Morphometric geometric differences between right and left human tali: A cadaveric study of fluctuating asymmetry via systematic measurement and three-dimensional scanning.

BACKGROUND: Little is known about differences in the size and morphology of the right and left human tali. The present study demonstrates differences between right and left talar morphometric geometric profiles as fluctuating asymmetry in matched pairs of cadaveric specimens.
METHODS: In total, 24 tali were collected in this study. All eligible tali were systematically measured with a Vernier caliper and three-dimensional laser scanner, which provided data for further analysis regarding the talar morphometric geometric profiles. Data were calculated to demonstrate differences between the right and left talar profiles using a matched-pair method, including the general size of the talus.
RESULTS: The average talar length was 53.5 mm, the average talar dome height was 31.2 mm, and the average talar body width was 41.3 mm. The average anterior trochlear width, middle trochlear width, posterior trochlear width, and trochlear length were 31.8, 31.2, 28.3, and 30.7 mm, respectively. Eleven matched pairs of intact tali were eligible for the matched-pair study. Paired t-tests showed significant differences in the talar dome height (P = 0.019), middle trochlear width (P = 0.027), and posterior trochlear width (P = 0.016) between the right and left tali. However, there were no significant differences in the surface area or volume between the right and left tali.
CONCLUSION: Significant differences in the morphometric profile were found between the right and left matched pairs of tali. This basic information indicates that the profile of the contralateral talus may not be used as a single reference to reconstruct or duplicate the talus of interest in certain conditions such as talar prosthesis implantation or customized total ankle replacement.

Introduction

Knowledge and technology in the field of foot and ankle surgery have progressed rapidly in recent decades. This is evident by the advances in total ankle replacement surgery [1], replacement surgery using total artificial tali [2], and arthroscopic surgery [3]. Such substantial technological progress in foot and ankle surgery has been made possible by the knowledge gained from morphological research in technologies such as computed tomography (CT) [4], three-dimensional (3D) printing technology [5], and computer-aided design programs, which transform CT images into 3D images [2]. These advanced technologies have led to developments in cutting-edge orthopedic surgery, such as the successful use of patient-specific 3D-printed titanium implants for the treatment of complex large bony defects and deformities and for use in arthrodesis procedures [5]. Prostheses have also been created to replace damaged or missing original bone [2], [6]. One of these advances is the development of the total talar prosthesis or customized total ankle prosthesis. The size and shape of the total talar prosthesis is designed based on the contralateral talus [2]. According to Zaidi, human bodies show both anatomical and functional asymmetries, some of which are of great clinical significance. Thus, the study of human body asymmetry is important to achieve an accurate diagnosis, perform effective treatment, and establish a management plan [7]. However, little is known about the anatomical and morphological variations of the foot and ankle in humans, especially in a pivotal bone such as the talus. Essential data needed for the manufacturing process and the outcomes of talar replacement surgery are related to variations in size, volume, and surface area between the right and left tali. The present study was performed to demonstrate the morphometric geometric variations between the right and left tali in matched pairs of human cadaveric specimens. The authors hypothesized that fluctuating asymmetry [8] [9] involving morphometric geometric differences exists between the bilateral tali and that this asymmetry may alter the current method used to manufacture templates from the normal contralateral talus.

