Blood Donation from 2006 to 2015 in Zhejiang Province

BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from PEER REVIEW HISTORY

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ARTICLE DETAILS

TITLE (PROVISIONAL) Blood Donation from 2006 to 2015 in Zhejiang Province, China: Annual consecutive cross-sectional studies AUTHORS HU, WEI; Meng, Hongdao; HU, QIUYUE; FENG, LIJUAN; QU, XIANGUO

VERSION 1 - REVIEW

REVIEWER Thomas Volken, PhD Professor for Health Service Research Institute for Health Service Research School of Health Professions Zurich Univerity of Applied Sciences Winterthur, Switzerland REVIEW RETURNED 26-Apr-2018

GENERAL COMMENTS GENERAL COMMENTS The authors use an impressive sample of over 3,000,000 whole

blood donors in Zhejiang to study the association of demographic http://bmjopen.bmj.com/ and anthropometric factors with the frequency and volume of blood donations. Generally, the authors could have invested more time in searching (and citing) the recent literature and therefore substantiating their statistical model choice and the respective variables used in the analyses. I am not a native English speaker but my feeling is that the manuscript could benefit from some language editing. Moreover, the authors should address the following issues before publication. on September 29, 2021 by guest. Protected copyright.

INTRODUCTION Page 4, line 36: „(…) from 4,950,000U to 23,600,00U.” What does “U” stand for? Whole blood units? Donations? Please explain. Page 4, line 39: It is unclear what you mean by “transfusion rate”. What ratio do you have in mind? – e.g. blood products transfused vs blood products issued by the blood transfusion service. If the latter is the case, the authors should explain the incredibly small loss of only 0.4% of the issued blood products. Page 5, lines 5-18: The authors should find and cite the relevant literature supporting their claims in this paragraph. Page 5, lines 31-39: I can’t really see the value of this paragraph. I suggest to delete it. On the other hand, body weight is important for blood donations. Consequently, the authors should explain why. Page 5, lines 42-44: The authors may want to consider rephrasing this sentence, e.g.: “This paper describes demographic and anthropometric factors associated with blood donation behavior of VNRBD in Zhejiang Province.” BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Page 6, lines 5-10: Consider rephrasing this sentence, i.e. it is not clear why and how recruitment and retention strategies “(…) promote population health”. Page 6, lines 10-11: The study population should be described in the methods section.

METHODS Page 7, lines 13-21: This sentence should be deleted and moved to the paragraph “Measures”. Page 7: Please add a paragraph that describes the study population. You may consider to replace “Patient and Public Involvement” with “Study population” and start the paragraph with something like: “For this study, all whole blood donations between 2006 and 2015 (n=5,299,729) of 3,226,571 VNRBDs were extracted from the Zhejiang Provincial Blood Management Information System.” Then continue with lines 40-48, i.e. “This study period was chosen (…) excluded to [eliminate] interference.” Page 7, lines 35-48 can then be deleted. Page 7, lines 33: Start this paragraph with “The database includes donors’ (….)”. Then, for each indicator, please specify the unit of measurement and for categorical variables the levels. For education level and occupation you should also specify which classification system, if any, has been used (e.g. ICO 88). Please also define your key terms here, e.g. “single-time blood donors”, “first-time blood donors” etc. Page 8, lines 17-19: “(…) only the last donation was included in the analysis.” The authors need to clarify for which analyses only the last donation was included, i.e. it would not make much sense to consider only the last donation when it comes to the analysis of repeated donations. Page 8, line 20-22: As indicated already in my evaluation of the introduction section, the authors did not discuss why weight is important for blood donation (beside being an eligibility criteria). http://bmjopen.bmj.com/ Hence, it is a bit puzzling that weight is then used together with gender in order to produce a stratified analysis. Moreover, the authors should explain why they provided extensive analyses of unadjusted trends over various factors but included only a population averaged time trends in their logistic regression. Given the huge number of observations, the authors may have considered to include interaction terms, e.g. an interaction between time and education. Please explain your model choice. Finally, the authors may consider to complement their analyses by on September 29, 2021 by guest. Protected copyright. reporting marginal probabilities, e.g. show the adjusted probability trajectory of donors with specific (fixed) characteristics over time. This would allow for a shift in perspective from relative (odds ratios) to absolute differences (marginal probability).

RESULTS While it is perfectly legitimate to report the proportion of donors by age group, this information is of limited use when it comes to donor recruitment (page 5, line 44-45: “The study provides directions for the recruitment of blood donors (…)”). Consequently, the authors may want to consider using whole blood donations and whole blood donors per 1’000 population in the respective age groups. (It seems that the authors picked up some of this in the discussion section…)

Page 9, lines 41-52: This claim could only be substantiated if the respective donors/donations per 1’000 population remained stable. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Otherwise, changes in recruitment and/or retention may also lead to changes in overall structure of donor age. Page 11, line 11. Change “correlated” to “associated”. Page 11, line 39-44. Consider to rephrase, e.g. “We also found that repeated donation (…)”.

DISCUSSION Page 11, line 56: “volumne” (typo) -> volume Page 12, line 13: “The overall age structure was younger than that in the Netherlands”. I’m not quite sure why the authors compare their results with those of a Dutch study. Please explain or clarify why you did not mention results from other (Non-) European countries where information on donor age structure are readily available. Similarly (on line 21): “The trend of blood donor number is a little different from that of EU.” While this is certainly true, the discussion should focus on why this is the case. For example, the decreasing number of blood donors and blood donations in many European countries can be explained by recent trends in Patient Blood Management (PBM) and new transfusion thresholds. Hence, European hospitals transfuse less blood products and consequently fewer blood donors and/or blood donations are needed. I trust the situation in China is entirely different in many respects. Page 12, lines 34-39: It may be worth investigating the association of age and single-time donation. Page 13, line 36: What are the “three groups”? Consider rephrasing.

REVIEWER L.M.G. van de Watering Sanquin and LUMC, Center for Clinical Transfusion Research, Leiden, the Netherlands

REVIEW RETURNED 16-Aug-2018 http://bmjopen.bmj.com/

GENERAL COMMENTS You have collected and analyzed the demographics of whole blood donors for 10 years, and looked for trends. Reading this extensive manuscript several questions/remarks came to my mind.

General: 1. This is NOT a cross-sectional study. A cross-sectional study looks at only one timepoint at both exposure and outcome and is, on September 29, 2021 by guest. Protected copyright. by definition, impossible to use when looking for trends. You have performed a cohort-study. Therefore the reporting checklist used and added is also not the correct one. 2. The huge number of >3,000,000 donors brings the risk of finding statistical significant differences without any clinical/practical relevance. How have you prevented this from happening? 3. Abstract: “… overnutrition may lead to poorer quality of donor blood.” This aspect is only stated in the abstract, and not mentioned in the introduction. Please add this to the introduction, with references. 4. P6, L48: “… a whole blood donor can choose to donate …” Please explain this more clearly. Where does the donor base his/her decision on? Do they get information from the blood bank or even a suggestion?

Specific: BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from 5. Page 5, Line 5: “Knowing who IS donating blood and donor demographic factors ARE important …”, please change accordingly. 6. P5, L10: “… male, WHITE, well-educated, …” These typical donors were white because in Europe most local people are. I would expect in most countries to see that the typical donors are locals. 7. P5, L31-40: this paragraph on body weight can be excluded 8. P7, L15: “… employment status information had missing DATA due to the …”, please add "data". 9. P7, L29: “… to ANALYZE the data of blood donors that HAS already BEEN collected …” 10. P7, L48: “exliminate interference” = “eliminate interference” 11. P8, L47: “… 18 to 25-year-old donor group ACCOUNTED for 45% …” 12. P8, L50: “Male donors remained stable at 57,6% of all donors.” Remove “are consistently” 13. P9, L24: Replace “It reached the peak in 2015.” with “, with a maximum of xxx in 2015.” 14. P10, L2: “For women, the year of 2009 …” Why for women? You look at the distribution men/women and later report that the percentage of men donating showed a bigger rise than the percentage in women. The distribution changed, but I see absolutely no reason why this was especially so for the women, as it changed identically for the men (only in the other direction, always adding up to 100%) 15. P10, L12: The lesser rise in donating by women may be explained by factors described in reference 12. It cannot be explained by the reporting of reference 12, as this was in 2016. 16. P11, L15-24: “… donation rate increased 19 percent from 50 to 89 kg ..” I think you mean to say that the donation rate increased 19 percent IN THE SUBGROUPS RANGING from 50 to 89 kg. 17. P11, L29-34: “… all individual characteristics … were http://bmjopen.bmj.com/ independently associated …” This is exactly the risk I mentioned above in general remark #2, because of the huge number of observations you have. In a confirmatory study, testing a hypothesis, this is no problem. But in a descriptive study, like yours, the very small confidence intervals will make every observation show a statistical significant difference between subgroups, on you the task to identify and report which ones are relevant, and why. 18. Figure 1: Remove the line “Year” from the graph on September 29, 2021 by guest. Protected copyright. 19. Figures 3, 5, 7, 8, 9: Present these graphs as stacked bars, showing the distribution 20. Checklist for cross-sectional study: Replace with and use the checklist for Cohort-study.

