Dear editor and reviewers:

We are extremely grateful to you for the constructive critique of our manuscript. We have responded to each of the comments of the referees on separate sheets and deeply appreciated your suggestions that have led to a significant improvement in this article. In response to your comments, we have revised the manuscript, tables and figures to enhance article readability. Several new sections of text are added. We have also reedited the abstract, results, methods, and discussion sections. All the changes are labeled in red color. Thanks for your encouragement and appreciation.

Reviewer(s)' Comments to Author:

Recommendations for improvement:

Reviewer #1: The article addresses a relevant topic for orthodontics. However, revisions needed to be made to improve the article and strengthen the study's findings.

1) INTRODUCTION:

• Authors should cite more data showing the prevalence of skeletal Class III midfacial hypoplasia found at the population level.

Remedy:

Yes, thank you for your suggestions. We added more data in the following statement: The prevalence of skeletal class III malocclusion varies in different populations. Based on some studies, the prevalence of Class III malocclusion is approximately 1% to 5% in white populations and around 9% to 19% in Asian populations.[1,2] (Please see Line 66, Page 4). According to surveys, 75% of skeletal Class III malocclusions are associated with maxillary retrognathism or a combination of maxillary retrognathism and mandibular prognathism [3]. In addition, nearly 30–40% of patients display some degree of maxillary deficiency [4] (Please see Line 71-74, Page 4)

• It is important to show data from studies that explain the etiology, clinical, epidemiological characteristics, and forms of treatment, highlighting their advantages, disadvantages and possible long-term effects.

Remedy:

Yes, thank you for your suggestions. We added more data in the following statement:

In skeletal Class III malocclusion, the etiology is multifactorial including genetic inheritance, ethnic, environmental and habitual components[5] and genetic is the main etiology of skeletal Class III malocclusion [6]. According to surveys, 75% of skeletal Class III malocclusions are associated with maxillary retrognathism or a combination of maxillary retrognathism and mandibular prognathism [3]. In addition, nearly 30 to 40% of patients display some degree of maxillary deficiency [4]. Several studies also claimed that maxillary retrognathism is the most common contributing component of Class III characteristics.[5,7] Thus, using maxillary protraction devices to enhance maxillary growth become more important [5,7]. (Please see Line 66-75, Page 4). However, the correction of skeletal Class III malocclusion is challenging in orthodontics due to the unpredictable growth potential of the maxilla and potentially unfavorable mandibular growth. Even though several studies evaluating maxillary anteroposterior effects following maxillary protraction have been reported, most are conflicting results and still uncertain in the long-term following up.

• The impacts on quality of life can also be highlighted.

Remedy:

Yes, thank you for your suggestions. The impact on quality of life was mentioned as following statement: Early treatment of growing patients with skeletal CIII malocclusion could provide them higher quality of life and make them more confident throughout the years they are most vulnerable by how they look like [8,9] (Please see Line 75-78, Page 4)

• Before the objectives, the authors should write the importance of studies like this for the advancement of scientific knowledge and clinical decision making.

Remedy:

Yes, thank you for your valuable suggestions. We added the importance of the study before the objectives as following: Even though several studies evaluating maxillary anteroposterior effects following maxillary protraction have been reported, most are conflicting results and still uncertain. Therefore, we systematically searched and analyzed the available literature for the advancement of scientific knowledge and clinical decision making. (Please see Line 105-108, Page 5)

• Is the review unprecedented? In the literature, I identified the existence of other systematic reviews on the topic. Therefore, the authors need to explain the differential of this review in relation to the others that have already been published and what it adds.

Remedy:

Yes, thank you for your suggestions. It is true that this topic is not novel since many systematic reviews have been published in the past on similar topics [3,10-15]. However, the follow up periods in most studies were short-term rather than long-term follow up. For clinicians, they hope the orthopedic treatment effect on growing skeletal CIII patients could be maintained to prevent the orthognathic surgery in the end of growth period. In addition, high heterogeneity was found in most systematic review and meta-analysis. In this article, we explored the heterogeneity using meta-regression and investigate that follow up periods was the main factor to cause the high heterogeneity.

2) MATHERIAL AND METHODS:

• Was the review protocol previously registered in an online database, such as PROSPERO?

