The authors have declared that no competing interests exist.
¶ The complete membership of the author group can be found in the acknowledgments.
Regional variations in gastric cancer incidence are not explained by prevalence of
We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile: Antofagasta (lower rate) and Valdivia (higher rate). Participants were 1–69 years old and provided interviews and blood for anti-
The prevalence of
The ENIGMA study in Chile contributes to better understanding regional variations in gastric cancer incidence and provides essential information for public health interventions.
Gastric cancer (GC) causes almost 800,000 yearly deaths worldwide, and despite declining trends, disease burden will not decline for decades because of population growth and aging [
The main risk factor for GC is chronic
Prevalence of
Considering the etiologic link between
Gastric atrophy is recognized as a critical step in the Correa pathway to intestinal-type gastric cancer, with consistent associations with gastric cancer, and it can be used as a surrogate of gastric cancer risk in population-based studies [
The ENIGMA (Epidemiological iNvestigatIon of Gastric MAlignancies) studies are a series of global prevalence surveys coordinated by IARC in high- and low-risk areas of GC. We are conducting population-based studies with standardized questionnaire data, biological specimens and laboratory procedures to describe worldwide epidemiology of
We selected two regions in Chile with different rates of GC mortality: 31.2 in Valdivia vs. 10.9 in Antofagasta in both sexes. Antofagasta is in the North with dry weather and more affluent economy and Valdivia is in the South with a rainy climate and less affluent population.
According to the ENIGMA protocol, in each area, age- and sex-stratified population-based samples were selected. The reference population were residents of the cities of Antofagasta and Valdivia aged 1 to 69 years old (25 men and 25 women in each 5-year age group). In each city, groups of socio-economically homogeneous blocks were defined, in numbers proportional to the total of blocks in each conglomerate. In a first phase, blocks were randomly selected within each conglomerate. In a second phase, systematic selection of households was carried out within selected blocks, initiating the count at the South-East corner of each block and contacting every third house. In a third phase individuals were chosen within households according to eligibility (see below).
In Antofagasta, the sampling frame was the entire city while in Valdivia it was the Barrios Bajos Sector, representing the city’s socio-economic diversity. Recruitment staff and interviewers were trained by Catholic University team and IARC researchers. In Antofagasta, recruitment was performed by advanced students from the Health Sciences Faculty of the University of Antofagasta, supported by educators in Obstetrics, Medical technologies and Nutrition. In Valdivia, nurse aides with population survey experience carried out recruitment. Recruitment period was from 10 May 2014 to 11 August 2015. Refusers were replaced until the required sample size of ~700 subjects in each site was obtained.
The study was approved by Ethics Committee of IARC (IEC No.14-17), the Ethics and Scientific Committe of the Faculty of Medicine of Pontificia Universidad Católica de Chile. [Comité Etico Científico de la Facultad de Medicina, Santiago, Chile] and the Ethics and Scientific Committe of the Comquimbo Health Service Direction, La Serena Chile [Comité Etico Científico de la Dirección de Servicio de Salud Coquimbo (La Serena, Chile)].
Eligible adults signed informed consent. Children between 12 and 18 provided informed assent and parental informed consent, and for children under 12 only parental informed consent was obtained.
Eligibility criteria included mental and physical competence and no history of GC. All procedures were conducted at home. A questionnaire was administered including socio-demographic and occupational information, educational level, smoking, medical history, medication use, diet (food frequency), alcohol consumption, exposure to pesticides in addition to standardized anthropometric measurements. Blood (20 ml) was collected and serum, plasma and buffy coats aliquots produced. Urine and faecal samples were also collected for future studies.
