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Sex difference in incidence of gastric cancer: an international comparative study based on the Global Burden of Disease Study 2017

Objectives To investigate sex difference in global gastric cancer incidence by year, age and socioeconomical status. Design An international comparative study. Setting We obtained the global and national sex-specific incidence of gastric caner by year and age from the Global Burden of Disease Study 2017. The human development index (HDI) in 2017 as an indicator of national socioeconomical status was extracted from the Human Development Report. Main outcome measures Sex-specific incidence of gastric cancer was compared by year and age at the global level. Linear regression analyses were performed to explore socioeconomic-associated sex difference in gastric cancer incidence. Results Despite declining incidence of global gastric cancer in both sexes between 1990 and 2017, relative sex difference showed an increasing trend, with male to female ratios of age-standardised incidence rates (ASRs) rising from 1.86 to 2.20. Sex difference was almost negligible under 45 years of age and relative difference maximised in the age range of 65–69 years with male to female ratios of ASRs being 2.74. Both absolute sex difference (standardised β=0.256, p<0.001) and relative difference (standardised β=0.387, p<0.001) in ASRs were positively associated with HDI. Conclusions This study revealed that decreasing incidence of global gastric cancer was accompanied by widening sex difference in the past few decades. Men always had higher incidence than women. Greater sex difference was found in older age and in more developed countries. These findings highlight the importance of making sex-sensitive health policy to cope with the global gastric cancer burden.


GENERAL COMMENTS
The investigators evaluated gender difference in global gastric cancer incidence by year, age, and socioeconomic status (SES) using data from the Global Burden of Disease Study from 1990 to 2017. They also used the human development index (HDI) of 2017 as an indicator of national SES. ASRs were downloaded directly from the GBD Results Tool. This research has merits as new evidence indicates a change in the stomach cancer rates by sex among younger populations in the US. The manuscript provides interesting results and suitable for the scope of BMJ Open subject to minor revisions: -The use of "gender" instead of "sex"the GBD has not published information on gender. He authors describe "sex" differences (i.e., make to female differences) -It will be informative to add a brief description of the population used to do the standardization, despite the citations provided.
-Explore/explain the data for younger populations (

GENERAL COMMENTS
This is an interesting and well analyzed paper looking at international registry data to investigate the differences in global gastric cancer incidence by sex, year, age and SES. The dataset used was from the Global Burden of Disease Study 2017. SES was estimated using the 2017 Human Development Report which provides a composite index representing life expectancy, education, and per capita income indicators. Some minor points: 1. The use of the word "gender" should be replaced with the word "sex". The word "sex" is objective while the word "gender" is a fluid social construct. If you notice in the report entitled "Findings from the Global Burden of Disease Study 2017" the word gender is never used.

2.
Under "Patients and Public Involvement", it might be good to clarify that no "identifiable" patients were used. 3.
The use of "95% uncertainty interval" should be replaced with "95% confidence interval". 4. Table 1 would be more readily interpretable if year was the stratification factor (columns) and the table was divided into Incidence and ASR (rows). Adding risk ratios (95% confidence interval) to compare time periods would also be helpful. Similarly, risk ratios (95% confidence interval) would be helpful in Table 2. Risk ratios would also be more readily interpretable than Z statistics (line 136). In addition, if allowed, I think the tables would be appropriate for the manuscript itself rather than as a supplement. 5.
In the discussion the authors state that "males may seek health care more frequently and benefit more from the progress in gastric cancer screening" (line 165). Referencing a study that shows men present with earlier stage gastric cancer than women would strengthen this statement. Also, information about how this changes incidence rates overall would be helpful since, take alone, lead time bias doesn't change incidence rates unless indolent disease is found. 6.
The clause "As known to all" in line 172 must be changed to something more appropriate, for example, "Studies have shown". 7.
A STROBE checklist is not attached. Based on the journals' questions, it appears that a STROBE checklist is needed. Overall, I thought this was an informative study looking at demographic differences in gastric cancer worldwide. The manuscript could benefit with another edit for grammar/syntax to fix some small errors, but is otherwise is well written. Some minor changes to the tables and the addition of risk ratios would make the tables more informative. More substantial changes are not needed.

