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Does Physiological Distribution of Blood Parameters In BMJ Open: first published as 10.1136/bmjopen-2017-019143 on 1 March 2018. Downloaded from PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. ARTICLE DETAILS TITLE (PROVISIONAL) Does physiological distribution of blood parameters in children depend on socioeconomic status?: Results of a German cross- sectional study AUTHORS Rieger, Kristin; Vogel, Mandy; Engel, C; Ceglarek, Uta; Harms, Kristian; Wurst, Ulrike; Lengfeld, Holger; Richter, Matthias; Kiess, Wieland VERSION 1 – REVIEW REVIEWER Molly Moor University of California, San Diego, USA; San Diego State University, USA REVIEW RETURNED 25-Sep-2017 GENERAL COMMENTS Clarification is required concerning the criteria for determining iron deficiency in this manuscript, and whether or not any participants actually met the case definition of having iron deficiency or anemia. Furthermore, the conclusions of this paper are not supported by the http://bmjopen.bmj.com/ results presented. In the Abstract under the design section, the word “londitudinal” is misspelled and should be “longitudinal.” The sentence regarding the study participants in the Abstract does not make sense. Page 4, Lines 17-18: Remove preterm delivery as a childhood consequence of low SES (preterm delivery is a maternal rather than on September 30, 2021 by guest. Protected copyright. childhood factor). Page 4, Lines 49-50 currently reads: “Here, no significant correlation could be shown for haemoglobin, whereas a significant correlation was visible between low ferritin levels and low parental income [13].” And should be reworded for clarity to: “There was a significant correlation between low parental income and low ferritin levels, but no associations found between income and haemoglobin levels.” Page 4, LINE 55-57 Rephrase “Since anaemia leads to a strong deprivation of the child’s well-being, this seems to be an important criterion of health in association with SES.” as it does not make sense as written. Page 6 Methods: Did parents provide consent for enrollment in LIFE child? Page 6 Laboratory Measures: Please include the normal ranges that you used for hemoglobin, ferritin, and transferrin. Page 6, Line 17-18 should be worded that children “were” recruited instead of “are” recruited since the participants have already been enrolled in the study. BMJ Open: first published as 10.1136/bmjopen-2017-019143 on 1 March 2018. Downloaded from Page 6, Line 42 should read “fasting blood samples were not a necessary” Page 7, Lines 12-13, please clarify the unit of time for the parental household income– is it per week? per month? Results: Please include the mean lab values for each age/sex group. What were the normal ranges for hemoglobin, transferrin, and ferritin for each age/sex group? Were any participants anemic? Anemia was discussed in the introduction but never mentioned in the results. Page 9, lines 14-18, Table 1 shows the differences in SD in blood parameters between genders, but doesn’t indicate if these differences are statistically significant. On Page 9, Lines 17-25 and Figure 1, please indicate if any of these differences by SES level are statistically significant. No causality can be inferred (speculation or otherwise) from a cross- sectional study. Thus, please remove the sentence “Therefore, it is tempting to speculate that WSI, especially income, influences haemoglobin levels” on Page 11, Lines 9-10. Page 11, lines 23-23 states “The combination of low haemoglobin- and ferritin-concentrations and high transferrin-concentrations fulfils the criteria of iron deficiency.” Taking this into account, we consider our results as a possible risk factor for development of anaemia in families with low SES. Thus, health inequalities starting in childhood might be the consequence of differences in SES. However, there are defined age and gender specific limits to determine iron deficiency [14, 17, 19]. Please remove these sentences from the paper because they do not support your findings as written. It is unclear if any participants in your study actually had blood laboratory values that were blow the normal range. Page 11, Line 34 , please change “most affecting” to “strongest”. Page 11, lines 34-55, Please also add that children of families of very low SES may be undernourished because they don’t receive enough food. Page 11, lines 37-38 the statement “Low-income families are very http://bmjopen.bmj.com/ skilled at budgeting” is not generalizable to all low SES families, so please remove it. The discussion section needs to be rewritten. Page 11 line 53- page 12, line 16 focuses on obesity. You cannot draw conclusion about SES and blood parameters and obesity from your study because you did not collect BMI from the children so you don’t know if they are overweight or underweight. Please remove the discussion about obesity. Please start a new paragraph with “Another predictor for iron- on September 30, 2021 by guest. Protected copyright. related….” on page 12, line 16. Transferrin