REVIEWER Wolfgang Hoffmann Prof. Dr. med. Wolfgang Hoffmann, MPH Institute for Community Medicine Section Epidemiology of Health Care and Community Health University Medicine Greifswald Ellernholzstr. ½ D-17487 Greifswald Phone +49-3834-86-7750/7751 Fax: +49-3834-86- 7752 e-mail: [email protected] http://www.community-medicine.de REVIEW RETURNED 22-Aug-2018

BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from GENERAL COMMENTS The authors present cross-sectional, primarily descriptive analyses of routine data on whole blood donors obtained in one Chinese province for consecutive calendar years 2006-2015. The authors study blood donor numbers as well as population- based period prevalences of donors, and donated whole blood volumes as outcomes and depict the respective time trends over the study period. Donor variables include sex, agegroup, education, categories of professions, one-time or repeated blood donation, and body weight of donors. The results are informative, because the data set covers the population of blood donors rather completely in an entire Chinese province and because the time period studied spans major demographic and public health changes in China. The manuscript is partly hard to read, and several passages are rather repetitive. The length should be reduced considerably (by about 30%). I only mention selected language mistakes and inconsistencies. The whole manuscript requires thorough English language editing. Recommendation: Allow for resubmission after major revision.

Major issues Keywords: “trend” is too broad. Please specify (e.g.) time trends, prevalence trends over time. Page 5 line 31-34: “Body weight is an index that comprehensively reflects…” – this statement ignores much of recent cardiovascular research- weight is rather less informative than previously thought since it does not reflect body fat distribution and composition. Please rephrase (e.g. an index that correlates with…) Page 5 line 39: Similar concern with “… the most important indicator of physical anthropology” – please explain physical anthropology and its meaning here, and rephrase more modestly the meaning of body weight. Patient and Public Involvement: The authors use data on the http://bmjopen.bmj.com/ individual level- have those been anonymized ? Pseudonymized ? How ? Do the patient consent to store their data for several years following blood donation ? Ifso, does the consent include analyses like the one that is presented ? P 8, l 17-19: “.. for individuals who donated twice in any calendar year, only the last donation was included in the analysis” – this restriction conflicts with the permission to doate blood every 6 months (P 7, l 10). Ignoring previous donations in the same year would likely bias the prevalence of repeated donors towards lower on September 29, 2021 by guest. Protected copyright. than correct values. P12 l23: “.. in the EU increased significantly from 1994-2009, with a small decrease later in 2014” – please report, what happens in the gap from 2010-2013. P15 l42: The authors’ observation, that weight correlates with blood donation prevalence does not extend to the statement, that controlling the weight would have a significant impact on blood donation. The argument is somewhat inconsistent in the manuscript- in other instances the authrs speculated that “a helthy diet” would influence the willingness to donate blood. It is likewise unclear, how the authors derive their statement, that obesity has an impact on blood donation (p15 52), and that a healthy lifestyle could prevent this impact. P16 l20: Either introduce the concept of “body shaming” properly, or – rather- delete it from the manuscript since this is obviously not supported by data and merely speculative. Tab. 1, Tab. 2: Please use “proportion” instead oif “%”. Always state explicitly, what the 100% would refer to. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Tab. 2: What is meant with “slightly different collection amount” in the footnote ? Please explain/rephrase. Tab. 3: Please use consstet order of women and Men (Male come fist in Tab. 2 and last in Tab. 3) Tab. 3.: Instead of “take xy as reference”, the reference category should be provided as “(Reference category: XY)” Tab. 3: Please specify the models used e.g. in a footnote to the table Fig. on page 26: What does the line for “Year” refer to ? Fig. on page 29: Please delete decimals in the percentages on the Y-axis. Fig. on page 31 can be deleted, since its information is redundant with following figs, that are more informative.

Minor issues Page 2, line 38-42: “.. gradually shifted from 400 ml or200 ml to 300 ml or 400 ml.” – what did you intend to say here ? Please rephrase. P8 l50: “The proportion of male donors consistently…” P9 l1: I suggest you use “body weight” instead of “weight” throughout the manuscript. P10 l1: “For the proportion of women, the year 2009 …” P11 l10: “.. were youngerand represented an overall low donation rate…” P11 l15: “For men, the rate of repeated donation increased…” P11 l23: “… increased 49.7% in the weight category 50 to 90 kg or more” – these would be two categories, please rephrase more precisely P13 l18: “… reached high levels in 2009” P13 l28: rather than “trough” I would suggest “the lowest value” or “nadir” P13 l42: “groups” rather than “kinds” of people P15 l0: please replace “amount volume” here and subsequently http://bmjopen.bmj.com/ with “amount” or, preferably, “volume”

VERSION 1 – AUTHOR RESPONSE

Reviewer(s)' Comments on September 29, 2021 by guest. Protected copyright. Reviewer #1:

GENERAL COMMENTS

The authors use an impressive sample of over 3,000,000 whole blood donors in Zhejiang to study the association of demographic and anthropometric factors with the frequency and volume of blood donations. Generally, the authors could have invested more time in searching (and citing) the recent literature and therefore substantiating their statistical model choice and the respective variables used in the analyses. I am not a native English speaker but my feeling is that the manuscript could benefit from some language editing. Moreover, the authors should address the following issues before publication.

Response: Thank you for this comment. We have conducted a new literature search and cited more recent literature to support our analyses. References added citing are citations 10, and 28-41.

INTRODUCTION

Page 4, line 36: „(…) from 4,950,000U to 23,600,00U.” What does “U” stand for? Whole blood units? Donations? Please explain. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Response: We have revised the text and replaced the “U” with “Units”.

Page 4, line 39: It is unclear what you mean by “transfusion rate”. What ratio do you have in mind? – e.g. blood products transfused vs blood products issued by the blood transfusion service. If the latter is the case, the authors should explain the incredibly small loss of only 0.4% of the issued blood products.

Response: We have revised the text to read: “blood component transfusion rate (proportion of blood component products transfused as the percentage of all blood transfusion)…”The remaining 0.4% is whole blood transfusion.

Page 5, lines 5-18: The authors should find and cite the relevant literature supporting their claims in this paragraph.

Response: Thank you for this comment. The paragraph has been edited and cited as follows:

“To better understand donors, knowledge about donor characteristics, such as demographic profiles, is required to describe the composition of the donor population. Insight into donor characteristics is essential for targeted donor recruitment and donor retention [6,7,8,9]. Demographic characteristics varied among countries within the region. Data from 118 countries on the profile of blood donors show that, overall, 70% of blood donations were given by male donors, and 40% of donations were given by donors aged 25–44 years [1].”

Page 5, lines 31-39: I can’t really see the value of this paragraph. I suggest to delete it. On the other hand, body weight is important for blood donations. Consequently, the authors should explain why.

Response: Thank you for this comment. The paragraph has been edited as follows:

Based on the assumption that blood volume can be estimated as 70 ml/kg, body weight was one of key selection criterions. The AABB standard for minimum donor weight of 110 b (50kg) and to limit collection to 10.5 ml/kg is sufficient to protect most, to limit blood loss to no more than 15% of a person’s total blood volume [12,13]. Furthermore, body weight is a very important determinant of vasovagal reaction rates in first-time donors [14,15,16]. Is the body weight a “true” statement when it comes to body weight? Over nutrition and overweight also represent a negative impact on blood http://bmjopen.bmj.com/ donation, since obesity cause or exacerbate a large number of health problems and are among the most significant contributors to poor health [17]. As the rate of obesity in youth and young adults is approximately tripling, China is one of the most worrisome within developing and middle-income countries [18]. Body weight is so important, however, research on the body weight is mainly in relation to the adverse events [14,15,16].Currently, few studies have been focused on the relationship between body weight and the frequency of blood donation.

(Also reedited Page 15, line 8 to “Based on the assumption that blood volume can be estimated as 70 on September 29, 2021 by guest. Protected copyright. ml/kg,”)

Page 5, lines 42-44: The authors may want to consider rephrasing this sentence, e.g.: “This paper describes demographic and anthropometric factors associated with blood donation behavior of VNRBD in Zhejiang Province.”

Response: This sentence has been rephrased as suggested:

This paper describes demographic and anthropometric factors associated with blood donation behavior of VNRBD in Zhejiang Province.

Page 6, lines 5-10: Consider rephrasing this sentence, i.e. it is not clear why and how recruitment and retention strategies “(…) promote population health”.

Response: Thank you for this comment. This sentence has been rephrased as follows:

Also, the gender-specific body weight analysis offers insight into future development of gender- specific donor recruitment and retention strategies as healthy lifestyles help maintain healthy body weight, which in turn increases healthy donor pool. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Page 6, lines 10-11: The study population should be described in the methods section.

Response: Thank you for this comment. This sentence has been moved to the Methods section (in paragraph of “Study population”)

METHODS

Page 7, lines 13-21: This sentence should be deleted and moved to the paragraph “Measures”.

Response: Thank you for this comment. This sentence was been moved to page 7, line 56.

Page 7: Please add a paragraph that describes the study population. You may consider to replace “Patient and Public Involvement” with “Study population” and start the paragraph with something like: “For this study, all whole blood donations between 2006 and 2015 (n=5,299,729) of 3,226,571 VNRBDs were extracted from the Zhejiang Provincial Blood Management Information System.” Then continue with lines 40-48, i.e. “This study period was chosen (…) excluded to [eliminate] interference.” Page 7, lines 35-48 can then be deleted.