Anti-
Among participants over 40 years (n = 616), we conducted additional analyses of
The Helicoblot 2.1 immunoblot kit (Genelabs Diagnostics, Singapore) was performed at Bordeaux University, France to detect IgG antibodies against specific proteins of
Pepsinogens I and II were blindly measured with a latex-agglutination test-system (Eiken Chemical, Tokyo, Japan) at University of Latvia. The cut-off value for pepsinogens considered to be associated with any gastric mucosal atrophy was PgI ≤70 ng/ml and PgI/PgII ≤3 while PgI ≤30 ng/ml and PgI/PgII ≤2 was considered marker of severe atrophy, according to manufacturer’s reference values and previous validation by Dr Leja and collaborators [
For all age groups, demographic characteristics and
The factors associated with the Valdivia study site and atrophy were compared using univariable and multivariable logistic regression models to estimate odds ratios (ORs) and 95% CIs. These variables included
(a) Flow diagram of field work in Antofagasta. *Empty houses or no contact after several attempts. **Not eligible includes 37 subjects who did not fulfil the eligibility criteria and 70 subjects who were enumerated but not recruited because the required numbers for the corresponding categories of sex and age were already enrolled. (b) Flow diagram of field work in Valdivia. *Empty houses or no contact after several attempts. ** Not eligible includes 33 subjects who did not fulfil the eligibility criteria and 170 subjects who were enumerated but not recruited because the required numbers for the corresponding categories of sex and age were already enrolled.
Considering all ages, the sample was balanced by age group, but Antofagasta had proportionally more women than Valdivia (
Overall age-adjusted
Study site | |||||
---|---|---|---|---|---|
Antofagasta | Valdivia | ||||
N = 690 | (95% CI) | N = 705 | (95% CI) | ||
N (%) | N (%) | ||||
Positive | 432 (67) | (63–71) | 434 (63) | (60–67) | |
Negative | 211 (33) | (29–37) | 250 (37) | (33–40) | |
Missing | 47 | 21 | |||
58 | [51–69] | 56 | [49–66] | ||
Women | 57 | [48–70] | 53 | [45–62] | |
Men | 59 | [50–69] | 58 | [49–70] |
† Based on the Segi World Standard (Segi M, Kurihara M. Cancer mortality for selected sites in 24 Countries no. 6 (1966–1967) Nagoya, Japan Cancer Society; 1972).
In Antofagasta, but not in Valdivia,
Seroprevalence of
The first two columns present the prevalence for each site, the right part of the graph presents the adjusted odds ratio for that variable in the high-risk vs low risk site.
Prevalence of atrophy and severe atrophy, as determined by PgI and II levels, showed a significant difference between the two sites. Atrophy prevalence was significantly higher in the high risk region (31% vs 21%,
* Pepsinogens I and II were measured with a latex-agglutination test-system (Eiken Chemical, Tokyo, Japan) and cut off values for any gastric mucosal atrophy were PgI≤70 ng/ml and PgI/PgII≤3.
In a multivariate model of risk factors associated with atrophy (including severe atrophy) combining both sites, atrophy was positively associated with being from Valdivia, daily consumption of chili pepper and detection of antibodies against CagA while negatively associated with higher educational level (
This is the first of a series of IARC international prevalence surveys to clarify the epidemiology of
We observed a very similar seroprevalence of
Overall,
In the 40+ year age group, the most likely to explain current rates of GC, we compared prevalence of
Among the interesting findings regarding differences in risk factors between the two sites was consumption of non-green vegetables, which was more common in the low risk area, but there were no significant differences for consumption of other vegetables and fruits. In the Chilean National Health Survey of 2009–2010, consuming at least five portions of fruit and vegetables daily was 32.5% in Antofagasta compared to 1.4% in the Valdivia region, but daily portions of fruits and vegetables was not significantly different by region [
Consumption of chili products was more common in the high risk area. Chili has been proposed as a direct irritant of the gastric mucosa but studies have been inconsistent on potential benefits or harms of its active principle capsaicin [
Alternatively, chili could be contaminated with aflatoxins as has been demonstrated for some chili products in Chile [
Contrary to our expectations, addition of salt at the table was more common in Antofagasta, the low risk area. However, salt intake is a particularly challenging variable for dietary assessment given large intraindividual variation and discretionary use, often not adequately captured [
We explored gastric atrophy as measured by reductions in the PgI/PgII ratio. Despite limited sensitivity and specificity for disease detection [
The strengths of our study include recruitment of population-based samples by invitation, preventing selection based on symptoms or attendance to clinics. We used standardized methods for interviewing, specimen collection and laboratory procedures. These methods will also be used in subsequent ENIGMA studies in other countries permitting direct comparison and pooling of results.