VERSION 1 -AUTHOR RESPONSE
Reviewer 1 Comment 1: The use of "gender" instead of "sex"the GBD has not published information on gender. He authors describe "sex" differences (i.e., make to female differences). Response: The authors thank the reviewer for this comment. The word "gender" has been replaced with the word "sex" throughout the manuscript.
Comment 2: It will be informative to add a brief description of the population used to do the standardization, despite the citations provided. Response: The GBD study used the GBD world population age standard to calculate agestandardized incidence rates. For GBD 2013, GBD 2015 and GBD 2016, the age-specific proportional distributions of all national locations from the UNPOP World Population Prospects 2012 revision for all years from 2010 to 2035 were used to generate a standard population age structure using the nonweighted mean across all the aforementioned country-years. For GBD 2017, the non-weighted mean of 2017 age-specific proportional distributions from the GBD 2017 population estimates for all national locations with a population greater than 5 million people in 2017 were used to generate an updated standard population age structure. The authors had added a brief description of the population used to do the standardization in the revised manuscript (see line 94-98, page 5).
Comment 3: Explore/explain the data for younger populations (Table 2). Response: The authors had added the explanation as follows: It is noteworthy that females had higher incidence than males in younger population. Evidence had shown rising incidence of gastric cancer in younger adults in recent decades, while more common autoimmune gastritis of which gastric cancers are important long-term complications and more antibiotics use which disrupts indigenous constituents of digestive tract microbiota in females would help explain the findings.31,32(see line 184-187, page 9) Reviewer 2 Comment 1: The use of the word "gender" should be replaced with the word "sex". The word "sex" is objective while the word "gender" is a fluid social construct. If you notice in the report entitled "Findings from the Global Burden of Disease Study 2017" the word gender is never used. Response: Thank you for this suggestion. The word "gender" had been replaced with the word "sex" throughout the manuscript.
Comment 2: Under "Patients and Public Involvement", it might be good to clarify that no "identifiable" patients were used. Response: The authors had added the sentence "This study was based on an open-access database with no identifiable information on the patients." Under "Patients and Public Involvement". (see line 90, page 5) Comment 3: The use of "95% uncertainty interval" should be replaced with "95% confidence interval". Response: The text "95% uncertainty interval" had been replaced with "95% confidence interval".
Comment 4: Table 1 would be more readily interpretable if year was the stratification factor (columns) and the table was divided into Incidence and ASR (rows). Adding risk ratios (95% confidence interval) to compare time periods would also be helpful. Similarly, risk ratios (95% confidence interval) would be helpful in Table 2. Risk ratios would also be more readily interpretable than Z statistics (line 136). In addition, if allowed, I think the tables would be appropriate for the manuscript itself rather than as a supplement. Response: Table 1 had been modified in which year was the stratification factor (columns) and the table was divided into Incidence and ASR (rows). Risk ratios (95% confidence interval) had been added in both Table 1 and Table 2. In addition to Z statistics, the authors had provided risk ratios of 1.883 (1.876-1.890) as shown in Table 1 and Table 2, to indicate male predominance in global gastric cancer (see line 124-125, page 6). The tables were uploaded as part of the manuscript, if allowed.
Comment 5: In the discussion the authors state that "males may seek health care more frequently and benefit more from the progress in gastric cancer screening" (line 165). Referencing a study that shows men present with earlier stage gastric cancer than women would strengthen this statement. Also, information about how this changes incidence rates overall would be helpful since, take alone, lead time bias doesn't change incidence rates unless indolent disease is found. Response: The authors had not yet found a reference to strengthen this statement. However, other evidence from the perspective of cost effectiveness had been found to support the gastric cancer screening in males. Screening of high-risk populations rather than mass population screening might be more cost effective in many countries, which makes screening more relevant for males. (see line 169-170, page 9)