Response: Thank you for this comment. According to the requirement of BMJ Open, “Patient and Public Involvement” must be included in METHODS, so this sentence has been rephrased as follows:

Patient and Public Involvement

There is no patient and public involved in this study. This study picked retrospective analysis of Blood donor database, to analysis the data of blood donors that have already collected in the database. For this study, all whole blood donations between 2006 and 2015 (n=5,299,729) of 3,226,571 VNRBDs were extracted from the Zhejiang Provincial Blood Management Information System. This study period was chosen because no major system modification happened during this period, thus ensuring consistent information collection and processing. Because of the different way to donate and different donation interval requirement, all apheresis donations were excluded to eliminate interference.

Page 7, lines 33: Start this paragraph with “The database includes donors’ (….)”. Then, for each indicator, please specify the unit of measurement and for categorical variables the levels. For http://bmjopen.bmj.com/ education level and occupation you should also specify which classification system, if any, has been used (e.g. ICO 88). Please also define your key terms here, e.g. “single-time blood donors”, “first-time blood donors” etc.

Response: Thank you for this comment. This paragraph has been rephrased as follows:

Measures

The database includes donors’ basic demographic characteristics, such as age (years), gender (male, on September 29, 2021 by guest. Protected copyright. female), education level(classification according to GB18467-2011), and occupation (classification according to GB18467-2011), body weight (used for eligibility assessment, kg), and blood collection information such as date (month/date/year), time (24h), volume (ml), and frequency of blood donations(one time, two times, etc.).

Single-time blood donors are those who have donated blood only one time in their whole blood donation career. First-time blood donors are donors who donate blood for the first time regardless whether the donor was single-time donor or multi-time donor. VNRBD stands for Voluntary Non- Remunerated Blood Donation.

Due to the complexity and privacy of the profession, there were 105 blood donors who chose not to complete forms. Because of this, their employment status information was missing. The occupation of these donors was included in the category ‘other’.

(Consequently, Page 2 line 48, Page 4 line 18, Page 4 line 54, all “voluntary non-remunerated blood donation” was revised to “VNRBD”) BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Page 8, lines 17-19: “(…) only the last donation was included in the analysis.” The authors need to clarify for which analyses only the last donation was included, i.e. it would not make much sense to consider only the last donation when it comes to the analysis of repeated donations.

Response: Thank you for this comment. This sentence has been rephrased as follows:

To accurately reflect the proportion of people who donated blood in the trend analysis, only the second donation record was included in the analysis for individuals who donated twice in a calendar year (Figure 1to Figure 8).

Page 8, line 20-22: As indicated already in my evaluation of the introduction section, the authors did not discuss why weight is important for blood donation (beside being an eligibility criteria). Hence, it is a bit puzzling that weight is then used together with gender in order to produce a stratified analysis. Moreover, the authors should explain why they provided extensive analyses of unadjusted trends over various factors but included only a population averaged time trends in their logistic regression. Given the huge number of observations, the authors may have considered to include interaction terms, e.g. an interaction between time and education. Please explain your model choice.

Response: Thank you for this comment. We have revised the part in Page 5, lines 31-39, which described that weight is very important for blood donation. So we need to analyze more details in the relation to blood donation characteristics. As the different eligible qualification was required for males and females in China, weight is used together with gender in order to produce a stratified analysis.

Due to our study focus, on the basis of preliminary analysis, combined with the development of the domestic economy, the research team pay close attention to how the blood donation changes with different time, and whether there is a short-term change. But your suggestion is very important for our further study.

In real life, as time goes by, the education and career status of donors also change. Here we have two kinds of analysis ideas. The first one is to treat each donation in the database as a record, ignoring the change of the year; the second one is to consider the changes in the characteristics of the donor's blood donation demographics. The initial analysis of the proportion of continuous

donations is very low (and it is true in fact); therefore, we use the first analytical approach to treat the http://bmjopen.bmj.com/ donation records as independent donations at different time points. Then, through the ID number, match the number of blood donations in ten years. As the proportion of consecutive donors in the total number is extremely small, and the interaction between the variables in the regression equation can be neglected.

Finally, the authors may consider to complement their analyses by reporting marginal probabilities, e.g. show the adjusted probability trajectory of donors with specific (fixed) characteristics over time.

This would allow for a shift in perspective from relative (odds ratios) to absolute differences (marginal on September 29, 2021 by guest. Protected copyright. probability).

Response: Thank you for this comment. This study uses several million data in this province. We analyze from a macro perspective, showing differential effects among age groups, weight groups, educations levels, and types of occupations. The goal is to identify heterogeneity within each category rather than quantify it. Adding the trajectory analysis will enrich the results, but is beyond the scope of the current study. In the follow-up study, we will focus on the impact of individuals (or have the same characteristic group) on blood donation behavior through a retrospective cohort study. It will be a good direction of follow-up research and thank you for your suggestion.

RESULTS

While it is perfectly legitimate to report the proportion of donors by age group, this information is of limited use when it comes to donor recruitment (page 5, line 44-45: “The study provides directions for the recruitment of blood donors (…)”). Consequently, the authors may want to consider using whole blood donations and whole blood donors per 1’000 population in the respective age groups. (It seems that the authors picked up some of this in the discussion section…) BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Response: Thank you for this comment. The reason we did not use whole blood donation per 1,000 population was that we do not have data on the year-specific population to be used as denominators. We plan to collect such information in a future study. Our original age group analysis mainly aims to discover the age structure developing trend, to better understand the changing of donors, to find which group was reduced such as 18-25 years old that needs to pay more attention to, or which group was increased to compare this structure with other country or region. The sentence on page 5, line 44-45has been rephrased as follows:

The study provides a specific analysis of blood donor demographic characteristics to increase repeated blood donations and ultimately to ensure adequate safe blood sources.

Page 9, lines 41-52: This claim could only be substantiated if the respective donors/donations per 1’000 population remained stable. Otherwise, changes in recruitment and/or retention may also lead to changes in overall structure of donor age.

Response: Thank you for this comment. We reviewed the data carefully, it is true that we can not conclude the donor age group change was caused by population aging. So we accept your advice, the sentence was reedited as follows:

The results show that the changing trend of the age structure of blood donors is the same as the direction of population aging.

Page 11, line 21. Change “correlated” to “associated”.

Response: The word “correlated” has been edited to “associated”

Page 11, line 39-44. Consider to rephrase, e.g. “We also found that repeated donation (…)”.

Response: Thank you for this comment. This sentence has been edited as follows:

We also found that repeated donation and blood volume each donation for both male and female blood donors in Zhejiang were directly proportional to body weight. (…)

DISCUSSION http://bmjopen.bmj.com/ Page 11, line 56: “volumne” (typo) -> volume

Response: The typo has been corrected.

Page 12, line 13: “The overall age structure was younger than that in the Netherlands”. I’m not quite sure why the authors compare their results with those of a Dutch study. Please explain or clarify why you did not mention results from other (Non-) European countries where information on donor age structure are readily available. Similarly (on line 21): “The trend of blood donor number is a little on September 29, 2021 by guest. Protected copyright. different from that of EU.” While this is certainly true, the discussion should focus on why this is the case. For example, the decreasing number of blood donors and blood donations in many European countries can be explained by recent trends in Patient Blood Management (PBM) and new transfusion thresholds. Hence, European hospitals transfuse less blood products and consequently fewer blood donors and/or blood donations are needed. I trust the situation in China is entirely different in many respects.

Response: Thank you for this comment. We have revised the text to include information from more regions in the world:

Compared to data reported from a total of 80 countries (23 high-income, 18 upper middle-income, 22 lower middle-income, and 17 low-income) [1], the overall age structure of Zhejiang blood donors was younger than the global average. This maybe mainly related to the relatively younger age structure of the populations in developing countries.

For Page 12 line21, this paragraph was edited as follows:

The trend of blood donor number is a little different from EU. The donor population of EU rose significantly from 1994 to 2009, then stabilized thereafter, with a small decrease later in 2014 [26]. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from This may partly be because of the Patient Blood Management (PBM) widely used in the EU, which emphasizes on minimizing the need for transfusion, thus reducing the potential risks and costs, and sparing limited resources [27, 28]. As we mentioned in the introduction, Zhejiang province was still far behind developed countries in terms of the number of donations per 1000 population per year, so it still belongs to the demand market. The measures to optimize recruitment, retention, and transfusion in Zhejiang work, but not significantly.

Page 12, lines 34-39: It may be worth investigating the association of age and single-time donation.

Response: Thank you for this comment. In this study, the donor data of 2006-2015 years was selected. We are unable to know whether the donors had donated blood before or had donated blood in other places during this period. Blood donation in 2006-2015 is our research period, and we observe and analyze whether donors have repeated blood donation during this period of time. In the follow-up study, we will randomly select donors from this group of people to conduct surveys. Through retrospective questionnaire, we can get the time of the first blood donation in their life, so that we can analyze the relationship between age and single-time blood donation. This will prove the age trend of the first donation of Chinese blood donors.

Page 13, line 36: What are the “three groups”? Consider rephrasing.

Response: Thank you for this comment. The sentence has been rephrased as follows:

Among them, there are three groups, donors aged 18-25years, students, and females, which have the same changing shape of the trend as the above overall blood donation. It showed that these three groups are greatly influenced by public opinion.

Reviewer: 2

You have collected and analyzed the demographics of whole blood donors for 10 years, and looked for trends. Reading this extensive manuscript several questions/remarks came to my mind.

Response: Thank you for this comment. We appreciate the thoughtful and detailed review of our http://bmjopen.bmj.com/ manuscript.

