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本帖最后由 ywshui 于 2012-2-19 18:48 编辑
这是我被接受的一篇文章（影响力大于5的）的意见回复信（只包括审稿人1和2以及学术编辑，不包括杂志助理编辑即审稿人3，原因为涉及到稿件信息），作为例子贴出来和大家分享（部分信息已经隐去，鉴谅）。
Dear Dr. XXX,
On behalf of my co-authors, we would like to thank you very much for giving us an opportunity to revise our manuscript entitled “XXXXXXXXXXXX” (Ms. Ref. No.: ##########). We appreciate reviewers very much for their valuable and constructive comments on our manuscript. We have revised the manuscript, and would like to resubmit it for your consideration. Please note the current version containing new line and page numbers in the text, some grammar and spelling errors have also been corrected. Furthermore, the relevant regulations had been made in the original manuscript according to the comments of reviewers, and all the revised portions were marked in red font. We also responded point by point to each reviewer’s comments as listed below, along with a clear indication of the location of the revision. Hope these will make it more acceptable for publication.
1 Replies to Reviewer #1
1.1 Major comments
Major comments #1: This study is timely, given the number of studies that have been published to date, and the need to consolidate the information across populations. The methodology is generally sound, the language used is concise and clear, and the approach appears to be a balanced one. In general, the presentation of results from each study should emphasize the various sub-populations, so that the comparisons are meaningful in the context of the XX-lung cancer hypothesis. E.g. results are summarized graphically in one Plot, which gives the overall results for each study - unfortunately, in many cases the populations are quite different, and presenting the results in this way is not optimal. It would be very helpful to the reader to stratify individual study results by gender, smoking status and Asian/non-Asian population and present these separately in the Plot.
Answer: Changes have been made as suggested.
We agree. Three figures have been plotted to display the results (XX intake and the risk of lung cancer) by gender, smoking status, and study population (shown in Supplemental Figure 1, 2, and 3. page 27-29). Considering the manuscript length, we decide to provide these graphs as online supplemental materials (OSM). And the relevant data can also be available in Table 3 in the text.
Major comments #2: Differences in average intake of XX and soy isoflavones between populations are notable, and this is mentioned on page 8 (line 3-4), but only briefly. Would strongly suggest that this is described in more detail, and that the discussion and interpretation of the results should take this into account. For example, in the Discussion, page 10 line 10, there could be some indication as to what level of intake would constitute a 'diet rich in soy', based on the available evidence.
Answer: Relevant data regarding levels of soy or soy isoflavones intake in studies we analyzed have been added in Table 1 (i.e., levels of soy or soy isoflavones consumption in the highest and the lowest category). In addition, comments have been made in Discussion section (line 3-9, page 12), and we only compared the values for soy isoflavones intake between Asian and Western populations, because values for total soy food intake are not available in studies from Western populations.
As the referee suggested, it is very meaningful that more recommendations based on the available evidence should be made for the public. For example, based on the epidemiological data, what amount of average soy or soy isoflavones intake is needed for a reduced risk in lung cancer. In order to answer this question, we extracted the dose-response data from included studies (shown in Table I, Supplemental data for reviewers only) and attempted to conduct a dose-response analysis (1. Greenland S, Longnecker MP. Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol 1992; 135:1301-9.; 2. Hamling J, Lee P, Weitkunat R, Ambuhl M. Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med 2008;27:954-70.). Unfortunately, we failed to summarize those dose-response data due to different methods used to assess and report soy intake across the included studies (Table I). Moreover, because no included study has simultaneously evaluated the three key elements of soy or soy isoflavones intake i.e. frequency, intensity, and duration, or at least two of the three, and the dose-response relationships are not fairly consistent (Table I), it is difficult to determine which levels of soy or soy isoflavones intakes are optimal in lung cancer prevention. This issue was discussed in the revised text (line 11-17, page 13).
Major comments #3: The differentiation between fresh and fermented soy food is not very clear (page 12 lines 14ff). I am not sure if I understood this paragraph, but were the two studies (trials?) selected based on the inclusion of fermented foods, and did this mean that the estimates for unfermented soy foods were not included in the analysis? If so, what would the potential impact be on the summary OR? The basis of selection of specific types of soy foods for specific studies would need to be explained in the methods section more clearly.
Answer: Changes have been made as suggested.
