张向阳教授发表SCI论文系列经验谈:如何答复审稿人意见(三)

正如我在上课时对大家所说：发表SCI 文章、尤其是高水平的文章，答复审稿者意见是关键，关系到一篇文章是否能被接受、是否能发表到高影响因子的杂志上。

针对答复审稿者的意见，大家普遍感到很困难，这种情况下，我们采用“实战”的方式，把我们组既往发表文章时，答复审稿者意见的原稿逐步发给大家，请大家对每篇都能详细去阅读，先反复看审稿者的问题，琢磨他们为什么要提出这样的问题，然后再看我们做的答复，有些答复很巧妙地避开审稿者故意“挖的坑”。希望能通过这种方式，使得大家在答复审稿者意见方面能逐渐得到提高。

按照我们上课时的顺序和发给大家的提纲，这是第三篇关于“如何答复审稿者意见”的总结：

《Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships to clinical phenotypes and cognitive deficits》

一）发表期刊：

这篇文章发表在《Psychological Medicine》（影响因子IF=5.49）杂志上。

二）文章题目：

正如我在课题上所讲，英语文章的题目很重要，常常起到画龙点睛的作用，从本文的这个题目来看，本项研究包含了下面几个方面：

1）首发未服药精神分裂症的糖耐量研究；

2）探讨糖耐量异常与临床症状和认知功能的关系。

三）研究对象：

一组精神分裂症（n=175）vs 一组正常组（n=31）。

四）研究指标：

1）口服糖耐量实验（OGTT）；

2）糖和脂代谢指标+胰岛素（来自化验单）；

3）病人检测PANSS；

4）病人组和正常组检测认知功能MCCB

五）结果：

1）病人组OGTT异常率24.5% vs 正常组0%；

2）病人组空腹血糖和2小时的血糖水平明显增高，胰岛素抵抗增强；

3）病人组中，与OGTT阴性组相比，OGTT阳性组年龄大、发病年龄晚、腹围腰围大和BMI高，低密度脂蛋白和甘油三酯高，而且胰岛素抵抗强。

有意思的是：OGTT组PANSS总分和阴性症状分高，但认知功能没有明显差异。

六）结论：

首发未服药精神分裂症存在糖耐量异常，而且与临床症状相关，但与认知损伤关系不大。

（一）这项研究做起来很困难的地方是：病人要做糖耐量检验 （OGTT），而且完成的量比较大（n=175）。

（二）这篇文章先投稿到Biological Psychiatry 和Schizophrenia Bulletin, 均被拒稿了，可能原因：

1）设计问题：病人组与正常组差异太大；

2）OGTT阳性组与阴性组之间的认知功能几乎没差异；

3）指标较为单一，只有血清糖脂水平指标。

（三）这项研究还做了临床药物干预后的OGTT检测，应该能出一篇好文章。另外再结合基因型、其它biomarkers，还能再出不少文章。

（四）大家还记得上一讲座里的那篇文章吧：“首发精神分裂症糖代谢异常与精神病理症状之间的关系”，那篇文章里的思路是在修稿目前这一篇文章时 （糖耐量试验 OGTT）产生的。当时我在修稿这篇OGTT文章时，想到：那么服75g糖前的基础水平如何呢？所以产生了那篇文章。

所以同学们，当你做分析数据库、做统计分析和写文章时，一定要“敢想、会想”，很多好思路、好文章都是在“敢想”过程中产生的，我已经太多次遇到这种情况了，以后会陆续地娓娓道来，与大家分享我的经验。

好，言归正传，看我是如何答复三位审稿者意见，让他们欣然地接受了我们的文章。

下面是修改后的Cover Letter, 这部分是重点，可以先看，而且需要反复看：

Dear Editor, 

Thank you very much for sending us the valuable comments of three reviewers on our manuscript (Ref.:  Ms. No. PSM-D-16-00167; Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships to clinical phenotypes and cognitive deficits), which have helped us to improve the quality of our paper greatly. We have thoroughly revised our manuscript according to the three reviewers’ comments and suggestions. The comments and the critiques of the reviewers have been addressed and itemized as follows:

This paper is important in that it furthers the narrative regarding schizophrenia and pre-diabetic states. It reiterates the relationship between schizophrenia and the potential to develop Type 2 Diabetes. One of its strengths is the fact it has a non-IGT patient comparison group. It further highlights the need to monitor all patients for pre-diabetes and T2D irrespective of medication.