General:

1. This is NOT a cross-sectional study. A cross-sectional study looks at only one time point at both exposure and outcome and is, by definition, impossible to use when looking for trends. You have performed a cohort-study. Therefore the reporting checklist used and added is also not the correct one. on September 29, 2021 by guest. Protected copyright. Response: While the blood donation database can be used to support a cohort study, we believe our present study is best described as a “multiple cross-sectional study” because cohort study requires an identification of a cohort at some time point and obtaining one or more measures at follow-up. Analyses based on a cohort design are beyond the scope of the present study (but are planned).

（Also, Page 2, line 14 was reedited to “Multiple Cross-sectional study.”）

2. The huge number of >3,000,000 donors brings the risk of finding statistical significant differences without any clinical/practical relevance. How have you prevented this from happening?

Response: Thank you for this comment. While it is generally true that exceedingly large sample can lead to statistical significance on trivial differences, the fact that we used the whole population blood donation data implies that we do not need to do statistical inferences for the rates presented in the manuscript. Therefore, no p values were used in this study.

Because of the large sample size, any statistical inference is meaningful; it seems that statistical inference, including regression equations, is not very meaningful. To this end, we specifically consulted statisticians; firstly, the study of the subject as a donor, then the subject is statistically as a BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from whole, any comparison of the size of the ratio is a true comparison. Secondly, doing regression equations is not only about whether the variables affect the outcome, but also the extent to which the variables are explored, and the interaction of the different variables. In addition, if all donors in a country are considered as a whole, then the donors in the study area are selected to have behavioral groups, and the characteristics of the research group can also infer the results of larger regions.

3. Abstract: “… overnutrition may lead to poorer quality of donor blood.” This aspect is only stated in the abstract, and not mentioned in the introduction. Please add this to the introduction, with references.

Response: Thank you for this comment. The following sentences were added to the introduction on Page 5, line 40 as follows:

Is the body weight a “true” statement when it comes to body weight? Over nutrition and overweight also represent a negative impact on blood donation, as overweight and obesity cause or exacerbate a large number of health problems, and are among the most significant contributors to poor health[17].China is one of the most worrisome countries within developing and middle-income countries, as the approximate tripling of obesity seen in youth and young adults[18].

4. P6, L48: “… a whole blood donor can choose to donate …” Please explain this more clearly. Where does the donor base his/her decision on? Do they get information from the blood bank or even a suggestion?

Response: Thank you for this comment. The sentence was edited as follows:

According to China’s regulations, after registration and physical examination on the donation site, professional staff will offer an advice, then donors can ultimately decide to donate 200ml, 300ml, or 400ml. The amount of blood donated is determined voluntarily.

Specific:

5. Page 5, Line 5: “Knowing who IS donating blood and donor demographic factors ARE important …”, please change accordingly. http://bmjopen.bmj.com/ Response: Thank you for this comment. This sentence was edited as follows:

To better understand donors, knowledge about donor characteristics, such as demographic profiles, is required to describe the composition of the donor population. Insight into donor characteristics is essential for targeted donor recruitment and donor retention[6,7,8,9].

6. P5, L10: “… male, WHITE, well-educated, …” These typical donors were white because in Europe most local people are. I would expect in most countries to see that the typical donors are locals. on September 29, 2021 by guest. Protected copyright.

Response: Thank you for this comment. We considered your suggestion seriously, and decide to compare to most countries, so the sentence was edited as follows:

Demographic characteristics varied among countries within the region. Data from 118 countries on the profile of blood donors show that, overall, 70% of blood donations were given by male donors, and 40% of donations were given by donors aged 25–44 years[1].

7. P5, L31-40: this paragraph on body weight can be excluded

Response: Thank you for this comment. Considered the body weight is important to blood donation, so we delete this paragraph, and edited as follows:

Based on the assumption that blood volume can be estimated as 70 ml/kg, body weight was one of key selection criterions. The AABB standard for minimum donor weight of 110 b (50kg) and to limit collection to 10.5 ml/kg is sufficient to protect most, to limit blood loss to no more than 15% of a person’s total blood volume [12,13]. Furthermore, body weight is a very important determinant of vasovagal reaction rates in first-time donors [14,15,16]. Is the body weight a “true” statement when it BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from comes to body weight? Over nutrition and overweight also represent a negative impact on blood donation, since obesity cause or exacerbate a large number of health problems and are among the most significant contributors to poor health [17]. As the rate of obesity in youth and young adults is approximately tripling, China is one of the most worrisome within developing and middle-income countries [18]. Body weight is so important, however, research on the body weight is mainly in relation to the adverse events [14,15,16].Currently, few studies have been focused on the relationship between body weight and the frequency of blood donation.

P7, L15: “… employment status information had missing DATA due to the …”, please add "data".

Response: Thank you for this comment. The sentence has been edited as follows:

“Due to the complexity and privacy of the profession, there were 105 blood donors who chose not to complete forms. Because of this, their employment status information was missing. The occupation of these donors was included in the category ‘other’.”

8. P7, L29: “… to ANALYZE the data of blood donors that HAS already BEEN collected …”

Response: Thank you for this comment. This sentence was restructured into ‘Patient and Public Involvement’.

For this study, all whole blood donations between 2006 and 2015 (n=5,299,729) of 3,226,571 VNRBDs were extracted from the Zhejiang Provincial Blood Management Information System. This study period was chosen because no major system modification happened during this period, thus ensuring consistent information collection and processing. Because of the different way to donate and different donation interval requirement, all apheresis donations were excluded to eliminate interference..

9. P7, L48: “exliminate interference” = “eliminate interference”

Response: Thank you for this comment. We are sorry for spelling mistake. This word has been edited to “eliminate”

10. P8, L47: “… 18 to 25-year-old donor group ACCOUNTED for 45% …” http://bmjopen.bmj.com/

Response: Thank you for this comment. We are sorry for tense mistake. This word has been edited to “accounted”, and so did other ‘account’ in manuscript.

11. P8, L50: “Male donors remained stable at 57,6% of all donors.” Remove “are consistently”

Response: Thank you for this comment. The sentence has been edited as follows:

Basically, the proportion of male donors remained stable(57.6%). on September 29, 2021 by guest. Protected copyright. 12. P9, L24: Replace “It reached the peak in 2015.” with “, with a maximum of xxx in 2015.”

Response: Thank you for this comment. The sentence has been edited as follows:

, with a maximum of 540,284 in 2015.

13. P10, L2: “For women, the year of 2009 …” Why for women? You look at the distribution men/women and later report that the percentage of men donating showed a bigger rise than the percentage in women. The distribution changed, but I see absolutely no reason why this was especially so for the women, as it changed identically for the men (only in the other direction, always adding up to 100%)

Response: Thank you for this comment. We are sorry for any confusion. Actually, we should use absolute donor number rather than proportion. The sentence has been edited as follows:

For the female donor number, the year of 2009 seems to be a turning point, (…)

The Figure 3 was replaced as follows: BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from

14. P10, L12: The lesser rise in donating by women may be explained by factors described in reference 12. It cannot be explained by the reporting of reference 12, as this was in 2016.

Response: Thank you for this comment. The sentence has been edited as follows:

Compared to men, this may relate to the fact that women are at risk for iron depletion because of menstruation ongoing blood loss, recent pregnancies, and inadequate dietary iron [20]. Female metabolic syndrome prevalence was 2.14 times higher in donors with high donation intensity compared with those with low donation intensity [21].

15. P11, L15-24: “… donation rate increased 19 percent from 50 to 89 kg ..” I think you mean to say that the donation rate increased 19 percent IN THE SUBGROUPS RANGING from 50 to 89 kg.

Response: Thank you for this comment. The sentence has been edited as follow:

For men, the rate of repeated donation increased 19 percent in the subgroups ranging from 50-88 kg, and that of women also increased 19 percent in the subgroups ranging from 45 to 70 kg and over 70 kg. http://bmjopen.bmj.com/ (Also, reedited Page 5, line21 to “For men, the rate of 400ml donations increased 49.7 percent from 50 to 90 kg and over 90 kg, and that of women also increased 47.9 percent from 45-49 kg to more than 70 kg”)

16. P11, L29-34: “… all individual characteristics … were independently associated …” This is exactly the risk I mentioned above in general remark #2, because of the huge number of observations you have. In a confirmatory study, testing a hypothesis, this is no problem. But in a

descriptive study, like yours, the very small confidence intervals will make every observation on September 29, 2021 by guest. Protected copyright. show a statistical significant difference between subgroups, on you the task to identify and report which ones are relevant, and why.

Because of the large sample size, any statistical inference is meaningful; it seems that statistical inference, including regression equations, is not very meaningful. To this end, we specifically consulted statisticians; firstly, the study of the subject as a donor, then the subject is statistically as a whole, any comparison of the size of the ratio is a true comparison. Secondly, doing regression equations is not only about whether the variables affect the outcome, but also the extent to which the variables are explored, and the interaction of the different variables. In addition, if all donors in a country are considered as a whole, then the donors in the study area are selected to have behavioral groups, and the characteristics of the research group can also infer the results of larger regions.

BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from 17. Figure 1: Remove the line “Year” from the graph

Response: Thank you for this comment.“Year” has been removed as follows:

18. Figures 3, 5, 7, 8, 9: Present these graphs as stacked bars, showing the distribution

Response: Thank you for this comment. The Figure3,5,7,8,9, has been presented as stacked bars as follows: http://bmjopen.bmj.com/

on September 29, 2021 by guest. Protected copyright.

BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from

19. Checklist for cross-sectional study: Replace with and use the checklist for Cohort-study.

Response: Thank you for this comment. While the blood donation database can be used to support a cohort study, we believe our present study is best described as a “multiple cross-sectional study” because cohort study requires an identification of a cohort at some time point and obtaining one or more measures at follow-up. Analyses based on a cohort design are beyond the scope of the present study (but are planned). http://bmjopen.bmj.com/

Reviewer: 3

The authors present cross-sectional, primarily descriptive analyses of routine data on whole blood donors obtained in one Chinese province for consecutive calendar years 2006-2015.

The authors study blood donor numbers as well as population-based period prevalence of donors, on September 29, 2021 by guest. Protected copyright. and donated whole blood volumes as outcomes and depict the respective time trends over the study period. Donor variables include sex, age group, education, categories of professions, one-time or repeated blood donation, and body weight of donors.

The results are informative, because the data set covers the population of blood donors rather completely in an entire Chinese province and because the time period studied spans major demographic and public health changes in China.

The manuscript is partly hard to read, and several passages are rather repetitive. The length should be reduced considerably (by about 30%).

I only mention selected language mistakes and inconsistencies. The whole manuscript requires thorough English language editing.

Recommendation: Allow for resubmission after major revision.

Response: Thank you for this comment. We appreciate for your thoughtful and detailed review of our manuscript. We have reedited the whole manuscript. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Major issues

Keywords: “trend” is too broad. Please specify (e.g.) time trends, prevalence trends over time.

Response: Thank you for this comment. The keyword “trend” has been edited to “prevalence trend”

Page 5 line 31-34: “Body weight is an index that comprehensively reflects…” – this statement ignores much of recent cardiovascular research- weight is rather less informative than previously thought since it does not reflect body fat distribution and composition. Please rephrase (e.g. an index that correlates with…)

Response: Thank you for this comment. Considered explaining why body weight is so important is more necessary, the paragraph has been deleted and edited as follows:

Based on the assumption that blood volume can be estimated as 70 ml/kg, body weight was one of key selection criterions. The AABB standard for minimum donor weight of 110 b (50kg) and to limit collection to 10.5 ml/kg is sufficient to protect most, to limit blood loss to no more than 15% of a person’s total blood volume [12,13]. Furthermore, body weight is a very important determinant of vasovagal reaction rates in first-time donors [14,15,16]. Is the body weight a “true” statement when it comes to body weight? Over nutrition and overweight also represent a negative impact on blood donation, since obesity cause or exacerbate a large number of health problems and are among the most significant contributors to poor health [17]. As the rate of obesity in youth and young adults is approximately tripling, China is one of the most worrisome within developing and middle-income countries [18]. Body weight is so important, however, research on the body weight is mainly in relation to the adverse events [14,15,16].Currently, few studies have been focused on the relationship between body weight and the frequency of blood donation.

Page 5 line 39: Similar concern with “… the most important indicator of physical anthropology” – please explain physical anthropology and its meaning here, and rephrase more modestly the meaning of body weight.

Response: Thank you for this comment. Considered explaining why body weight is so important is more necessary, so this sentence was deleted, and the paragraph is edited as follows: http://bmjopen.bmj.com/ Based on the assumption that blood volume can be estimated as 70 ml/kg, body weight was one of key selection criterions. The AABB standard for minimum donor weight of 110 b (50kg) and to limit collection to 10.5 ml/kg is sufficient to protect most, to limit blood loss to no more than 15% of a person’s total blood volume [12,13]. Furthermore, body weight is a very important determinant of vasovagal reaction rates in first-time donors [14,15,16]. Is the body weight a “true” statement when it comes to body weight? Over nutrition and overweight also represent a negative impact on blood donation, since obesity cause or exacerbate a large number of health problems and are among the most significant contributors to poor health [17]. As the rate of obesity in youth and young adults is on September 29, 2021 by guest. Protected copyright. approximately tripling, China is one of the most worrisome within developing and middle-income countries [18]. Body weight is so important, however, research on the body weight is mainly in relation to the adverse events [14,15,16].Currently, few studies have been focused on the relationship between body weight and the frequency of blood donation.

Patient and Public Involvement: The authors use data on the individual level- have those been anonymized?Pseudonymized ? How? Do the patient consent to store their data for several years following blood donation ? If so, does the consent include analyses like the one that is presented ?

Response: Thank you for this comment. The data is anonymized, instead of name, the information that identified as one person was his/her identity number. In the analyses that presented in this manuscript, the identity number was also hidden. Blood donors consent store their data, and it is also required by Chinese regulations. This study passed by Ethics Committee of Blood Center of Zhejiang Province.

P 8, l 17-19: “..for individuals who donated twice in any calendar year, only the last donation was included in the analysis” – this restriction conflicts with the permission to donate blood every 6 months BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from (P 7, l 10). Ignoring previous donations in the same year would likely bias the prevalence of repeated donors towards lower than correct values.

Response: Thank you for this comment. Yes, it should be clarified. Only Figure 1 is related to the second donation included in the analysis, other analysis is not influenced. This sentence has been rephrased as follows:

P12 l23: “. in the EU increased significantly from 1994-2009, with a small decrease later in 2014” – please report, what happens in the gap from 2010-2013.

Response: Thank you for this comment. The sentence has been edited as follows:

The donor population of EU rose significantly from 1994 to 2009, then stabilized thereafter, with a small decrease later in 2014 [26].

P15 l42: The authors’ observation, that weight correlates with blood donation prevalence does not extend to the statement, that controlling the weight would have a significant impact on blood donation. The argument is somewhat inconsistent in the manuscript- in other instances the authrs speculated that “a helthy diet” would influence the willingness to donate blood.

Response: Thank you for this comment. We accept your comment, and P15, line 42-52 was reedited as follows:

However, as we mentioned, over nutrition and overweight were among the most significant contributors to ill-health [17].Most obese person can not pass the blood screen even if they want to donate, controlling body weight within a reasonable range is helpful for donation.

It is likewise unclear, how the authors derive their statement, that obesity has an impact on blood donation (p15 52), and that a healthy lifestyle could prevent this impact.

Response: Thank you for this comment. P15, line 42-52 was reedited as follows: http://bmjopen.bmj.com/

However, as we mentioned, over nutrition and overweight was among the most significant contributors to ill health [17].Most obese person can not pass the blood screen even if they want to donate, controlling body weight within a reasonable range is helpful for donation.

P16 l20: Either introduce the concept of “body shaming” properly, or – rather- delete it from the manuscript since this is obviously not supported by data and merely speculative. on September 29, 2021 by guest. Protected copyright. Response: Thank you for this comment. We delete body shaming, the sentence has been rephrased as follows:

(…), we should encourage a healthy diet to promote better nutrition and health status.

Tab. 1, Tab. 2: Please use “proportion” instead of “%”. Always state explicitly, what the 100% would refer to.

Response: Thank you for this comment. It has been reedited as “proportion” instead of “%”,

Tab. 2: What is meant with “slightly different collection amount” in the footnote? Please explain/rephrase.

Response: Thank you for this comment. We have deleted this foot note.

Tab. 3: Please use consistent order of women and Men (Male come fist in Tab. 2 and last in Tab. 3)

Response: Thank you for this comment. We edited the order, put men always first, then women. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Tab. 3.: Instead of “take xy as reference”, the reference category should be provided as “(Reference category: XY)”

Response: Thank you for this comment. We reedited it to “Reference category: XY”

Tab. 3: Please specify the models used e.g. in a footnote to the table

Response: Thank you for this comment. We added the footnote in the table 3 as follows:

This is multivariable logistic regression model.

Fig. on page 26: What does the line for “Year” refer to ?

Response: Thank you for this comment. We are sorry for confusion, it has been reedited, “year” has been deleted.

Fig. on page 29: Please delete decimals in the percentages on the Y-axis. (Q)

Response: Thank you for this comment. Decimals in the percentages on the Y-axis have been removed. For this image, to clearly state that female has a different shape of trend, we use number instead of proportion.

Fig. on page 31 can be deleted, since its information is redundant with following figs, that are more informative. (Q)

Response: Thank you for this comment. It has been deleted.

Minor issues

Page 2, line 38-42: “..gradually shifted from 400 ml or200 ml to 300 ml or 400 ml.” – what did you intend to say here ? Please rephrase.

Response: Thank you for this comment. The sentence has been rephrased as follows: http://bmjopen.bmj.com/ The blood volume per donation focus on 400ml and 200 ml has been gradually shifted to 300ml and 400ml

(Also did Page 2, line 38-40)

P8 l50: “The proportion of male donors consistently…”

Response: Thank you for this comment. The sentence has been rephrased as follows:

Basically, the proportion of male donors remained stable (57.6%). on September 29, 2021 by guest. Protected copyright.

P9 l1: I suggest you use “body weight” instead of “weight” throughout the manuscript.

Response: Thank you for this comment. We edited “weight” to “body weight”

P10 l1: “For the proportion of women, the year 2009 …”

Response: Thank you for this comment. The sentence has been rephrased as follows:

For the female donor number, the year of 2009 seems to be a turning point, (…)

P11 l10: “..were younger and represented an overall low donation rate…”

Response: Thank you for this comment. The sentence has been rephrased as follows:

As Table 2 shows, low body weight donors were younger and represented an overall low donation rate.