Among study limitations, participation rates were lower in Valdivia because of idiosyncratic characteristics plus logistic and climatic reasons. Another limitation is that the difference in GC incidence between the two sites may not be sufficiently large to detect the differences in exposure to risk factors explaining it. We also had small numbers for some analyses and did not have biopsy materials to study the prevalence of histologically confirmed preneoplastic lesions or the
In conclusion, we found no differences in the prevalence of
(PNG)
(DOCX)
(DOCX)
(DOCX)
(DOCX)
(CSV)
(XLS)
Dr Paula González, our beloved colleague and leader of cancer research in Latin America passed away before the submission of the final version of this manuscript. Rolando Herrero accepts responsibility for the integrity and validity of the data collected and analyzed.
We thank Drs Sabina Rinaldi and Maria de la Luz Hernandez for their input and support in
PONE-D-19-35057
Regional variations in Helicobacter pylori infection, gastric atrophy and gastric cancer risk: the ENIGMA study in Chile
PLOS ONE
Dear Dr Herrero,
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Reviewer #1: The authors have conducted a survey of H. pylori infection in Chile using conventional methods. Importantly, this prevalence estimates a structured population sample rather than simply controls from a case-control study or other continence sample. Overall the prevalence data on Hp seropositivity and the virulence factors was valuable. The cut points used for the presence of atrophy are OK, but it would be much better to see the actual distributions of PG1, PG2, and the PG ratio in the two communities after standardization for age sex differences in the samples. The atrophy cut points are not optimized for assessing gastric cancer risk, the main purpose of their inclusion here.
Overall, I found much of the presentation extraneous to the stated core goal of the project – the seroprevalence of Hp, CagA, VacA, and Pepsinogen. Drawing conclusions about potential dietary risk factors diminished the focus on what is most valuable about the project.
ABSTRACT
The two sentences of background in the abstract are contradictory. They properly state that the rates of gastric cancer don’t follow prevalence estimates, but then state they do the survey to explain regional differences in gastric cancer risk. The prevalence is important whether it directly explains the rates or not. According to the intro, the rates of GC in Valdivia and Antofagasta (in men) are 33.1 and 21.2, respectively. That isn’t approximately two-fold different as written, although the mortality rate is nearly 3-fold different.
• Please be more specific than ‘virulence factors’ in the methods
• Age standardized to what?
• The comments on dietary factors are supposed to inform the prevalence of Hp, gastric atrophy, or gastric cancer?
• Not clear if they create a single model for assessing risk factors for atrophy across Chile and if they did, does geographic location remain a risk factor?
The first sentence of the conclusion doesn’t seem to be paired to the data presented in the results and it isn’t clear what ‘regional variation’ refers to, gastric cancer or atrophy?
Drawing any conclusions about novel risk factors for gastric cancer, such as chili peppers, from this modest study seems a bit much in the abstract.
The abstract doesn’t present any data on prevalence! I thought that was the primary goal of the study?
MAIN TEXT
H. pylori seropositivity is highly dependent on the senstivitiy of the test. This is less important when making risk estimates comparing case and controls within a population, but here it seems all important given that event6ually they will be comparing these rates to other populations (Page 14 “This is the first of a series of IARC international prevalence surveys.”) An independent assessment of Hp would be really helpful here because there is no guarantee the test will work the same in other parts of the world that have different strains of Hp. Can the authors point to any data on the sensitivity of the Biohit test in Chilean people? It was reassuring that the Eiken and Biohit values are similar.