Remedy:

Yes, thank you for your valuable reminding. We registered this review protocol with the Open Science Framework platform (protocol available at osf.io/39kfs). (Please see Line 114-117, Page 6)

• In the methodology, it is recommended to insert a table with the search strategy used in each specific database, for reasons of search transparency and also because each database requires adaptations in the strategy.

Remedy:

Yes, thank you for your valuable suggestion. We insert a table with the search strategy in table 1 for reasons of search transparency.

• How was the selection and exclusion of duplicate references made? Manually? Using any software? The authors need to provide more details in the materials and methods on how the studies were selected, according to the PRISMA items.

Remedy:

Yes, thank you for your suggestions. We selected the references into Endnote software and excluded the duplicated references. In addition, protocol section was added in the materials and methods (Please see Line 114-118, Page 6 ) and the studies was selected following the PRISMA items.(Please see S1 Table).

• How was the examiner calibrated? Did the authors carry out any previous training? Was the kappa test to assess agreement between examiners calculated?

Remedy:

Yes, thank you for your valuable suggestions. In order to measure inter-rater reliability, we measure the kappa test to assess agreement between examiners calculated. The kappa score was 0.85, indicating a high level of agreement.

• The list of references for eligible studies needs to be consulted to identify possible articles that were not identified through searches.

Remedy:

Yes, thank you for your suggestions. We re-organized the eligible studies from the databases and manual searching was done to find studies that may not have been indexed in the databases. In addition, we verified and discussed the eligible studies with other authors.

• As it involves a review of clinical trials, it is recommended to apply the GRADE tool (Grading of Recommendations, Assessment, Development and Evaluations) to summarize the quality of available scientific evidence.

Remedy:

Yes, thank you for your valuable suggestions. We conducted the GRADE tool to summarize the quality of available scientific evidence.(Please see Line 356-364, Page 22 and table 6)

• Why did the authors not use the standardized mean difference in the meta-analysis instead of the mean difference? This detail needs to be justified.

Remedy:

Yes, thank you for your suggestions. All study effect sizes are weighted in a meta-analysis regardless to whether they are standardized mean differences, mean differences, odds ratios, risk ratios, correlations, etc. The mean difference is preferred when all studies use the same outcome (a continuous one) and unit of measure. For example, studies on the effect of a drug on blood pressure will almost all use mmHg as the unit of measure and if they don't, the reported value can be easily converted to mmHg. On the other hand, the standardized mean difference is used when the studies don't use the exact same outcome measure. For example, all studies measure depression but they use different psychometric scales Here we have to use the standardized mean difference. In this meta-analysis, all included studies use the same outcome (SNA and continues one) and unit of measure (degree). That is the reason why this meta-analysis uses the mean difference rather than standardized mean difference.

Reference: https://training.cochrane.org/handbook/current

The standardized mean difference is used as a summary statistic in meta-analysis when the studies all assess the same outcome but measure it in a variety of ways (for example, all studies measure depression but they use different psychometric scales). In this circumstance it is necessary to standardize the results of the studies to a uniform scale before they can be combined.

The mean difference (more correctly, ‘difference in means’) is a standard statistic that measures the absolute difference between the mean value in two groups in a clinical trial. It estimates the amount by which the experimental intervention changes the outcome on average compared with the control. It can be used as a summary statistic in meta-analysis when outcome measurements in all studies are made on the same scale.

3) RESULTS

• The results need to be described in more detail.

Remedy:

Yes, thank you for your suggestions. We described the results in more detail as following statement:

The FM treated group versus untreated control group

The overall mean difference in the FM treated group versus the untreated control group regarding SNA angle was 1.79° (95% CI, 1.20-2.39 and p < 0.001 for the FM treated group). The subgroup analysis showed a significantly increased SNA angle with FM treatment than that in the untreated control group with a follow-up period of less than 3 years (Mean difference, 2.29°; 95% confidence interval, 1.86-2.73; and p < 0.001 after facemask protraction), but not in the groups with more than 3 years of follow-up (Mean difference, 0.28°; 95% confidence interval, -057-1.13; and p= 0.52 after facemask protraction). Regarding SNA angle heterogeneity, the I2 was 54.96% in the overall included studies, less than 0.01% in the group with follow-up periods of less than 3 years, and less than 0.01% in the group with follow-up periods of more than 3 years.