P11 l15: “For men, the rate of repeated donation increased…” BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Response: Thank you for this comment. The sentence has been rephrased as follows:

For men, the rate of repeated donation increased 19 percent in the subgroups ranging from 50-88 kg, and that of women also increased 19 percent in the subgroup ranging from 45 to 70 kg and over 70 kg.

P11 l23: “… increased 49.7% in the weight category 50 to 90 kg or more” – these would be two categories, please rephrase more precisely

Response: Thank you for this comment. The sentence has been rephrased as follows:

The rate of donating 400ml per time was associated with increasing weight too. For men, the proportion of 400ml donations increased 49.7 percent in the subgroup ranging from 50 to 90 kg and over 90 kg.

P13 l18: “… reached high levels in 2009”

Response: Thank you for this comment. The sentence has been rephrased as follows:

(…), so the number of blood donors reached high levels in 2009.

P13 l28: rather than “trough” I would suggest “the lowest value” or “nadir”

Response: Thank you for this comment. The sentence has been rephrased as follows:

Female blood donors were reduced to the nadir in 2012.

P13 l42: “groups” rather than “kinds” of people

Response: Thank you for this comment. The sentence has been rephrased as follows:

(…), it suggested that these groups of people are greatly influenced by outside public opinion.

P15 l0: please replace “amount volume” here and subsequently with “amount” or, preferably, “volume”

Response: Thank you for this comment. The sentence has been rephrased as follows: http://bmjopen.bmj.com/ (…), the greater the volume of blood, the less impact of blood donation on the body.

Note:

To make the manuscript more concise, we reedited other parts as follows:

Page 2, line 9-12: (…) to examine the trends in gender, age, weight and blood donation; and to examine the relationship between weight and donation. on September 29, 2021 by guest. Protected copyright. Page 2, line 32-35:Donors were dominated by males and between the age of 18-25, but this major age group shifted to the 26-45 age group over time

Page 2, line 51-53: However, given the expected growth in demand for whole blood, more research is needed to increase the donor pool and increase the rate of repeated donation.

Page 2, line 56: (…) body weight and blood donation also warrants further (…)

Page 3, line 22:This study is the largest scale study in blood donation of any province in China (…)

Page 3, line 38-40:To improve blood donation efficiency, the data was somewhat limited due to pragmatic needs and regulations.

Page 5, line 19-26: Among the 1.39 billion people in China in 2017, the number of seniors, aged 60 and above, reached 240.9 million. This accounted for 17.3% of the total population. Ages 65 and above reached158.31 million and accounted for 11.4%[10]

Page 5, line 49: It is unique in several aspects. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Page 6, line 43: Collections are conducted in fixed blood donation stations in urban areas and mobile (…)

Page 6,line 53: Since 2012, ‘blood donor health examination requirements’ (acronym as GB18467- 2011) was issued, repeated blood (…)

Page 6, line 32: (…) and supply blood to healthcare facilities. (…)

Page 8, line 4: Data extraction was performed by using (…)

Page 8, line 8: (…) regression analysis were performed by using (…)

Page 8, line 42: From 2006 to 2015, a total of 3,226,571 individuals donated 5,299,729 donations of whole blood in Zhejiang province (Table 1)

Page 8, line 19-27: We then examined characteristics of blood donors by body weight level for male and female respectively, using descriptive statistical methods to analyze the distribution of blood donations, etc.

Page 10, line 10: The same rates were 0.76% and 0.88% respectively for women.

Page 11, line 53: Our study aimed to identify the trends in (…)

Page 11, line 47-53: Since July 1, 2012, the proportion of people over the age of 56 increased slowly onwards.

Page 12, line 3: The results revealed that the average age of blood donors increased,(…)

Page 12, line 44: Considering the loss of blood donors who only donate once, it is crucial to (…)

Page 13, line 23-26: However, negative reports about the Red Cross in 2010 and 2011 led to a loss of confidence in blood donations, which resulted in a decrease in blood (…)

Page 13, line 44-50: More attention should be paid to strengthening public opinion and giving general guidance and emotional guidance. This is especially relevant, considering that the proportion of female blood donation has been on a downward trend since 2009. http://bmjopen.bmj.com/

Page 18, line 6 and line 14: Delete the original reference [9] and [12], so, all the references was reordered.

Page 13, line 18-21: GB18467-2011 further expanded the age to 60 years old(…)

Page 14, line 37-47: Considering that the 18-25-years-old are mainly college students who are likely to have different channels for media consumption and considering that the new generation has a very on September 29, 2021 by guest. Protected copyright. different value systems and strong personalities, blood establishments should adapt their education tools and methods to accommodate this condition to increase their interests in blood donation.

Page 14, line 5: Although the age group of 18-25-year-olds (…)

Page 15, line 36: Compared to the (…)

Page 15, line 13-21: Given that the blood volume of each donation is changing gradually from 200 ml to 300 or 400 ml, we might say that long-term blood donation publicity in Zhejiang has played a positive role. Additionally, the body weight gain year by year has played a positive role in influencing the choice of high volume blood donation and the possibility to participate in multiple blood donations.

Page 15, line 26: (…)and prevent weight gain too much for(…)

Page 15, line 21-29: delete “However, given the significant negative health consequences of obesity and the screening requirement prior to blood donation, potential donors should be educated to maintain healthy body weight and prevent weight gain too much for themselves and for maintaining the high quality of blood donated.”

Page 16, line 23-26:(…)and active lifestyle, to change the current trajectory of (…) BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Page 18, line 6 and line 14: Delete the original reference [9] and [12], so, all the references was reordered.

VERSION 2 – REVIEW

REVIEWER Thomas Volken, PhD Professor for Health Sciences Institute for Health Sciences School of Health Professions Zurich Univerity of Applied Sciences Winterthur, Switzerland REVIEW RETURNED 11-Oct-2018

GENERAL COMMENTS The authors have substantially improved their manuscript. I have no further comments.

REVIEWER Wolfgang Hoffmann Prof. Dr. med. Wolfgang Hoffmann, MPH Institut für Community Medicine Abt. Versorgungsepidemiologie und Community Health Universitätsmedizin Greifswald, Körperschaft des öffentlichen Rechts Ellernholzstr. ½ 17487 Greifswald Tel. 03834-86- 7750/7751 Fax: 03834-86-7752 e-mail: wolfgang.hoffmann@uni- greifswald.de http://www.community-medicine.de REVIEW RETURNED 01-Nov-2018

GENERAL COMMENTS In their revised manuscript, the authors address most of my concerns well and in detail. To my impression this is similar for the

points of criticism and the comments of the other two reviewers. http://bmjopen.bmj.com/ Assumed an equally adequate response to the remaining comments listed below I suggest the manuscript should be accepted for publication.

Remaining comments from my side: The design should be “Annual consecutive cross-sectional studies for the time period 2006-2015” The title could be: “Blood Donation from 2006 to 2015 in Zhejiang on September 29, 2021 by guest. Protected copyright. Province, China: Annual consecutive cross-sectional studies” P25: Table 1 column head “Number of blood donors” Categories of education: Please define the difference between “University” and “Graduate”. Is University really “university student” ? All Tabb: In their response the authors mention that donors with unknown professional status were grouped together with “others” – for education, however the authors differentiate between “others” and “missing”. This should be handled consistently – preferably with separate categories for “others” and “missing”, since only a fraction of missing values will really be “others” Table 2: “Donate frequency” should be “Donation frequency” (change other tables accordingly) Table 3: Add unit to each category of weight (change other tables accordingly) Fig 2: add “years” also to the categories in the legend (as correctly done for “kg” in the legend to fig. 5) P 14, line 49: instead of “same rates” it should be “corresponding rate” BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from

REVIEWER Daniele Pastori Sapienza University of Rome REVIEW RETURNED 29-Jan-2019

GENERAL COMMENTS This is a large cross-sectional study describing the characteristics of blood donors in China. The work is essentially descriptive and few clinical information are available.

- Some sentences would benefit from a rephrasing such as in the Introduction: “per 1000 population per year in high-income countries, 14.9in upper-middle-income countries, 7.8 in lower- middle-income countries, and 4.6 in low-income countries” - Spell out VNRBD in the text at first use. - Please clarify “(Figure 1to Figure 8)..” - This sentence needs a reference in support: “From 1998 to 2016, China's annual blood collection increased by 377% from 4,950,000Units to 23,600,000Units” - A lot of information not useful for the work in the Introduction. Please shorten. - The rationale of exploring the relationship between obesity and blood donation is unclear. Did the Authors expect an increase in the frequency of blood donations according to the increasing rate of obesity in China? And why? The increase in “healthy donor pool” would not automatically translate in an higher number of blood donations. - From a methodologic point of view, the assumption that “Because the body weight eligibility criteria for blood donation differs by gender, we performed separate regression analyses for men and women” is totally arbitrary. The inclusion criteria is not

related to the choice of the model. Furthermore, the use of body http://bmjopen.bmj.com/ mass index or waist circumference would be more informative than weight alone. - Multivariable logistic regression analysis is unclear. “Logistic regression models predicting donations each time ≥ 300ml and repeated donations, stratified by gender”. What is the dependent variable? How was defined the “repeated donation” (for example >/= 2 per year)? How was the cut-off of 300 ml chosen? If the Authors want to analyze these endpoints, two separate models should be built. on September 29, 2021 by guest. Protected copyright. - I would not stratify the logistic regression analysis by gender (this could be a secondary analysis), but rather I would put gender as covariate. - Addition of p values is necessary. - Chi squared analysis is essential to compare changes in the proportions of variables of interest (i.e. gender groups or age classes) across different time frames. - The value and implication of estimating the volume of blood donation is unclear, as it is not decided by donors. - Please provide reference number for ethical approval. - “other” for education category is unclear please define or delete.

BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from REVIEWER Calistus Wilunda Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Japan. REVIEW RETURNED 05-Feb-2019

GENERAL COMMENTS I was requested to review this manuscript with a particular emphasis on the statistical methods and analyses used. I have therefore not paid much attention to the other sections. The authors seem to have analyzed and presented the data appropriately. The statistical methods used are rather straight forward. I have only these three minor comments: 1. There is no explicit mention of the study design in the Methods section. This could have been a more appropriate place to situate the statement on the use of STROBE guidelines for reporting. 2. Page 10, line 17: consider using “…analysis of ….” Instead of “analysis on …” 3. Page 10, line 33: It is not clear what etc. means. Please specify what was analyzed.

VERSION 2 – AUTHOR RESPONSE

Reviewer(s)' Comments

Reviewer #1:

The authors have substantially improved their manuscript. I have no further comments.

Response: Thank you very much. We have revised and improved our paper because of your former valuable and helpful comments. We appreciate so much. http://bmjopen.bmj.com/

Reviewer #2:

In their revised manuscript, the authors address most of my concerns well and in detail. To my impression this is similar for the points of criticism and the comments of the other two reviewers. on September 29, 2021 by guest. Protected copyright. Assumed an equally adequate response to the remaining comments listed below I suggest the manuscript should be accepted for publication.

Response: Thank you very much. We have revised and improved our paper because of your former thoughtful and helpful comments. We appreciate so much.

Remaining comments:

1. The design should be “Annual consecutive cross-sectional studies for the time period 2006-2015”

Response: Thank you for this comment. We considered and accepted it, the design in Page 2,line 42 has been modified as follows:

Annual consecutive cross-sectional studies for the period 2006-2015. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from 2. The title could be: “Blood Donation from 2006 to 2015 in Zhejiang Province, China: Annual consecutive cross-sectional studies”

Response: Thank you for this comment. We considered and accepted it, the title has been modified as follows:

Blood Donation from 2006 to 2015 in Zhejiang Province, China: Annual consecutive cross-sectional studies.

3. P25: Table 1 column head “Number of blood donors”

Response: Thank you for this comment. Table 1 column head has been modified as Number of blood donors

4. Categories of education: Please define the difference between “University” and “Graduate”. Is University really “university student” ?

Response: Thank you for this comment.“University” including junior college degree and bachelor degree, “Graduate” means master degree. To be more clear, we have modified “Graduate” as “Postgraduate” in Table 1, Table 2 and Table 3, and added the sentence at the bottom of Table 1, Table 2 and Table 3 as follows:

“University” including junior college degree and bachelor degree.

5. All Tabb: In their response the authors mention that donors with unknown professional status were grouped together with “others” – for education, however the authors differentiate between “others” and “missing”. This should be handled consistently – preferably with separate categories for “others” and “missing”, since only a fraction of missing values will really be “others”

Response: Thank you for this comment. We explained it in the third paragraph in Page 8.”Due to the complexity and privacy of the profession, there were 105 blood donors who chose not to complete http://bmjopen.bmj.com/ forms. Because of this, their employment status information was missing. The occupation of these donors was included in the category ‘other’.”

Because the number is so small that the proportion is nearly 0 percent, so we put these donor into category “Other”. But the proportion of missing data in education is 2%, so we write separately.

6. Table 2: “Donate frequency” should be “Donation frequency” (change other tables accordingly) on September 29, 2021 by guest. Protected copyright. Response: Thank you for this comment. Each “donate frequency” has been modified as “Donation frequency” in Table 1 and Table 2

7. Table 3: Add unit to each category of weight (change other tables accordingly)

Response: Thank you for this comment. We have added unit to each category of weight in Table1, Table3 and Table 4.

8. Fig 2: add “years” also to the categories in the legend (as correctly done for “kg” in the legend to fig. 5)

Response: Thank you for this comment. We have added “years” to the categories in the legend in Figure2 as follows:.

And correspondingly, added “ml” to the categories in the legend in Figure8 as follows:

9. P 14, line 49: instead of “same rates” it should be “corresponding rate” BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Response: Thank you for this comment. We have modified “same rates” to "corresponding rate"

Reviewer #4

This is a large cross-sectional study describing the characteristics of blood donors in China. The work is essentially descriptive and few clinical information are available.

1. Some sentences would benefit from a rephrasing such as in the Introduction: “per 1000 population per year in high-income countries, 14.9in upper-middle-income countries, 7.8 in lower-middle-income countries, and 4.6 in low-income countries”

Response: Thank you for this comment. We have edited the sentence as follows:

A recent WHO report indicated that every year the median whole blood donation per 1000 population differs with different income level, which was 32.1 in high-income countries, 14.9in upper-middle- income countries, 7.8 in lower-middle-income countries, and 4.6 in low-income countries.

In introduction, we delete the sentence in Page 5 line 7-14: “As a developing country, China's whole blood donation rate (median) was 10.5 donations per 1000 population in 2016, which is between upper-middle-income countries and lower-middle-income countries [3].

We edited the sentence in Page5 line 30-41as follows:

Zhejiang province, located on China's eastern coast with 55.9 million residents (10th largest), is one of the most economically developed provinces of China[4]. In 2016, the blood donation rate (median) in Zhejiang province was 11.8 donations per 1000 population, higher than the national average of 10.5 but still falls short of meeting the need for clinic transfusion.

We edited the sentence in Page 6 line 3 as follows: http://bmjopen.bmj.com/ Demographic characteristics varied among countries or region.

2. Spell out VNRBD in the text at first use.

Response: Thank you for this comment. VNRBD in the text at first use is in Page 4. The sentence has been modified as follows:

South-East Asia had the highest percentage increase (75%) in VNRBD (Voluntary Non-Remunerated on September 29, 2021 by guest. Protected copyright. Blood Donation) among 159 countries from 2008 to 2013

And Correspondingly, delete the sentence “VNRBD stands for Voluntary Non-Remunerated Blood Donation. ” in Page 8.

3. Please clarify “(Figure 1to Figure 8)..”

Response: Thank you for this comment. We have edited in Page 10,line27 as follows:

(Figure 1 Blood donor numbers in2006-2015, Figure 2Blood donor age category(years)in 2006-2015, Figure 3 Blood donor number of different gender in 2006-2015,Figure 4Blood donor average body weight(kg)in 2006-2015,Figure 5 Male blood donor body weight category(kg)in 2006-2015, Figure 6 Female blood donor body weight category(kg)in 2006-2015,Figure 7Blood donor education in 2006- 2015; Figure 8 Donation volume per time(ml)in 2006-2015)

4. This sentence needs a reference in support: “From 1998 to 2016, China's annual blood collection increased by 377% from 4,950,000Units to 23,600,000Units” BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from Response: Thank you for this comment. We have add the reference as follows:

[3] National Health Commission of the People’s Republic of China website. Interpretation of the "Notice on 2016 Blood Safety Technology Verification. Available at: http://www.nhc.gov.cn/yzygj/s7658/201704/d40d657217dd4ead8dd37ee7d38d22d4.shtml

[5 ] National Health Commission of the People’s Republic of China website. Bulletin on the 2017 National Blood Safety Technology Verification. Available at: http://www.nhc.gov.cn/yzygj/s7658/201805/77ba80726c694b188e617f0d43d23856.shtml

And all the references were reordered.

5.A lot of information not useful for the work in the Introduction. Please shorten.

Response: Thank you for this comment. In the introduction, we delete the sentence in Page 5 line 7- 14: “As a developing country, China's whole blood donation rate (median) was 10.5 donations per 1000 population in 2016, which is between upper-middle-income countries and lower-middle-income countries [3].

We edited the sentence in Page5 line 30-41as follows:

Zhejiang province, located on China's eastern coast with 55.9 million residents (10th largest), is one of the most economically developed provinces of China [4]. In 2016, the blood donation rate (median) in Zhejiang province was 11.8 donations per 1000 population, higher than the national average of 10.5 but still falls short of meeting the need for clinic transfusion.

We edited the sentence in Page 6 line 3 as follows:

Demographic characteristics varied among countries or region. http://bmjopen.bmj.com/ 6.The rationale of exploring the relationship between obesity and blood donation is unclear. Did the Authors expect an increase in the frequency of blood donations according to the increasing rate of obesity in China? And why? The increase in “healthy donor pool” would not automatically translate in an higher number of blood donations.