Material and methods

Twenty-four tali from 12 matched pairs of fresh human cadaveric ankles were collected in this study. All tali were removed from the tibiotalar, talocalcaneal, and talonavicular joints with an effort to preserve the native cartilage by trained research assistants (resident physicians/fellows) under the supervision of fellowship-trained foot and ankle surgeons. All tali were systematically measured with a Vernier caliper to document their morphometric profiles using the method established by the senior author and Eun et al. (Figs 1–3) [10]. Each talar measurement was performed by the research assistants (resident physicians/fellows) under supervision by a trained research fellow. All tali were also scanned using a 3D laser scanner (HandySCAN 700; Creaform, Levis, Canada) to create a database of geometric profiles by a technician. These methods provided essential data for further analyses of morphologic variances between the right and left tali. A computer program (Autodesk Netfabb version 2020; Autodesk, Inc., San Rafael, CA, USA) was used to analyze the surface area and volume of each talus (Fig 4). The data were analyzed to assess the difference in measurement parameters, including the general size of the talus, between the right and left tali using a matched-pair method. Parallax error was avoided by keeping the eye in a straight line directly above the marking of the Vernier caliper. One talus was excluded because of morphologic changes caused by crystal deposition from an underlying disease affecting the donor cadaver. The remaining tali showed no signs of trauma, arthritis, previous hindfoot surgery, gouty arthritis, or other abnormalities. Therefore, both above-mentioned matched tali were excluded from the matched-pair study, and data were retrieved from 11 matched pairs of tali. In addition, baseline data of each cadaver were collected (including age, sex, and height) and recorded in the database for further analyses. The present study was approved by the ethics committee of the authors’ institution (The Human Research Ethics Committee of Thammasat University No.1 (Faculty of Medicine)). The author’s institute had discussed with the patients who provided the informed written consent prior to death for the use of their bodies in the education of medicine and medical research.

Fig 1

Abbreviations: Talar length (TaL); Anterior trochlear width (TrAW); Middle trochlear width (TrMW); Posterior trochlear width (TrPW); Trochlear length (TrL).

Fig 3

Abbreviations: Talar dome height (TaH).

Fig 4

The image of scanned talus from the computer program (Autodesk Netfabb version 2020, USA) which was used to analyze the surface area and volume of each talus.

Statistical analysis was performed using IBM SPSS software version 22 (IBM Corp., Armonk, NY, USA). Differences in quantitative data were analyzed using Student’s t-test because the data were parametric. Pearson’s correlation coefficient was used to express the correlation between the parametric parameters. A P value of <0.05 was considered statistically significant.

Results

In total, 24 tali from 12 matched-pair ankles were collected from 10 male and 2 female cadavers. The mean age of the cadavers was 69.4 ± 11.6 years. The mean height of the cadavers was 163.2 ± 5.6 cm. With respect to the morphometric profiles, an average talar length was 53.5 mm, the average talar dome height was 31.2 mm, and the average talar body width was 41.3 mm. The average anterior trochlear width, middle trochlear width, posterior trochlear width, and trochlear length were 31.8, 31.2, 28.3, and 30.7 mm, respectively. Paired t-tests among the 11 matched pairs of tali showed statistically significant differences in the talar dome height (P = 0.019), middle trochlear width (P = 0.027), and posterior trochlear width (P = 0.016) between the right and left tali (Tables 1 and 2).

Table 1

The morphometric profiles of talus from 11 matched pairs of tali.

		Mean	Number	Std. Deviation	Std. Error Mean
Pair 1	TaL_R	53.95	11	3.08	.93
	TaL_L	53.13	11	4.30	1.29
Pair 2	TaH_R	32.18	11	2.44	.73
	TaH_L	30.09	11	2.90	.87
Pair 3	TaW_R	40.86	11	2.47	.74
	TaW_L	41.81	11	2.92	.88
Pair 4	TrAW_R	30.45	11	3.71	1.12
	TrAW_L	33.27	11	6.64	2.00
Pair 5	TrMW_R	33.09	11	2.94	.88
	TrMW_L	29.45	11	5.76	1.73
Pair 6	TrPW_R	30.93	11	3.22	.97
	TrPW_L	25.81	11	5.36	1.61
Pair 7	TrL_R	32.54	11	3.53	1.06
	TrL_L	28.59	11	8.13	2.45

Abbreviations: Talar length (TaL); Talar dome height (TaH); Talar body width (TaW); Anterior trochlear width (TrAW); Middle trochlear width (TrMW); Posterior trochlear width (TrPW); Trochlear length (TrL); Standard (Std).

Table 2

The morphometric differences of talus from 11 matched pairs of tali.