Fermentation is a processing method for improving nutritional and functional properties of soybeans due to the increased content of small bioactive compounds. The large protein, lipid, and carbohydrate molecules in raw soybean are broken down by enzymatic hydrolysis during fermentation to small molecules such as peptides, amino acids, fatty acids, and sugars, which are responsible for the unique sensory and functional properties of the final products (Kwon DY, Daily JW, Kim HJ, Park S. Antidiabetic effects of fermented soybean products on type 2 diabetes. Nutrition Research.2010;30:1-13.). In addition, human in vivo study showed that fermentation can increase the availability of isoflavones in soy via increasing the urinary isoflavonoid recovery (Hutchins AM, Slavin JL, Lampe JW. Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products. J Am Diet Assoc 1995;95:545-51.). However, to the best of authors' knowledge, no published data, to date, has compared the effects of fermented soy foods with those of unfermented soy foods on carcinogenesis in animal experiments. Although dietary supplementation with miso shows an inhibitory effect on breast (46), stomach (47), and colon (48) tumorgenesis, there is currently no published study available in a lung model. Therefore our finding (i.e. the different effect on lung cancer was observed between fermented and unfermented soy foods) underscores the need for future studies to clarify the difference between fermented and unfermented soy food in the etiology and prevention of lung cancer, and we rewrote the comments on this issue in discussion section (line 13-23, page 12).
Because two studies (28, 29) separated the risk estimates according to the different types of soy foods (i.e. tofu, miso soup, soybean, and soybean curd), and did not report the effect of total soy food or soy product intake, we only selected tofu in overall analysis in our previous version. But in current revised manuscript, the study-specific estimate was recalculated in these two studies (28, 29), via pooling the risk estimates of those various soy types reported in each study, weighted by inverse variance (18) (line 18-21, page 6 and line 11-13, page 8). However, the study-specific OR/RR in overall analysis from other studies we analyzed was based on a wide range of soy foods and can be most representative of the total soy or soy product intake (Table 1-footnote, page 22).
1.2 Minor comments
Minor comments #1: Table 1: The OR/RRs quoted in the table are assumed to be the overall estimates for each study. For Ref 29, the OR quoted is the figure for smokers only (this also applies to Fig 2).
Answer: Errors have been corrected in the revised version.
Minor comments #2: References in Table 1 are not in accord with the text and reference list.
Answer: Errors have been corrected in the revised version.
Minor comments #3: Would suggest removing the analysis by specific isoflavones (table 3 and page 12 lines 19-22) because of the limited number of studies that reported results separately for genistein/daidzein/equol.
Answer: Changes have been made according to the referee’s suggestion.
2 Replies to Reviewer #2
2.1 Major comments
Major comments #1: The authors conducted a study on the association of xx and xxx intake with risk of lung cancer. They found an inverse association in the overall studies, and inverse association seemed to be restricted to women, never smokers, and Asian populations.
This meta-analysis included a study using plasma isoflavone concentration (reference no. 33). All other studies seem to assess dietary intake using questionnaire. Plasma isoflavone concentration is not identical to dietary intake because plasma level reflects not only intake but also absorption and metabolism of isoflavones. In fact the total isoflavone concentration in the plasma study includes equol. The exclusion of the study from main analysis should be considered.
Answer: Changes have been made based on this constructive suggestion.
Arai Y and colleagues found that the dietary intake of daidzein and genistein after adjustment for total energy intake was significantly correlated with the plasma concentration (r = 0.335 for daidzein and r = 0.429 for genistein) (Arai Y, Uehara M, Sato Y, et al. Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake. J Epidemiol 2000; 10:127-135), suggesting that measurements of plasma concentration of isoflavones (genistein and daidzein) are useful biomarkers of dietary intake. However, whether the plasma equol or the three (i.e., genistein, daidzein, and their metabolite: equol) can reflect the level of total dietary isoflavones intake is unknown. In addition, no evidence shows that almost the entire dietary isoflavones intake in the study by Shimazu T et al (Shimazu T, Inoue M, Sasazuki S, et al. Plasma isoflavones and the risk of lung cancer in women: a nested case-control study in Japan. Cancer Epidemiol Biomarkers Prev 2011;20:419-27.) is from soy foods.
For the above uncertainties, inclusion of a study by Shimazu T et al, may threat to the validity of research synthesis in our analysis, and we cautiously excluded it in the current version of our manuscript and modified the study selection criteria in Methods section (line 17-19, page 5).