The FM+RME treated group versus untreated control group

The overall mean difference in the FM+RME treated group versus the untreated control group regarding SNA angle was 1.54° (95% CI, 1.06-2.02 and p < 0.001 for the FM+RME treated group). The subgroup analysis showed a significantly increased SNA angle in the FM+RME treated group than in the untreated control group with follow-up period of less than 3 years (Mean difference, 1.73°; 95% confidence interval, 1.36-2.11; and p < 0.001 after rapid maxillary expansion and facemask protraction), but not in the groups with follow-up period of more than 3 years (Mean difference, 0.34°; 95% confidence interval, -0.64-1.33; and p= 0.5 after rapid maxillary expansion and facemask protraction). Regarding SNA heterogeneity, the I2 was 41.59% in the overall included studies, 6.26% in the group with follow-up period of less than 3 years, and less than 0.01% in the group with follow-up period of more than 3 years. (Please see Line 314-338 , Page 21-22 )

• In the abstract, the authors declare that: “However, no statistically significant changes (mean difference, 1.54°; 95% confidence interval, 1.06-2.02; and p < 0.001) were observed in the SNA angle in the groups, when measured after 3 years of follow-up.” If the p-value was significant, why was there no statistical difference? The results are conflicting.

Remedy:

Yes, thank you for your valuable suggestions and reminding. We corrected the paragraph as following: There was a statistically significant increase (Mean difference, 2.29°; 95% confidence interval, 1.86-2.73; and p < 0.001 after facemask (FM) protraction. Mean difference, 1.73°; 95% confidence interval, 1.36-2.11; and p < 0.001 after rapid maxillary expansion(RME) and facemask protraction) in the Sella-Nasion-A point (SNA) angle in the treatment groups as compared with the control groups, when measured during the less than 3-year follow-up period. However, no statistically significant changes (Mean difference, 0.28°; 95% confidence interval, -057-1.13; and p= 0.52 after facemask protraction. Mean difference, 0.34°; 95% confidence interval, -0.64-1.33; and p= 0.5 after rapid maxillary expansion and facemask protraction) were observed in the SNA angle in the groups, when measured after 3 years of follow-up. (Please see Line 40-50 , Page 2 )

4) DISCUSSION

• The discussion can be improved. The results of the studies need to be discussed in greater depth. The review included a large number of studies, but in the discussion, it is necessary to make clear the implications for the clinical practice of the results obtained. What are the strengths of this review compared to those already published on the topic? What can be better evaluated in future studies?

Remedy:

Yes, thank you for your suggestions. The implication for the clinical practice is the difference of orthodontic treatment time. From this review, it is shown that early treatment of growing patients with skeletal CIII malocclusion could provide them higher quality of life and make them more confident throughout the years they are most vulnerable by how they look like [8,9]. (Please see Line 75-78, Page 4). However, the patients may wear the orthodontic appliance (orthopedic + orthodontic treatment) for a long time (from young age to adult) and patient’s compliance may gradually decrease in the orthodontic treatment period. The strength of this review was that follow up periods were long-term rather short-term. In addition, the studies we included were RCTs and observational studies instead of only RCTs. (Please see Line 431, Page 26). About what can be better evaluated in future studies, we hope to evaluate long-term three–dimensional changes in different structures (ex: maxilla and mandible) after maxillary protraction.

 

Reviewer #2:

This is a potentially interesting study, but has several issues with the methods and reporting of it. These need to be taken into account and the study revised, before this can be further assessed for appropriateness. Thanks for letting me see this.

Specific comments

1. The abstract seems well-written. I would suggest however to also add the quality

of evidence and existing limitations.

Remedy:

Yes, thank you for your positive and encouraging comments on this manuscript. We add the quality of evidence and existing limitations as the following statement: Limitations on this review were only the SNA angle was used and clinical heterogeneity was not discussed. The quality of evidence was moderate. (Please see Line 57-59 , Page 3 )

2. The last search date (Dec 19) is half a year old, therefore the review might be outdated.

Remedy:

Yes, thank you for your suggestions. We followed your comments and re-searched the database up to Sep. 2020. (Please see Line 34, Page 2)

3. Please provide the full exact search strategy for at least one database.

Remedy:

Yes, thank you for your valuable suggestion. We insert a table with the search strategy in table 1 for reasons of search transparency.