		Paired Differences					Sig. (2-tailed)
		Mean	Std. Deviation	Std. Error Mean	95% Confidence Interval of the Difference
					Lower	Upper
Pair 1	TaL_R—TaL_L	.81	5.79	1.74	-3.07	4.71	.65
Pair 2	TaH_R—TaH_L	2.09	2.47	.74	.42	3.75	.01*
Pair 3	TaW_R—TaW_L	-.95	4.17	1.25	-3.75	1.84	.46
Pair 4	TrAW_R—TrAW_L	-2.81	8.56	2.58	-8.57	2.93	.30
Pair 5	TrMW_R—TrMW_L	3.63	4.65	1.40	.51	6.76	.02*
Pair 6	TrPW_R—TrPW_L	5.11	5.86	1.76	1.17	9.05	.01*
Pair 7	TrL_R—TrL_L	3.95	6.73	2.02	-.56	8.47	.08

*Significant difference. Abbreviations: Talar length (TaL); Talar dome height (TaH); Talar body width (TaW); Anterior trochlear width (TrAW); Middle trochlear width (TrMW); Posterior trochlear width (TrPW); Trochlear length (TrL); Standard (Std); Significance (Sig).

Based on the 3D analysis of geometric profiles using the computer program (Autodesk Netfabb version 2020), the surface area and volume of the tali were calculated and are listed in Table 3. There were no significant differences in the surface area or volume between the right and left tali (Table 4).

Table 3

The geometric profiles of talus from 11 matched pairs of tali.

		Mean	Number	Std. Deviation	Std. Error Mean
Pair 1	Talar surface (Right)	68.59	11	5.47	1.65
	Talar surface (Left)	68.06	11	6.06	1.82
Pair 2	Talar volume (Right)	36.64	7	3.02	1.14
	Talar volume (Left)	35.58	7	2.45	.92

Standard (Std).

Table 4

Differences of geometric profiles from 11 matched pairs of tali.

		Paired Differences					Sig. (2-tailed)
		Mean	Std. Deviation	Std. Error Mean	95% Confidence Interval of the Difference
					Lower	Upper
Pair 1	Talar surface (Right versus Left)	.52	2.31	.69	-1.03	2.08	.46
Pair 2	Talar volume (Right versus Left)	1.05	1.83	.69	-.64	2.75	.18

Standard (Std); Significance (Sig).

Discussion

The present study highlights the morphometric geometric variations between the right and left tali in matched pairs of fresh human cadaveric ankles. The results demonstrated significant differences between the left and right matched-pair talar morphometric profiles, specifically in three important parameters. However, there were no significant differences in the surface area or volume between the right and left tali.

The talus is a pivotal bone in the foot and ankle. Its key functions are related to both motion preservation of the ankle and load distribution [11]. With respect to these unique functions, the native shape of the talus is also unique and asymmetrical because of its three articulations with the tibia, fibula, navicular bone, and calcaneus. Several ligaments attach the talus to its surrounding articular structures [12]. Based on these exclusive characteristics, the talus is prone to several pathologies and injuries, but the native talus is difficult to reconstruct or duplicate in patients with conditions such as peritalar instability [13], talar bone damage [14], and loss of the talus [2]. Several reports have proposed the characteristics of the talus in terms of its biomechanical and morphologic aspects. Akiyama et al. reported that the dorsal articular side of the talocrural joint could withstand fewer loads than the ventral side [4]. Angthong reported the trochlear length/width ratio of the talus from a 3D file study based on CT images [2]. These data were inconsistent with the data from previous studies by Fessy et al [15]., Stagni et al. [16]. and Kuo et al [17]. Islam et al. conducted a study on the morphology of the right and left tali in the same living subjects using a CT database with contributions by 3D analyses [18]. They found a strong degree of symmetry between the two sides [18]. However, their measurements were derived from simulations made from CT images [18]. Based on measurement of the actual talus with no need for simulation, the present study combined data collection via systematic Vernier caliper measurement of morphometric profiles and 3D scans using a 3D scanner to obtain geometric measurement parameters of the human talus. Direct combination of these measurement methods revealed morphologic variations in contrast to the findings by Islam et al. The right and left tali demonstrated several differences in terms of their morphometric profiles. These deviations from bilateral symmetry may exceed the body’s ability to maintain its usual development in stressful conditions [8, 9]. Regarding the stressful condition, Julius Wolff and others realized that mechanical loads can affect bone architecture in living beings [19]. The fluctuating asymmetry may occur from this mechanism. In a meta-anaysis done by Beasley et al they found that fluctuating asymmetry is a sensitive biomarker of environmental stress. They concluded that fluctuating asymmetry as a biomarker of environmental stress is a legitimate tool particularly when studies verify the biological relevance of stressors for the study organism [20]. Bone asymmetry is thought to basically result from disproportionate mechanical stress which influences bone remodeling and plasticity [21, 22]. Similarly, Hallgrímsson found evidence suggesting an increase in fluctuating asymmetry of skeletal traits with increasing age in a heterogeneous sample [23]. Other studies also have found that fluctuating asymmetry is highest at the extremes of age i.e elderly people have more body asymmetry [24, 25]. Our study found the consistent findings in accordance with the previous studies. These evidences recommended that the talar-related implant may need to customize its size regarding the specific side of the ankle especially on the elderly patient. Angthong found that the mean age of patients who had the indications for the total ankle replacement was 65.2 years [26]. This age number was also high and seemed to be closed to the mean age of cadavers (69.4 years) in the present study. The present study’s evidence may help support the concept of patient-specific implant in the total ankle replacement for the elderly patient. In a study done by Teo et al they found 89.13% of right handed participants were also right legged. Right handed individuals are 8.2 times more likely to have ipsilateral leg dominance [27]. Shugaba et al also found similar result with 85% right handed participants were also right footed [28]. They found that the dominant leg was associated with greater volume which is consistent with our findings where the size of the right talus was more than the left ones.