levels may be impacted by inflammation, infections, and malignancies, not just iron deficiency. Please make note of this in the paper. It is important to note that iron differences increase in female adolescents with the onset of menses. This should be added to your paper in the introduction and in the discussion. Page 13, lines 5-7. Please replace “it is tempting to speculate” with “it is plausible” It is stated in the conclusion that there is “a shift towards physiological distribution of iron-related parameters in the direction towards iron deficiency in families with lower income”. This statement is not justified because this study does not indicate the proportion of children/adolescents with below normal laboratory values that meet the definition for iron deficiency or anemia. BMJ Open: first published as 10.1136/bmjopen-2017-019143 on 1 March 2018. Downloaded from A small shift in these values does not necessarily mean a child or adolescent is in danger of being iron deficient because the normal ranges of laboratory values for widely, especially for ferritin and transferrin. Please clarify if any of the children/adolescents in this study have laboratory results that were below the normal range. Also, is there published evidence that serum iron parameters that are on the lower end of the normal physiologic range have an adverse effect on a child/adolescent’s health? If so please cite. Otherwise, please remove the sentences in the abstract and conclusion that state “We demonstrate that iron-related blood parameters shift in the direction of iron deficiency in families with lower income. Therefore, insufficient iron alimentation due to lower socioeconomic status has a direct and adverse effect on children’s health.” The paper as written does not support these conclusions. In summary, the paper contributes some new information to the correlation between SES and iron-related blood parameters; however, the discussion is weak and makes assumptions that cannot be extrapolated based on the cross-sectional nature of this study. REVIEWER Jun Ma Institute of Child and Adolescent Health, China REVIEW RETURNED 17-Oct-2017 GENERAL COMMENTS This study examined the association between SES and iron-related blood parameters among German children aged 2.5 to 19 years. it imay be helpful for the future prevention of iron deficiency in children. However, I have some comments on this study. Major comments: 1. The associations found in this study confirm the previous studies. http://bmjopen.bmj.com/ However, those findings are limited to improve our knowledge on that topic. More details are warranted to answer why those associations happen? For example, is it because the differences in food intake and physical activity between various SES groups influence those haemoglobin relative indicators? These details could benefit the intervention and policy making. 2. Regarding the impact of puberty on haemoglobin relative indicators, which are also different between sexes, analyses are on September 30, 2021 by guest. Protected copyright. suggested to be performed by different age-and-sex groups. Minor comments: 1. Page 2 Line 15 Do not start a sentence by a number. "1,214 health volunteers" could be “A total of 1,214 health volunteers”. 2. Page 3 Line 39: “all test subjects involved have signed a consent form”. Regarding the young children were involved, did the authors got their parents’ consents? 3. Page 6 line 27, describe the random method used to select one child. 4. Page 7 line 4，please list the studies using WSI. 5. Page 7 line 54, how did the authors calculate Z-score? Where are the references of mean and deviation come from? Are these references age-and-sex-specific? 6. The formats of tables are not academic. 7. Table 1, the original values of the blood parameters should be shown with means and SDs. 8. Figure 1, adjusted means and standard errors could be better. BMJ Open: first published as 10.1136/bmjopen-2017-019143 on 1 March 2018. Downloaded from VERSION 1 – AUTHOR RESPONSE Response to Reviewer 1: -Clarification is required concerning the criteria for determining iron deficiency in this manuscript, and whether or not any participants actually met the case definition of having iron deficiency or anemia. We are grateful for this important comment. Accordingly,we added the following section in the methods (page 8 line 12-16) and results (page 12 line 19-23) parts: “Based on the AWMF guideline for iron deficiency diagnostics in children [17] states of iron deficiency were categorized as follows: latent iron deficiency (decrease in ferritin with normal haemoglobin, MCV, and MCH), manifest iron deficiency (decrease in haemoglobin and MCV). Anaemia of other cause was defined as age-related median haemoglobin decreased by more than two standard deviations [17], excluding manifest iron deficiency as mentioned above.” “Anaemia in genereal was shown for 4.2% of the children, whereas 0.7% showed a manifest iron deficiency and 3.6% had anaemia of other cause.
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