这个审稿者是友军，意见比较positive，所以赶紧表扬一下。实际上这也是给主编看的，让他觉得我们的研究比较好，常言道“细节决定成败”，说不定某个环节就决定了一篇文章的结局。

Answer:  Thanks very much for these positive comments.

Question 1: The Ryan 2003 paper examined IFG and not IGT. This needs to be corrected in the paper. 

这位审稿者对精神分裂症糖代谢领域的研究非常熟悉，对这篇文献Ryan 2003文章中的结果细节也了如指掌，真是佩服这位审稿者。但大家也能想到：有可能，这位审稿者就是Ryan本人，或者是来自同一课题组的人。

Answer: Thanks so much for such careful reviewing. Indeed, the Ryan 2003 paper examined IFG and not IGT, which has been corrected throughout the paper.

Question 2: Is there any genetic pre-disposition in the Han population to develop Type 2 diabetes?

这个问题对于来自中国的稿件十分常见：当发现血中的生物学指标改变时，审稿者常常会问：是不是由于基因差异的问题？因为血中的生物学指标往往是蛋白，是受基因调控，而往往基因型在中国和白人人群中的差异很大。

Answer: This point is excellent. There is genetic pre-disposition in the Han population to develop Type 2 diabetes, which has been added to the Discussion section on page 12, showing as “In addition, T2DM is experiencing a rapidly rising prevalence in China. The rapid rise of T2D prevalence in China is largely believed to be driven by several environmental factors comprising economic development, nutrition transition, and changes in lifestyles (Hu et al 2015). However, several convincing T2D loci have been identified from large-scale genome-wide association studies and meta-analyses in the Han population (Ma et al 2015), suggesting that there may exist genetic predisposition in the Han population to develop T2D. However, the genetic basis of T2D and schizophrenia, especially the inter-relationships of their genetic loci warrants further investigation”.

Question 3: Were HBA1c levels done in the population? If so were there differences between the 2 groups? 

这个问题常常是审稿者喜欢提出的，就是：与本研究中的生物学指标相关联的一些指标，但本文中又没检测，同时又不可能再去补实验或检测指标来，在这种情况下应该如何办？比较好办，最简单的方法就是在Discussion 的倒数第二段，作为一个limitation 列出来。或者是像在本文中这样，因为stress 对糖脂代谢影响比较大，就装模作样地先去讨论一番，这也显得对审稿者很尊重，然后再说，可惜我们没能去检测，是一种limitation。 

Answer: This point is excellent. HBA1c levels were not measured in the subjects, and we have added this point to the Discussion section on page 12, showing as follows:

      “It is worthy of mentioning that the HbA1c concentration reflects the mean glucose concentration over a period of 8 to 12 weeks from both fasting and postprandial glucose concentrations (Geijselaers et al 2014). In a recent study, HbA1c concentration was significantly higher in schizophrenia with than without diabetes (Zhang et al 2015). Moreover, several studies have indicated that poorer glycemic control and higher HbA1c are significantly associated with cognitive deficits in both schizophrenia patients and healthy population (Dickinson et al 2008; Sanz et al 2013). Hence, having no HbA1c measured in our current study should be considered as one of the methodological limitations, which should be remedied in the future investigations”.