In addition, the deviations in these parameters are important in terms of talar reconstruction/surgery and the manufacture of total talar prostheses for duplication and replacement of this bone. These results also support the emphasis on the manufacture of talar components of patient-specific size for use in total ankle arthroplasty implants [29]. Even if the measurement of the ankle-related bones had been done for the sizing of implant in the total ankle arthroplasty, Hsu et al found that talar implant sizing was not as accurate due to individual surgeon preference regarding the extent of gutter debridement [30]. Based on the results of the present study, measurement of the contralateral talus may not be the only useful method for determining the size of the talus of interest. Future 3D measurement of the talus on the pathologic/injured side may require the use of mirrored reconstruction images from articulations of the surrounding bones, such as the tibial plafond, navicular bone, and calcaneal facets to develop a more anatomically morphometric geometric template for further reconstruction or manufacturing than the conventionally manual measurement on two dimensional images. Similarly, CT images are extremely consistent and can be easily reconstructed to 3D model through computer software [31]. It is also important to do measurement of talar dome of the same side when aiming to design more anatomical ankle implant [32]. This technically challenging issue requires further study.

The main limitation of the present study is that the sample size was limited to 11 pairs of cadaveric ankles. However, the results still showed significant differences in the morphometric profiles between the right and left tali. Further study involving a larger sample size is needed to validate this information in a larger population. Regarding other limitation, the present study had no available data about the occupation and weight of the cadavers before their deaths. In addition to age, gender and height of cadavers, the bone morphometry might have the influence from these factors which should be considered in the further study. However, this study conducted the matched-pair analysis as right versus left ankle in the same cadaver; therefore, the different occupation and/or weight among cadavers may have less effect to the results of analysis.

Conclusion

The present study confirmed significant differences in the morphometric profiles as fluctuating asymmetry in the bilateral tali, providing basic information for talar-related treatment. The morphometric profile of the contralateral talus may not be used as a single reference to reconstruct or duplicate the talus of interest in certain conditions as discussed above.

The supplementary file of the data of this study (Microsoft excel form) was uploaded in the submission system.

(XLSX)

Click here for additional data file.

19 Feb 2020

PONE-D-19-33551

Morphometric geometric differences between right and left human tali: A cadaveric study of fluctuating asymmetry via systematic measurement and three-dimensional scanning

PLOS ONE

Dear Dr. Angthong,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by Apr 04 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Shang-Chun Guo

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

1. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the human tissues used in this study. Specifically, please ensure that you have discussed whether next-of-kin provided informed written consent for the use of the tissues. If patients provided informed written consent prior to death to have their bodies used in medical research, please include this information.