I am not sure how to interpret the prevalence odds ratios used in figure 3. It seems it would be simpler to just present a table of a figure with the point estimate for each location and then some measure on uncertainty around the prevalence estimate. Or maybe just the net difference in the prevalence? I also don’t know what it means to have an adjusted OR for, example, of chili intake. Chili consumption if ~5-fold more common in Valdivia (24%) than in Antofagasta (5%), so what does the OR of 8.6 mean and in what sense did the other factors in table 3 confound the chili intake estimate?
The prevalence of atrophy seems to parallel the incidence of gastric cancer quite nicely for both the lower and more stringent cut point. It would be nice if the authors showed us all values (and ratios ) for the two areas for GC incidence, GC mortality, Hp positvity, CagA, VacA, Pep1, Pep2, and PG ratio, and atrophy in a single table
Page 14, line 302 – please don’t use the term ‘developed countries’ with out a modifier such as economically-developed countries.
I don’t understand this conclusion on page 18 drawn from the analysis presented in figure 5. “…one of the main risk factors for atrophic gastritis is consumption of chili pepper.” An OR of 1.97 and a prevalence of 22% in cases seems like a modest association in a single study. In fact, chili pepper consumption would have no individual level predictive value for whether or not an individual has atrophy. In fact, lack of education has a stronger association (OR of almost 3) and the same prevalence. Why was CagA included rather than the whole cell Hp antibody? I don’t see any evidence that CagA was more predictive that just seropositivity. In some previous studies, disease risk is greatest in those that are CagA positive and whole cell negative, but it doesn’t seem that was explored here.
Finally, an established risk factor for gastric cancer, tobacco seems to be missing from the results. The methods noted that smoking was collected so it should be included in the report.
Reviewer #2: This is an ecologic study of Helicobacter pylori, gastric atrophy, selected aspects of diet and gastric from two areas of Chile with different gastric cancer mortality.
The only consistent finding is higher atrhopy in the high risk area. The others, with the exception of vegetable consumption, are difficult to explain.
Given the limitations of the study design, their interpretation therefore, should be more cautious.
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7 April 2020
Eric J Duell
Academic Editor
PLOS ONE
PONE-D-19-35057
Regional variations in Helicobacter pylori infection, gastric atrophy and gastric cancer risk: the ENIGMA study in Chile
Dear Dr Duell:
Thanks for the careful review of our manuscript and request for revisions. Please find below our responses to the Editor and reviewers’ comments
Editor’s comment:
The weaknesses of the ecologic study design should be clearly stated in the discussion (e.g., that areas are the unit of analysis, and that the individuals with Hp information are not the same individuals with gastritis or gastric cancer within the study areas). Ecologic studies may help to define hypotheses that can then be tested using analytic (observational) study designs with individual-level data. Interventions would only be considered after analytic studies, so the final sentence of the Discussion should be revised accordingly.
The Editor’s suggestion has been considered and the following text has been added to the discussion: ‘In addition, this is an ecologic study where the areas are the unit of analysis and the study participants are not the same individuals with gastric cancer in the population. Therefore, the associations described should be considered hypothesis-generating and need to be corroborated in individual-based longitudinal studies.’
Journal requirements
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The manuscript and tables have been prepared following PLOS ONE’s style requirements, including those for file naming
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We have included more details in the methods section about the questionnaire and submitted the actual questionnaire in English and Spanish as supporting documentation
3. Thank you for including your ethics statement: The study was approved by IARC Ethics Committee (IEC No.14-17) and local ethical committees (Comité Ética de la Investigación, Escuela de Medicina Pontificia Universidad Católica de Chile, Comité de Ética Zona Norte, Servicio de Salud Coquimbo). Eligible adults signed informed consent. Children between 12 and 18 provided informed assent and parental informed consent, and for children under 12 only parental informed consent was obtained. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.
The ethics statement has been modified to include the full name of the IRBs that approved our study.
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The modified text has been added to the Ethics Statement
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The authors and affiliations have been moved to the acknowledgements section and the team leader and her email are now indicated
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We have removed the reference to Data not shown, it is not necessary.