4. Why was January 1990 chosen as a date?

Remedy:

Yes, thank you for your valuable suggestions and correction. We should not choose January 1990 as a date. Hence, we re-searched the database and corrected as the following statement: The included studies were cohort studies and randomized controlled trials (RCTs) with at least 6 months of follow-up that were published until September 2020. (Please see Line 157-159 , Page 8)

5. “Another inclusion criterion was adherence to the PICOS principle.”: What is meant with this?

Remedy:

Yes, thank you for your suggestions and correction. We corrected this sentence to “other inclusion criteria were following the PICOS principle.” (Please see Line 160-161, Page 8)

6. “…age ranged from 6 to 16 years…”: why was this chosen? Was this criterion checked for all included studies?

Remedy:

Yes, thank you for your valuable suggestions and alert. The treatment timing in growing patients with Class III malocclusion was ranged from the early mixed dentition to early permanent dentition[3]. The main objective of early facemask treatment is to enhance forward displacement of the maxilla by sutural growth. Histologic studies have shown that the midpalatal suture is broad and smooth during the“infantile” stage (8 to 10 years of age). The suture becomes more squamous and overlapping in the “juvenile” stage (10 to 13 years), and becomes more heavily interdigitated around puberty[16]. Some reports suggest that the optimal time for FM or FM / RME is before the age of 8 years [17-19]. It was also claimed that the suggested time of treatment in early orthopedic treatment is between the ages of 6 and 8 years after the maxillary permanent first molars and incisors have erupted[17]. However, other studies have found that patient’s age had little influence on treatment response and outcome [3,20]. The age of the participant was also divided into three time points: 6–8, 10–12, and 14–16 years of age to investigate craniofacial facial growth of CIII subjects [21]. From previous studies, the treatment timing for Orthopedic CIII treatment was inconsistent in different studies. Hence, we chose the age ranged from 6 to 16 years. We also checked all included studies and they were all in this range.

7. “the intervention was the selection of different treatment of FM and FM/RME”: this is unclear, please explain.

Remedy:

Yes, thank you for your suggestions. The treatment of FM means facemask protraction therapy and FM/RME means the combination of facemask and rapid maxillary expansion.

8. “The outcome (O) of interest was long-term (lasting 9 years) maxillary changes in sagittal dimensions, defined as Sella-Nasion-A point (SNA).”: you should be here explaining the a priori methods. Not the results of your study.

Remedy:

Yes, thank you for your valuable suggestions. We changed this sentence as the following statement: We performed two different types of comparisons (C) separately: 1) FM vs. control, 2) FM/RME vs. control in the long-term follow up. The outcome (O) of maxillary changes in sagittal dimensions, defined as Sella-Nasion-A point (SNA), was obtained by cephalometric radiography. (Please see Line 166-171 , Page 8)

9. The term ‘quality’ that you use when evaluating RCTs is not correct. Please check the PRISMA statement for the appropriate terminology.

Remedy:

Yes, thank you for your valuable suggestions. We corrected the term “Quality assessments of the included studies” to “Risk of Bias in Individual Studies” when evaluating the included studies. (Please see Line 185, Page 8)

10. Choosing between a fixed- or random-effects model according to the observed (calculated) heterogeneity is a very problematic method. The two models are not interchangeable and have different assumptions/method/interpretation. Please check with your statistician.

Remedy:

Yes, thank you for your valuable suggestions and reminding. It is true that it is a very problematic method by choosing between fixed or random effects models according to the observed (calculated) heterogeneity. In this meta-analysis, we check our statistician and explored the source of heterogeneity by meta-regression using an average summary value. Possible moderators (age, sex, publication year, follow-up period and study design) were tested to explore heterogeneity. And then we conducted a subgroup analysis from the meta-regression result. (Please see Line 202-206, Page 9)

11. “…to perform sensitivity test, meta-regression analysis, and subgroup analysis.”: please explain in detail.

Remedy:

Yes, thank you for your valuable suggestions. There are three major sources of heterogeneity: clinical, statistical and methodological heterogeneity. In order to explore the source of heterogeneity (I2 value >50% indicated a moderate

to high heterogeneity[22]), we conducted with meta-regression using an average summary value. Possible moderators (age, sex, publication year, follow-up period and study design) were tested to explore heterogeneity. This study considered a p-value <0.05 to be significant for the analysis. And then we conducted a subgroup analysis from the meta-regression result.