2. Thank you for including your ethics statement:  'This study was approved by the ethical committee of the institution's author.'

a) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

b) Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

3. Thank you for including the following funding information within the acknowledgements section of your manuscript; "The author would like to propose the special thanks to Thammasat University that provide the research grant for this research project (grant number: ทป2/43/ 2561, year 2018)"

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"Dr. Angthong reports grants from Thammasat University, during the conduct of the study; other from Amgen, personal fees from Phoenix Surgical Equipment (Thailand) Co., Ltd, outside the submitted work; In addition, Dr. Angthong has a patent Manufacture protocol for the artificial total talus issued"

4. a. Thank you for including your funding statement; "Dr. Angthong reports grants from Thammasat University, during the conduct of the study; other from Amgen, personal fees from Phoenix Surgical Equipment (Thailand) Co., Ltd, outside the submitted work; In addition, Dr. Angthong has a patent Manufacture protocol for the artificial total talus issued"

We note that you received funding from a commercial source: AMgen and Phoenix Surgical Equipment (Thailand) Co., Ltd

Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc.

Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

b.

We note that you have a patent relating to material pertinent to this article. Please provide an amended statement of Competing Interests to declare this patent (with details including name and number), along with any other relevant declarations relating to employment, consultancy, patents, products in development or modified products etc. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

This information should be included in your cover letter; we will change the online submission form on your behalf.

Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

5. Please amend your supporting information COI files to 'other' as these need not be included within your published manuscript

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this study, a total of 24 tali were measured with a vernier caliper and three-dimensional laser scanner. The significant differences in the morphometric profile were found between the right and left matched pairs of tali. However, there are some points that need to be addressed.

1. Is it possible that the differences in the morphometric profile between the right and left matched pairs of tali due to the samples of elderly cadavers？

2. Please use a unified decimal place in the tables.

Reviewer #2: In this study, the authors demonstrated the morphometric geometric variations between the right and left tali in matched pairs of human cadaveric specimens. There are a few concerns on the methodology and interpretation of the findings.

1. In addition to age, gender and height, we understand that the bone morphometry especially for calcaneum and talus, also depends on the occupation and weight. Did the authors consider these factors as well?

2. From line 134 to line 136, the authors mentioned that 'Differences in categorical data were analyzed using the chi-square … Pearson's correlation coefficient was used to express the correlation between the parametric parameters'. In the Result section, I couldn't find the findings using correlation analyses or analyses of categorical data. Is this part of analysis missing in the Result section?

3. From line 201 to line 207, the authors cited several articles using different methods to measure the talus morphometry. However, they didn't describe whether their findings are similar/different from the others. What is the purpose of citing these articles?

4. It is not clear what 'stressful conditions' the authors are referring to in line 213.

5. In Table 1, five out of seven parameters of tali showed that right tali were larger than left tali. It seems that there is right dominance of talus morphometry, like handedness. The authors did not discuss the potential relationship between limb dominance and talus morphometry.

6. The clinical significance is not clear. Ankle arthroplasty implant definitely requires the measurements on the articulations of the bones surrounding the pathologic/injured talus. It is not clear how the findings in this study contribute to the improvement of current technology of making the implants.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

18 Mar 2020

We have responded to the editor and reviewers' comments as point to point as in the attached letter of revision. Thank you for your consideration.

Submitted filename: Letter of Revision - Plos One.docx

Click here for additional data file.

7 Apr 2020

Morphometric geometric differences between right and left human tali: A cadaveric study of fluctuating asymmetry via systematic measurement and three-dimensional scanning

PONE-D-19-33551R1

Dear Dr. Angthong,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Shang-Chun Guo

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this study, a total of 24 tali were measured with a vernier caliper and three-dimensional laser scanner. The significant differences in the morphometric profile were found between the right and left matched pairs of tali.

Thanks for your revision.

Reviewer #2: Minor suggestions: In Tables 1-4, the units for the numbers under the columns of Mean, SD and SEM are missing.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

10 Apr 2020

PONE-D-19-33551R1

Morphometric geometric differences between right and left human tali: A cadaveric study of fluctuating asymmetry via systematic measurement and three-dimensional scanning

Dear Dr. Angthong:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Shang-Chun Guo

Academic Editor

PLOS ONE