6. Thank you for stating the following in the Competing Interests section: "The authors have declared that no competing interests exist." We note that one or more of the authors are employed by a commercial company: International Agency for Research on Cancer and Advanced Center for Chronic Diseases.
None of these organizations are commercial companies. IARC is a research agency of the World Health Organization and as such it is a United Nations institution. The Advanced Center for Chronic Diseases, ACCDiS, is a research center publicly funded by the Chilean Government, after a national competition, the Direction is shared by the two main research Universities in Chile: University of Chile, and Pontificia Universidad Católica de Chile, both public non-for-profit organizations.
a. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.
There is no commercial affiliation as described above
b. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors
As described in a. there are no commercial organizations involved
Reviewers' comments:
……
Review Comments to the Author
Reviewer #1: The authors have conducted a survey of H. pylori infection in Chile using conventional methods. Importantly, this prevalence estimates a structured population sample rather than simply controls from a case-control study or other continence sample. Overall the prevalence data on Hp seropositivity and the virulence factors was valuable.
We appreciate the positive comment of the reviewer
The cut points used for the presence of atrophy are OK, but it would be much better to see the actual distributions of PG1, PG2, and the PG ratio in the two communities after standardization for age sex differences in the samples.
We have included in the text a description of the mean values of the PG1/PG2 ratios, indicating that there were no differences by sex (table below for the reviewers)
Antofagasta Valdivia
N=297 N=308
Pepsinogen mean(SD) mean(SD) P values1
PGI 71.0 (44.5) 67.4 (43.2) 0.318
PGII 20.1 (13.0) 21.2 (13.3) 0.321
Ratio 4.0 (1.8) 3.6 (1.8) 0.008
1 Student t-test
Women Men
N=354 N=264
Pepsinogen mean(SD) mean(SD) P values1
PGI 71 (46.7) 66.6 (39.5) 0.2164
PGII 21.3 (14.5) 19.7 (10.9) 0.1193
Ratio 3.8 (1.9) 3.7 (1.7) 0.519
1 Student t-test with unequal variances
2 Student t-test with equal variances
The atrophy cut points are not optimized for assessing gastric cancer risk, the main purpose of their inclusion here.
We agree with the reviewer that the atrophy cutpoints are not aimed at directly estimating gastric cancer risk. Instead, they are generally accepted cutoffs to indicate the presence of gastric atrophy, which in this context represents a surrogate marker of gastric cancer risk, given the known association of atrophy with risk of gastric cancer. Additional text has been included in the discussion to clarify this aspect, as follows: ‘We explored gastric atrophy as measured by reductions in the Pg1/Pg2 ratio. Despite limited sensitivity and specificity for disease detection [42], Pgs are strongly associated with prospective GC risk [43] and in the context of this ecologic study we consider them as surrogate markers of gastric cancer risk.’
Overall, I found much of the presentation extraneous to the stated core goal of the project – the seroprevalence of Hp, CagA, VacA, and Pepsinogen. Drawing conclusions about potential dietary risk factors diminished the focus on what is most valuable about the project.
We accept the suggestion of the reviewer. Throughout the paper and following the other comments and the observation of the other reviewer, we are now emphasizing more the findings about prevalence and the differences in atrophy between the two centers than the dietary associations.
ABSTRACT
The two sentences of background in the abstract are contradictory. They properly state that the rates of gastric cancer don’t follow prevalence estimates, but then state they do the survey to explain regional differences in gastric cancer risk. The prevalence is important whether it directly explains the rates or not.
We accept the critique and modified the description of the aims as follows: ‘The IARC worldwide H. pylori prevalence surveys (ENIGMA) aim at systematically describing age and sex-specific prevalence of H. pylori infection around the world and generating hypotheses to explain regional variations in gastric cancer risk’. We think this removes the contradiction described by the reviewer.
According to the intro, the rates of GC in Valdivia and Antofagasta (in men) are 33.1 and 21.2, respectively. That isn’t approximately two-fold different as written, although the mortality rate is nearly 3-fold different.