12. Reporting biases are best performed only when you have a sufficient number of studies at your disposal. Please check the recommendations for such tests.

Remedy:

Yes, you are absolutely right and thank you for your valuable suggestions. It is true that reporting biases are best performed only when we have a sufficient number in this study. And insufficient number of studies was included in this meta-analysis. Hence, we deleted the publication bias and funnel plots in the manuscript. (Please see Line 340-343, Page 22)

13. The authors should provide a list with all included/excluded studies from their search together with the exclusion criteria.

Remedy:

Yes, thanks for your suggestion. We provided a list with all included/excluded studies from their search together with the exclusion criteria. (Please see the table S2)

14. Is it prudent to naively include/combine both RCTs and non-RCTs, since the latter can introduce additional bias in your results?

Remedy:

Thank you very much for the valuable consideration and comment. Admittedly, RCTs can provide the strongest and most epidemiologic evidence for causality if the RCTs are blinded[23]. In the present study, the non-randomized studies (NRS) were enrolled. It has been shown that the shortage of NRS may have strong likelihood of bias and confounding, data are more likely to be incomplete and of poor quality and outcomes are less likely to be validated[24,25] In particular circumstances, however, the non-randomized studies may provide certain advantages, such as providing us long-term information in early treatment of CIII malocclusion or maxillary transverse deficiency. Moreover, in ethical issue, the patients that are seeking for treatment due to their orthodontic problems and the observational studies may be more applicable in real-world settings than RCTs because of their broader range of participants included, large sample size and longer follow-up[23,26]. In the present analysis, nevertheless, there is few RCTs base available evidence. Alternatively, the studies we included were through the evaluation of risk of bias in individual studies (please see the Table 3).

15. What kind of cohort studies were included? Prospective or retrospective? The latter are usually more biased than the former.

Remedy:

Yes, thank you for your reminding. Of the 13 included cohort studies, nine [27-35]are prospective (including two partially prospective), and four [36-39] are retrospective, and all studies included untreated Class III controls. Two studies [28,35]are partially prospective, meaning that they present a retrospective control group (CG). We added which kinds of cohort studies into table 2. (Please see table 2)

16. Please provide additional details in Table I regarding the patients’ (how was skel. Class III defined), the treatment (appliance, duration, etc), and the outcomes assessed. Also relaying the actual conclusions of each study might be confusing, since they might disagree with the results of the meta-analysis.

Remedy:

Yes, thanks for your valuable suggestion. We re-organized the provide additional details in Table 2. In addition, in order to prevent the confusion when relaying the actual conclusions of each study, we decided to delete the authors’ conclusions. (Please see table 2)

17. I am having issues with the risk of bias assessment presented. I checked randomly 2 included studies and I do not agree with the lenient assessment done with the authors. This needs to be checked to see if methods were appropriately applied.

Remedy:

Yes, thanks for your valuable suggestion. We re-checked and corrected the risk of bias assessment of the included studies in table 3.

18. The authors need to provide in a table the full results of all meta-analyses performed, including studies, estimate with imprecision, p value, and heterogeneity statistics.

Remedy:

Yes, thanks for your valuable suggestion. We performed the summary results from primary and subgroup analyses as in table 4.

19. How come the ‘explained variance’ is presented in table 3 but has not been described in the methods before? This is inappropriate. Also, reporting such a thing in meta-regressions that are not statistically significant is misleading. Please check with your statistician.

Remedy:

Yes, thank you for your valuable suggestions. It is true that it is inappropriate and misleading to reporting explained variance in meta-regressions. After checking with the statistician, we decided to remove this in the table. (Please see table 5, Line 294, Page 20)

20. I see no mention of assessing the quality of evidence with the GRADE framework, even though this is a standard approach for all systematic reviews nowadays.

Remedy:

Yes, thank you for your valuable suggestions. We have added the GRADE framework into this manuscript. (Please see Line 356-364, Page 22 and table 6)

21. I see no clear section outlining the limitation of the present study.

Remedy:

Yes, thank you for your excellent suggestions and through review. We have edited our manuscript and make clear section regarding the limitation of the present study. (Please see Line 424-431, Page 26)

22. Figure 2 is not necessary—you can give this information plainly in text.

Remedy:

Yes, thank you for your constructive suggestions. We followed your recommendations and gave the information plainly in text. (Please see Line 221 , Page 10)

 

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