependent, multilayer state‑transition model. To estimate annual deaths prevented and the proportion of mortality reduction attributable to eradication, the model integrated age‑specific biological hazard, cumulative infection history, cohort‑specific \u003cem\u003eH. pylori\u003c/em\u003e prevalence, and annual changes in eradication uptake.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eObserved gastric cancer mortality declined from 48,632 deaths in 2013 to 41,624 deaths in 2021, whereas counterfactual mortality declined more modestly, from 49,794 to 45,654 deaths. The divergence between observed and counterfactual mortality steadily widened from 1,162 deaths in 2013 to 4,030 deaths in 2021. Model‑based estimates indicated that eradication prevented 1,427 deaths during 2013\u0026ndash;2021, with annual deaths prevented increasing from 17 in 2015 to 417 in 2021, particularly among adults aged 50\u0026ndash;79, who showed the most pronounced early benefit reflecting cumulative infection history and real-world uptake patterns.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe early population‑level impact of \u003cem\u003eH. pylori\u003c/em\u003e eradication has already contributed to a 10.4% reduction in gastric cancer mortality by 2021. These findings provide real‑world evidence of how primary prevention can shape short‑term national cancer trends. This provides a framework that may guide prevention strategies in high‑prevalence settings seeking to evaluate early implementation effects.\u003c/p\u003e","manuscriptTitle":"Early Population-Level Impact of Helicobacter pylori Eradication on Gastric Cancer Mortality in Japan: A Counterfactual Analysis of Short-Term Divergence","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 15:01:46","doi":"10.21203/rs.3.rs-8750837/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-08T02:33:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-14T22:13:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25929726698139878857037814264473106248","date":"2026-03-12T11:07:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-09T13:55:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223606260806482687928401999995356058318","date":"2026-03-09T09:26:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-25T02:53:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-05T11:49:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-05T11:48:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Population Health Metrics","date":"2026-01-31T14:54:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"population-health-metrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pohm","sideBox":"Learn more about [Population Health Metrics](http://pophealthmetrics.biomedcentral.com/)","snPcode":"12963","submissionUrl":"https://submission.nature.com/new-submission/12963/3","title":"Population Health Metrics","twitterHandle":"@PHMjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1ad42046-f431-4121-9b1b-fb02d7ee4e43","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-25T13:38:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-27 15:01:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8750837","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8750837","identity":"rs-8750837","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}