Question 1: Let me begin by saying to editor and authors alike that I am not a physician and have limited ability to comment on the most aspects of the study.  I am well aware, as is everyone who has worked with patients in recent times, that diabetes is a significant health issue for our patients and it is clearly the case that many of our newer medicines, unfortunately including clozapine, as associated with significant weight gain, thereby potentially exacerbating risk for type 2 diabetes.  The question of whether the diagnosis itself is associated with diabetes risk that cannot be explained by drugs and weight gain is an important question where there is limited data in the literature.  It appears the current paper addressed this issue with a sizeable sample of drug naïve patients where the answer is clear: prior to treatment patients show rates of impaired glucose tolerance that far exceed the levels seen in controls. (Note, the control group is only 31 people, quite small by any reasonable standard but unlikely to significantly impact the conclusions drawn here).  This finding has important but difficult implications for clinical care in that one would think that avoiding medicines associated with the greatest weight gain is an important strategy in preserving physical health.  Unfortunately, that means losing access to the one medicine with differential efficacy (clozapine), among others.

这位审稿者比较友好，而且比较谦虚：直接说明自己不是临床医生，对本文的大部分内容不很清楚。所以遇到这样的审稿者，比较好“对付”哈，因为他/她给的评价不错，就不要答复很多。我对此问题就是在最后总结时，加入他/她评价的中心意思：“首发精神分裂症出现糖代谢异常，不能用药物治疗和体重增加来解释”。

Answer:  These points are excellent. Indeed, the question of whether the diagnosis of schizophrenia itself is associated with diabetes risk that cannot be explained by drugs and weight gain is an important question, which has been answered to some extent by our current study. We have added this point to the last paragraph of the Discussion section on page 16, showing that “In summary, our data show significant higher IGT rate shown on standard OGTT in the acute early phase of schizophrenia compared to healthy controls, suggesting that the diagnosis of schizophrenia itself is associated with diabetes risk that cannot be explained by drugs and weight gain”.

Question 2: The paper demonstrates some subtle differences between patients with and without impaired glucose tolerance.  The findings are straightforward and pretty clear.  The only surprise is the lack of a cognition signal.  This issue may deserve a bit more discussion.  In people with type 2 diabetes：Are cognitive deficits associated with duration of illness? How do the present findings compare to prior results from the same authors in a chronic sample? Were the same measures used? Is it possible to compare effect sizes across studies and estimate the possible rate of change? How might the authors compare their sample to others in the literature where relationships with cognitive impairment have been observed in schizophrenia cohorts?

虽然此位审稿者比较友好，也谦虚地说自己不懂临床，但还是提出一连串的问题来, 包括重点提出“你们本研究为什么没有发现OGGT阳性病人的认知损伤与阴性病人无显著差异？”尤其是令人头疼的是：他/她提出本研究的结果要与以前慢性的结果进行比较，同时要与其它的报道中的结果进行比较，如何答复这些问题？尤其是如何巧妙避开让人头疼的问题？

Answer: These points are very excellent. First, the new statistical analyses have been re-performed, and no associations were found between cognitive deficits and duration of illness. The results have been added to the Results section on page 10, under the subtitle-Cognitive Functioning in patients with IGT versus non-IGT, showing that “The MCCB total and index scores of 29 IGT, 73 non-IGT patients and 28 healthy controls are shown in Table 3. Correlation analyses showed no significant associations of the MCCB total and index scores with the following clinical variables: sex, age, age of onset, duration of illness and BMI”. Second, unfortunately, the present findings were not able to compare to prior results in our chronic sample, because we have used the different cognitive measures (轻轻一句话，巧妙地说“本研究不能与以前的慢性比较，避开了很大麻烦”). Although we have provided the effect sizes in the Results section based on the suggestion of the reviewer (showing as “One-way ANOVA analyses shows that there were significantly lower cognitive scores on the MCCB total and nearly all of its 10 subscale scores (all p<0.001) except for the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and category fluency (both p>0.05) in patients than normal controls with effect sizes ranging from 0.36 to 2.09.”), we could not compare them across studies because of different cognitive measures. Third, according to the suggestions of the reviewer, we have discussed more about the lack of a cognition signal, and compared our sample to others in the literature where relationships with cognitive impairment have been observed in schizophrenia cohorts, which are highlighted in blue words, in the Discussion section on page 15 and 16, under the subtitle- Impaired glucose tolerance and cognitive impairment in SCZ, showing as follows:

“We found significantly lower cognitive performance on the MCCB and nearly all of its subscales in FEDN patients than normal controls, as have the majority of studies assessing cognitive performance in SCZ patients (Ma et al., 2007; Palmer et al., 2009; Sharma and Antonova, 2003), including in those first episode patients (Aas et al 2014; McCleery et al 2014; Wu et al 2016). Since diabetes is also associated with cognitive impairment (Keefe 2007; Leifker et al 2009; Zhen et al 2012), and we and other studies have shown that T2DM in SCZ is associated with impairment in many domains of cognitive function, we expected greater cognitive impairment in those FEDN patients with IGT (Kumar et al 2009; Ruis et al 2009; Zhen et al 2012). Our prior study showed that schizophrenia with diabetes performed worse than schizophrenia without diabetes in immediate memory (p<0.01) and total RBANS scores (p<0.05), and also showed a trend to decreases in attention (p= 0.052) and visuospatial/constructional functioning (p=0.063), with effect sizes ranging from 0.37–0.45 (Han et al 2013), suggesting that schizophrenia with diabetes had worse cognitive functioning than schizophrenia without diabetes. Therefore, we particularly expected that memory and processing speed would be impaired, as they are in diabetes (Allen et al 2004; Manschot et al 2006; Kumar et al 2009). However, the IGT patients were more impaired than the NGT patients only on the Mayer-Salovey- Caruso Emotional Intelligence Test, on which our FEDN patients overall did not differ from the controls. Thus, this first study exploring glucose metabolism and cognitive impairment in FEDN patients with SCZ has found little evidence for those cognitive impairments being greater with IGT. This result is not in agreement with our expectation. Maybe the dysfunction of glucose metabolism is more sensitive or more vulnerable than the cognitive impairments in early course of illness of schizophrenia. However, this is only our speculation, and we cannot offer reasonable mechanisms to explain why the IGT was not associated with cognitive impairments in the first-episode schizophrenia. Further research using a longitudinal and prospective study with first-episode and drug naïve patients is needed to clarify the relationship between IGT and cognitive impairments in schizophrenia”. 

Major concerns:

Question 1: Definition of first episode: it is not clear in your criteria what the definition for first episode is. Is it first symptom onset, or first hospitalization? I see that you have the criteria for duration of symptoms not longer than 60 months (meaning 5 years). This is more proper to call "early course" instead of first episode.

这位审稿者提出了一个看似简单、但也很重要的问题“首发的定义？”。

Answer: This point is excellent. The definition for first episode is “first symptom onset”, which has been added to the Methods section under the subtitle- Subjects, showing as “One hundred seventy-five (male, 80 and female, 95) FEDN inpatients were recruited from Beijing Huilongguan hospital, a Beijing-city owned psychiatric hospital. The definition for first episode was first onset of psychotic symptoms”. Also, early course have been used throughout the text instead of first episode.

Question 2: Your findings showed later age at onset in IGT group as compared with non-IGT group. This gives me an impression that having IGT is somehow protective, and delays the onset of symptoms/illness. Interestingly, other studies you cited in your paper (e.g. Spelman et al 2007) found 10.5% IGT in FEDN, while 18.2% in unaffected relatives. This gives me again the impression that patients have less opportunity to have IGT. Based on these, I have an overall impression that IGT and FEDN are anti-correlated, meaning having one is preventing the occurrence of the other. Please provide explanation.