This has been modified to avoid the inconsistency and now reads: We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile.
Please be more specific than ‘virulence factors’ in the methods
We have modified the sentence and now it mentions the specific virulence factors tested for.
Age standardized to what?
To the world population, as described in the statistical methods. Modified in the abstract for clarity.
The comments on dietary factors are supposed to inform the prevalence of Hp, gastric atrophy, or gastric cancer?
It is meant to inform gastric cancer differences in the context of the ecological analysis. It was modified to read: ‘The comparison of the prevalence of known and potential cofactors of H pylori in gastric carcinogenesis between the high and the low risk area showed that consumption of chili products ….’ There is also a new section in the discussion where we discuss the ecologic nature of the study as a limitation, as proposed by the Editor.
Not clear if they create a single model for assessing risk factors for atrophy across Chile and if they did, does geographic location remain a risk factor?
Correct, we created a single model to assess risk factors for atrophy across Chile (figure 5), and geographic location remained a risk factor associated with an OR of 1.67 (95%CI=1.1-2.5). A clarification was added to the abstract.
The first sentence of the conclusion doesn’t seem to be paired to the data presented in the results and it isn’t clear what ‘regional variation’ refers to, gastric cancer or atrophy?’
This sentence was modified and does not use the phrase ‘’regional variation’’ anymore and is now more consistent with the data presented. Now it reads: ‘The prevalence of H. pylori infection and its virulence factors was similar in the high and the low risk area, but atrophy was more common and occurred at younger ages in the higher risk area’.
Drawing any conclusions about novel risk factors for gastric cancer, such as chili peppers, from this modest study seems a bit much in the abstract.
We modified the conclusion in the abstract to say just ‘dietary factors’, reducing the emphasis on chili pepper’. There is also additional paragraph in the discussion about the interpretation of the findings in an ecologic study.
The abstract doesn’t present any data on prevalence! I thought that was the primary goal of the study?
We now include more details about the prevalence of H pylori in the abstract as follows: ’H. pylori seroprevalence (age-standardized to world population) and antibodies against CagA and VacA were similar in both sites. H. pylori seroprevalence was 20% among children <10 years old, 40% among 10-19 year olds, 60% in the 20-29 year olds and close to or above 80% in those 30+ years’.
H. pylori seropositivity is highly dependent on the sensitivity of the test. This is less important when making risk estimates comparing case and controls within a population, but here it seems all important given that event6ually they will be comparing these rates to other populations (Page 14 “This is the first of a series of IARC international prevalence surveys.”) An independent assessment of Hp would be really helpful here because there is no guarantee the test will work the same in other parts of the world that have different strains of Hp. Can the authors point to any data on the sensitivity of the Biohit test in Chilean people? It was reassuring that the Eiken and Biohit values are similar.
Thanks for this important comment given the aim of the ENIGMA study is to compare seroprevalence between countries. We consider that using the same methodology offers advantages for standardization of results from country to country making them comparable. However, validation of serologic assays with local antigens has been proposed for use of serology in the clinical context. In our view, this could introduce additional variability and validation of the method in each country is at this point out of the scope of the ENIGMA studies. The ELISA method we used is based on multiple antigens from the bacterium and has been used in many epidemiologic studies in various populations. In addition, the concordance of our results between the ELISA and the Western Blot, which use antigens of different sources are reassuring as indicated by the reviewer. Additional text has been added in the discussion as part of the potential limitations of our study as follows: ‘The ELISA assay in this study (Biohit) is a standardized test based on purified H. pylori antigens that has been used in multiple studies. Although the use of local antigens is recommended to assure the validity of serologic methods in clinical practice, in ENIGMA we are using the same test in the different study sites to assure standardization. The fact that the results of the Western Blot test were comparable to those of the ELISA is reassuring in this regard.’
I am not sure how to interpret the prevalence odds ratios used in figure 3. It seems it would be simpler to just present a table of a figure with the point estimate for each location and then some measure on uncertainty around the prevalence estimate. Or maybe just the net difference in the prevalence?