2.2 Minor comments:
Minor comments #1: Title: Because soy foods are not equal to isoflavones, “Soy intake is…” should be “Soy and isoflavone intake is…”
Answer: No change has been made.
Our present meta-analysis mainly focused on the relationship between soy food intake and the risk of lung cancer. Although the constituents responsible for the hypothesized anticancer effects of soy have not been definitively identified, soy isoflavones have received the most attention, and considerable evidence suggests that they are the primary soy chemopreventive agents (Messina M, Flickinger B. Hypothesized anticancer effects of soy: evidence points toward isoflavones as the primary anticarcinogens. Pharm Biol 2002; 40:S6–S23). Thus, we also, with interest, tested the effect of soy-derived isoflavones (daidzein and genistein) intake on lung carcinogenesis based on currently available epidemiological studies (refs. 25-27, 32, please see the reference list in the revised version), while other isoflavones (e.g., biochanin A and formononetin) or other dietary isoflavones sources rather than soy in relation to lung cancer was not studied in current analysis. We therefore believe that the title in the text can sufficiently and accurately summarize our work.
Minor comments #2: Table 1: The authors used the word “Soy isoflavones”. Foods other than soy may contain isoflavones. Almost all of the isoflavone sources in Asian populations may be soy foods. However, is this the case in non-Asian populations? If not, “Soy isoflavones” should be “Isoflavones”. Also, if available, absolute value of isoflavone intake in the highest category is informative.
Answer: Yes, it has been known that isoflavones are found in a number of legumes, grains and vegetables in addition to soy. Although dietary soy is the main contributor to the total isoflavones intake worldwide, no evidence suggests that almost the entire dietary isoflavones sources are soy foods, even in countries with high soy consumption, such as Japan, Singapore, and China (Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer 2006; 55:1-12).
“Soy isoflavones” in current version of our manuscript means the isoflavones ONLY derived from soy foods, and we only included studies if they evaluated the association between soy or soy-derived isoflavones (refs. 25-27, 32) and lung cancer risk (line 13-19, page5).
The data as to the amount or the frequency of soy or soy isoflavones intake in two compared categories have been added in the revised version (shown in Table 1). Moreover, some comments have been made in the Discussion section (line 3-10, page 12) regarding this issue.
3 Replies to editor’s comments
There are several places in the paper in which the authors overstate or over interpret the lack of statistical significance to mean the lack of evidence of an effect. The issue is clearest in the discussion of males versus females. The point estimate of the association for males shows a larger benefit for men (RR-0.65) then it is for women (RR=0.75), but because of the lack of formal statistical significance the authors state thate 'there was no evidence of preventive effect in men'. This is an overstatement for two reasons. First, the evidence of preventive effect IS the point estimate NOT the fact that the confidence interval crosses the null value. The point estimate for men clearly suggests a preventive effect, but when inspecting the confidence intervals one cannot rule out the chance as an explanation. This leads to the second point. Unless there is an interaction with gender there is no basis for the gender stratification in the first place. The needless stratification leads to a loss of statistical power and a type II error when interpreting the stratum-specific results. Please revise the paper in a way that does not overstate the importance of the lack of statistical significance in the stratified analysis.
Answer: In accordance with the editor’s wishes, corrections have been made.
We agree with the editor that the needless stratification leads to a loss of statistical power and a type II error when interpreting the stratum-specific results due to the smaller sample size in each stratum, and the evidence of preventive effect IS the point estimate NOT the fact that the confidence interval crosses the null value. Indeed, we overstated or over interpreted the lack of statistical significance in some situations in the previous version of our manuscript. However, we cannot either rule out the possible interaction between soy food intake and gender as well as other factors (i.e., smoking status, and ethnicity). Because epidemiological studies cannot directly evaluate mechanisms, we believe that insights from studies of stratified analyses (subgroup analyses) are necessary. Especially when different protective effect of soy consumption on lung cancer are observed in different smoking status, ethnicity, and gender, such possible effect modifications or interactions, if they do exist (not by chance), can provide clues to biological mechanisms i.e. soy might exert its preventive effect on lung carcinogenesis through the EGFR-mediated signaling pathway. (More detailed explanation: line 13-19, page 21). But given the limited number of studies included and the possible consequence of insufficient statistical power, those results should be interpreted with caution and need to be confirmed in future research (the relevant comment has been made in line 20-21, page 21)
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