Response: Thank you for this comment. As we explained in the introduction, body weight is very important for donation. But there is a degree, it cannot meet the donation criterion if body weight is too low, but it is also bad for blood donation because of bad health problem of obesity if body weight is on September 29, 2021 by guest. Protected copyright. too high, so this research intends to study a good gender-specific body weight range for donation based on the retrospective analysis of database. We noticed the relationship between body weight and blood donation from the result, but we do not expect an increase in the frequency of blood donations according to an increasing rate of obesity. Because of the bad health problem that obesity can cause, we want to remind people to consider the problem of obesity in China and other countries which may influence the blood donation. And it is correct that the increase in “health donor pool” would not automatically translate in a higher number of blood donations. The increase of “health donor pool” indeed provides the base of the blood donors, however, to translate into higher blood donations need a more recruitment efforts to increase awareness, acceptance, and participation in voluntary blood donation. To be more clear, we edited the sentence in Page 7 line 22-27:

Also, the gender-specific body weight analysis offers insight into the future development of gender- specific donor recruitment and retention strategies as healthy lifestyles help maintain healthy body weight, which in turn increases the base of healthy recruitable donors. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from 7.From a methodologic point of view, the assumption that “Because the body weight eligibility criteria for blood donation differs by gender, we performed separate regression analyses for men and women” is totally arbitrary. The inclusion criteria is not related to the choice of the model. Furthermore, the use of body mass index or waist circumference would be more informative than weight alone.

Response: Thank you for this comment. This study is different from clinical trials in that it is an analysis of VNRBDs in Zhejiang Province who are all eligible for blood donation and have successfully donated blood. The separate logistic regression analysis by gender is to make the body weight better classified, because the weight limited standards of male and female blood donation are not the same, and the range of male body weight is larger than female in China, the separation can better set the reference system, 50- 59 kg is the male reference category , and women with 45-50 kg as the reference category , it can make the next weight category contrast with the reference category more clearly, which is very important for the next recruitment.

BMI index or waist circumference value you mentioned is very inspiring and more reflective of the overall situation of the blood donor, but unfortunately, due to pragmatic needs and regulations, the demographic information composition was to a minimum to improve blood donation efficiency. In the initial blood donation collection system, these two indicators were not collected. We plan to collect such information in a future study.

8.Multivariable logistic regression analysis is unclear. “Logistic regression models predicting donations each time ≥ 300ml and repeated donations, stratified by gender”. What is the dependent variable? How was defined the “repeated donation” (for example >/= 2 per year)? How was the cut-off of 300 ml chosen? If the Authors want to analyze these endpoints, two separate models should be built.

Response: Thank you for this comment. Sorry for any confusion. To be more clearly, we built two separate models. Table 3 (Logistic regression models predicting donations each time ≥ 300ml,

separated by gender) takes donations each time ≥ 300ml as the dependent variable, table 4 (Logistic http://bmjopen.bmj.com/ regression models predicting repeated donations, separated by gender) takes repeated donations as the dependent variable.

Repeated donations mean the blood donor will come back to donate again in the future, the total blood donations times are more than once.

There are three types of blood donation in China, they are 200ml, 300ml, and 400ml.The limit volume of blood donation is 200ml. So our goal is encouraging people to donate more volume, not the on September 29, 2021 by guest. Protected copyright. minimum blood donation 200ml, Hence, we choose more than 300ml as the dependent variable, that including 300ml and 400ml.

9.I would not stratify the logistic regression analysis by gender (this could be a secondary analysis), but rather I would put gender as covariate.

Response: Thank you for this comment. In the initial construction of the model, gender was used as a covariate to control the variables. In the process of analysis, the classification of body weight (the type of division) became a problem, because the weight of males and females was transformed into categorical variables. The spacing and the range are very different, so in order to increase the scientificity of the prediction model, the gender is distinguished to establish two equations.

10.Addition of p values is necessary.

Response: Thank you for this comment. We have added p values in both table 3 and table 4. BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from 11.Chi squared analysis is essential to compare changes in the proportions of variables of interest (i.e. gender groups or age classes) across different time frames.

Response: Thank you for this comment. The chi-square analysis results were analyzed, and all the results were P<0.001, the professor of statistics also suggested us to delete it, because the sample size we investigated was large, reaching millions of times, and the most important is that it was a concept of "overall" in terms of the group of blood donors in Zhejiang province we studied.

12.The value and implication of estimating the volume of blood donation is unclear, as it is not decided by donors.

Response: Thank you for this comment. In Page 6 line 22-32, these sentences illustrate the relationship between body weight and blood volume in order to help people realized the importance of body weight. From this perspective, the choice of blood donation volume is closely related to body weight. It offers the scientific basis for the recommendation of blood donation volume.

13. Please provide reference number for ethical approval.

Response: Thank you for this comment. The ethical approval is Medical Ethics Committee of Blood Center of Zhejiang Province (NO. 2006002).

14. “other” for education category is unclear please define or delete.

Response: Thank you for this comment. We add define of “other” for education at the bottom of Table 1, Table 2,Table 3 and Table 4 as follows:

“Other” including lower than Elementary school or higher than Postgraduate

Reviewer #5 http://bmjopen.bmj.com/ 1. There is no explicit mention of the study design in the Methods section. This could have been a more appropriate place to situate the statement on the use of STROBE guidelines for reporting.

Response: Thank you for this comment. We have edited the “Study setting” to “Study setting and design” in Page 6. And add the sentence in the last paragraph of Study setting and design in Page 7as follows:

Design: Annual consecutive cross-sectional studies for the time period 2006-2015. on September 29, 2021 by guest. Protected copyright.

2. Page 10, line 17: consider using “…analysis of ….” Instead of “analysis on …”

Response: Thank you for this comment. We have modified “…analysis of ….”to “analysis on …”

3. Page 10, line 33: It is not clear what etc. means. Please specify what was analyzed.

Response: Thank you for this comment. We edited “etc.” as follows:

, we considered from the perspective of men and women, using regression analysis, to predict blood donation more than 300 ml and to predict repeated blood donation

Note:

To make the manuscript more concise, we reedited other parts as follows: BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from 1. Page 3, line 9-15: Results: The number of blood donations generally trended up in Zhejiang province from 2006 to 2015.Donors were predominately males aged 18-25 years but this major donor age group shifted to the 26-45 year range by 2015.

2. Page 3, line20: Approximately one-third of donors have a college education.

3. Page 6, line 12: As a result, the proportion of younger donors (…)

4. Page 8, line 17: (…), professional staff will offer advice, (…)

5. Page 8, line 50: There is no patient and public involvement in this study.

6. Page 8, line 53: (…), to analyze the data of blood donors (…)

7. Page 9, line 42: (…) regardless of whether the donor was single-time donor or multiple-times donor.

8. Page 10, line 17: We performed a descriptive analysis of (…)

9. Page 13, line 3: Regarding blood volume of each donation, (…)

10. Page 13, line 17: (…) while the proportion of high schools (…)

11. Page 13, line 46: (…) and an increasing proportion of (…)

12. Page 13, line 46: The trend of blood donor number is a little different from the EU. The donor population of the EU (…)

13. Page 16, line 33: (…) the social atmosphere of blood donation (…)

http://bmjopen.bmj.com/

VERSION 3 – REVIEW

REVIEWER Wolfgang Hoffmann Institute for Community Medicine Section Epidemiology of Health Care and Community Health University Medicine Greifswald Ellernholzstr. ½ 17487 Greifswald e-mail: [email protected] http://www.community- on September 29, 2021 by guest. Protected copyright. medicine.de REVIEW RETURNED 08-Mar-2019

GENERAL COMMENTS Thank you for responding to my remaining comments and the other reviewer's comments carefully and convincingly. I have no further comments and recommend accept.

REVIEWER Daniele Pastori Sapienza University of Rome REVIEW RETURNED 27-Feb-2019

GENERAL COMMENTS The manuscript improved after revision. Few residual comments:

- Please change "Design: Annual consecutive cross-sectional studies for the period 2006-2015" with " Cross-sectional study BMJ Open: first published as 10.1136/bmjopen-2018-023514 on 19 May 2019. Downloaded from comparing characteristics of blood donors and annual donations for the period 2006-2015". - List of figures in the statistical paragraph is not appropriate - Please delete the following sentence from the Introduction: "Rapid advances in medical technology, sustained trend in population aging, and the growth rate of chronic diseases are among the main contributors to an upward trending demand for blood and blood products". - Please delete the following sentence from the Introduction: "Zhejiang province, located on China's eastern coast with 55.9 million residents (10th largest), is one of the most economically developed provinces, with top-ranking annual per capita disposable income for 21 consecutive years".

VERSION 3 – AUTHOR RESPONSE

Reviewer(s)' Comments

Reviewer #4:

- Please change "Design: Annual consecutive cross-sectional studies for the period 2006-2015" with " Cross-sectional study comparing characteristics of blood donors and annual donations for the period 2006-2015".

Response: Thank you for this comment. We have modified the sentence in the abstract and Page 7,line29 as suggested.

- List of figures in the statistical paragraph is not appropriate

Response: Thank you for this comment. We deleted the list of figures in the statistical paragraph. http://bmjopen.bmj.com/

- Please delete the following sentence from the Introduction: "Rapid advances in medical technology, sustained trend in population aging, and the growth rate of chronic diseases are among the main contributors to an upward trending demand for blood and blood products".

Response:We have deleted these sentences from the Introduction.

- Please delete the following sentence from the Introduction: "Zhejiang province, located on China's on September 29, 2021 by guest. Protected copyright. eastern coast with 55.9 million residents (10th largest), is one of the most economically developed provinces, with top-ranking annual per capita disposable income for 21 consecutive years".

Response: We have deleted these sentences from the Introduction. Consequently, the references have been reordered.

Reviewer #3:

Thank you for responding to my remaining comments and the other reviewer's comments carefully and convincingly. I have no further comments and recommend accept.

Response: Thank you for your review.