这位审稿者提出了一个更头疼的问题，就是“出现OGTT异常的病人，其发表年龄比较晚，也就是说OGTT异常反而是精神分裂症的保护因素”，实际上这个结果与我们本来的设想正相反，而且也似乎违背了我们的常识。在这种情况下，如果避开这个“陷阱”呢？如果让审稿者接受你的解释呢？请仔细阅读我们的答复，反复读几次，琢磨一下我们的巧妙答复。一个原则：不要与审稿者argue, 顺着他/她的意思去discuss, 如果实在不好回答，正如我们的答复那样：内在机制不明，我们也提不出合理解释，有待进一步的研究和发现。

Answer: These points are very excellent. Indeed, our findings showed later age at onset in IGT group as compared with non-IGT group, suggesting that having IGT is somehow protective, and delays the onset of symptoms/illness. We have added these excellent points and consideration to the Discussion section on page 13, showing as: “However, it is worthy of mentioning that our findings showed later age at onset in IGT group as compared with non-IGT group, suggesting that having IGT is somehow protective, and may delay the onset of symptoms/illness. Interestingly, Spelman et al reported 10.5% IGT in FEDN patients, but 18.2% IGT in unaffected relatives of the patients (Spelman et al 2007), suggesting that patients have less opportunity to have IGT. Taken together, these findings demonstrate that IGT and FEDN are anti-correlated, meaning the having one is preventing the occurrence of the other.  This anti-correlation seems to be opposite to our expected direction. The exact mechanisms responsible for these findings are unknown, and we currently could not offer a reasonable explanation for them due to cross-sectional design of our present study.  Thus, the relationships between glucose metabolism, IGT and onset of schizophrenia, and the mechanisms underlying their associations deserve further investigation”.

Minor points:

Question 1: In your introduction, you talked about prevalence of T2DM and IGT in schizophrenia patients. Could you please also provide information about the prevalence in general population? Without knowing the rates in general population, it's hard to say which is higher. 

审稿者自己说是minor points, 所以答复起来就比较直截了当，简单就好。

Answer: The point is excellent. The information about the prevalence in general population has been provided in the first paragraph of the Introduction section, showing as “Globally, the overall age-adjusted prevalence of diabetes in adults was 7·0% (6·1–7·9%) (Sarwar et al 2010); however, the prevalence rate of diabetes in developing countries is higher (Whiting et al 2011). In China, the prevalence rate of diabetes had reached 9.3% in 2014, with the number of diabetes of 96.3 million (Hu et al 2015).”.

Question 2: The sample with cognitive evaluations seems a portion of your total sample for other clinical phenotype evaluation. Are these subjects also matched for demographics? If possible, please provide such information in your results.

老外审稿者往往注意细节问题，比如此处他/她提到“认知功能检测的病人只占总被试人数中的一部分，那这部分人的人口学资料是否也相配呢？没办法，只好把这部分病人+正常人的人口学资料再做统计分析。

Answer: The point is excellent. Indeed, the sample with cognitive evaluations only takes a portion of our total sample for other clinical phenotype evaluation. The new statistical analyses have been performed to compare the demographics between the subgroups that have cognitive evaluations. And these subjects are also matched for demographics. These results have been added to Table 3, and also to the Results section under the subtitle- Cognitive Functioning in patients with IGT versus non-IGT, showing as “The MCCB total and index scores of 29 IGT, 73 non-IGT patients and 28 healthy controls are shown in Table 3. The subjects from these three subgroups were matched for demographics including sex, age, education, smoking and BMI (all p>0.05; Table 3)”.

Question 3: Your finding of a 25% IGT rate is somewhat higher than those reported in previous studies, which needs some explanation.

这位审稿者看似问了一个很简单的问题“你们发现OGTT阳性率为25%，比如以前报道的要高，请提供一些解释”。但我洋洋洒洒地说了一大堆，现在看来好像没必要哈，这也是我自己的毛病：常常喜欢讨论的很多，不像一些同学在讨论时常常感到“无话可说”。

Hopefully, we have made an appropriate revision based on the reviewers’ comments. Please let me know if there is anything else we need to do with the revision, and we’ll prepare it as soon as possible.

We thank you wholeheartedly for your excellent work. Your kind assistance is greatly appreciated. We look forward to any future correspondence.

Yours sincerely,

Xiang Yang Zhang, M.D., Ph.D.