Figure 3 is an effort to summarize the information: the first two columns present the prevalence for each site, the right part presents the adjusted odds ratio for that variable in the high-risk vs low risk site. We clarify this now in the footnote of the figure 3.
I also don’t know what it means to have an adjusted OR for, example, of chili intake. Chili consumption if ~5-fold more common in Valdivia (24%) than in Antofagasta (5%), so what does the OR of 8.6 mean and in what sense did the other factors in table 3 confound the chili intake estimate?
All significant factors were included in the logistic model, and we retained those significantly associated to the high-risk area. The adjusted OR was not similar to the unadjusted prevalence ratio because there were several variables that when included in the model made the association of chili pepper to Valdivia more evident and improved the fit. The OR of 8.6 indicated that if we take into account the effect of other variables and their correlations, the odds of consuming chili are much higher if you are from Valdivia. We added in the discussion that chili consumption is a typical element of the diet in Sothern CHile
The prevalence of atrophy seems to parallel the incidence of gastric cancer quite nicely for both the lower and more stringent cut point. It would be nice if the authors showed us all values (and ratios ) for the two areas for GC incidence, GC mortality, Hp positvity, CagA, VacA, Pep1, Pep2, and PG ratio, and atrophy in a single table
Thanks for the suggestion. The information about each indicator is presented in the different sections of the article following an order that we consider logical based on the importance of the markers. Including another table with the summarized information would be repetitive. On the other hand, removing the other tables where the information is now presented and using only one table is a possibility but that would somehow alter the flow of the text. We prefer to keep it the way it is now but we are totally open to changing based on the reviewer and editor’s recommendation.
Page 14, line 302 – please don’t use the term ‘developed countries’ without a modifier such as economically-developed countries.
The sentence was modified and the term was replaced by high-income countries.
I don’t understand this conclusion on page 18 drawn from the analysis presented in figure 5. “…one of the main risk factors for atrophic gastritis is consumption of chili pepper.” An OR of 1.97 and a prevalence of 22% in cases seems like a modest association in a single study. In fact, chili pepper consumption would have no individual level predictive value for whether or not an individual has atrophy. In fact, lack of education has a stronger association (OR of almost 3) and the same prevalence.
We have modified the discussion to include more details about the different factors associated with atrophy and de-emphasized the chili pepper finding as a novel association that requires further exploration.
Why was CagA included rather than the whole cell Hp antibody? I don’t see any evidence that CagA was more predictive that just seropositivity. In some previous studies, disease risk is greatest in those that are CagA positive and whole cell negative, but it doesn’t seem that was explored here.
The whole cell Hp antibody was included in the model but it was not associated with risk of atrophy, while CagA was associated. We now explain this in more detail in the results section.
Finally, an established risk factor for gastric cancer, tobacco seems to be missing from the results. The methods noted that smoking was collected so it should be included in the report.
In Chile, tobacco is expensive and low-income people (who are a high-risk group for GC) smoke less than higher income people, thus smoking is always confounded by age, sex and socioeconomic status. Current smoking was more common in Valdivia (34% vs 25%), but the association was not significant in the adjusted model. It was also not associated with atrophy in the adjusted model. We have added details of these findings in the text
Reviewer #2: This is an ecologic study of Helicobacter pylori, gastric atrophy, selected aspects of diet and gastric from two areas of Chile with different gastric cancer mortality.
The only consistent finding is higher atrophy in the high risk area. The others, with the exception of vegetable consumption, are difficult to explain.
Given the limitations of the study design, their interpretation therefore, should be more cautious.
Based on this comment and those of the other reviewer, we are now giving more importance to the finding in relation to atrophy than the dietary factors and have added several caveats about the interpretation of the findings in an ecologic study.
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Regional variations in Helicobacter pylori infection, gastric atrophy and gastric cancer risk: the ENIGMA study in Chile
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Regional variations in Helicobacter pylori infection, gastric atrophy and gastric cancer risk: the ENIGMA study in Chile
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