The electrical heart axis of the fetus between 18 and 24 weeks of gestation: A cohort study

Carlijn Lempersz; Lore Noben; Sally-Ann B. Clur; Edwin van den Heuvel; Zhouzhao Zhan; Monique Haak; S. Guid Oei; Rik Vullings; Judith O. E. H. van Laar

doi:10.1371/journal.pone.0256115

Peer Review History

Original SubmissionJanuary 28, 2021
28 Jan 2021 Author Response Attachments Attachment Submitted filename: respons to reviewers Plos 24-1.docx https://doi.org/10.1371/journal.pone.0256115.r001
6 Apr 2021 Decision Letter - Gabor Erdoes, Editor PONE-D-21-02858 The electrical heart axis of the fetus between 18 and 24 weeks of gestation: a cohort study. PLOS ONE Dear Dr. Lempersz, 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. Please submit your revised manuscript by May 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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. 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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: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: 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: No Reviewer #2: Yes Reviewer #3: Yes ****** 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 Reviewer #3: No ****** 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: This study examined the electrical axis of the fetal heart between 18 and 24 weeks gestation in a cohort study. This was a normative study in fetuses shown to have a normal fetal echo at a mean of 20 weeks gestation. Utilizing a non-invasive method with NEMO technology resulted in 6 dipolar electrodes in a standardized array on the maternal abdomen. Fetal echo orientation of the body position allowed the generation of a fetal vectorcardiogram from which a mean frontal fetal cardiac electric axis was generated equaling 123 degrees with 90% PI of 26 – 271 degrees. They concluded that this is consistent with the expected rightward electrical axis of the normal fetus and that they have generated reference values. While there is indeed a great need to perfect non-invasive fetal ecg’s for research and clinical purposes, and the authors are making a great contribution to science by developing this technology, unfortunately, the very wide confidence intervals of the mean value, even with such a large cohort, implies that this particular parameter is not clinically useful as is, and this is acknowledged by the authors. However, they are encouraged to continue to explore the utility of this technique. In fact, they have included a copy of their large long-term pilot study of fetal non-invasive electrocardiograms, of which this project is a small part. It was unexpected that the electrical axis turned out to be so variable in this study. I posit that the greatest source of error is in their estimation of the fetal chest position. The mean frontal electric cardiac axis is very dependent on the orientation of the heart in relation to the 3-dimensional thorax. Postnatally, our electrode arrays are oriented to the usual levocardia, can be corrected for dextrocardia, and are known to vary with altered positional anatomy of the heart (eg, mesocardia) and the thorax (eg, scoliosis). The study’s method of having trainees periodically assess the fetal lie during the ecg, while the fetus may be moving, is the probable source of error. It is neither accurate nor precise. I would humbly suggest that they try this again, but next time carefully correct the vectorcardiogram for a fixed, anatomically and easily identified landmark, such as diaphragm, or even spine. Shortening the length of study might also reduce error due to fetal movement. A few questions and comments: Was this a convenience sample, or all consecutive normal fetal echos? The technical success rate was remarkable in that only 5 of 281 eligible fetuses could not be analyzed. The Title and Abstract are good. The Introduction is long, but clear and informative. The Methods are adequate, and while they mostly refer to their previous publications, these and the Research Protocol are all readily available. The Results are straightforward. The Discussion is a bit lengthy, but complete, including strengths, weaknesses, and future directions. The text is clear and well written, but still needs careful proofreading. This group has many prior publications in this field, which is supportive. The References are comprehensive and relevant. The Figures and Tables are good. Overall, the science appears to be valid, technically believable and thus reproducible. The results are unique. Again, I encourage the authors to improve their correction for fetal thorax orientation. Specific Comments: The copy of the manuscript provided to me somehow included all of the preceding editorial markups and corrections. In addition, the text version I accessed included prior assessments by 3 previous reviewers. However, I generated my review before reading the other opinions. Reference 30 is a book and appears incomplete without the name and location of the publisher. The word “data” is always plural. The sentence on lines 163-165 is unclear to me. Reviewer #2: Thank you for the opportunity to read this interesting paper about fetal ECG´s performed in normal pregnancies. The authors conclude, that the range of a normal fetal heart axis is wide and the fetal heart axis alone is not suitable for screening of CHD due to the wide prediction interval. I agree to the comments of the three previous reviewers. The comments of the authors and their changes within the text improved the paper. In conclusion, the authors showed that despite an optimal setting (study setting, optimal time window) the fetal heart axis is wide [and its use not applicable for screening of CHD]. Although they did not include fetuses with CHD als reference group, it many be reasonable to draw the above mentioned conclusions. This should be published. comment to the revision: lines 292 to 299: The statement that the heart axis has been shown to rotate in a fetus with aortic stenosis or critical pulmonary stenosis is an assumption that has not yet been proven. A fetal echo has a significantly greater significance here. I recommend deleting this section. Reviewer #3: Lempersz et al performed a prospective study to evaluate the normal cardiac axis in fetuses. Abstract: This study does not evaluate electrical heart axis in CHD, it only evaluates normal fetuses. Please do not put in the discussion anything regarding the electrical axis in CHD screening. Introduction: Please cite: NI-fECG enables the production of a 12-lead electrocardiogram by means of a standardized method. Methods: Study population, how do doctors evaluate cardiac health? Do they do echocardiograms? I find this paragraph from 124-130 confusing. Either describe the protocol in full or leave it out. Results/conclusions: I think the major limitation of this study is the utility of this information. I think using this information to then compare to patients with CHD should be the next step and would make this a much more robust and useful study. Otherwise, the study should be reframed as a "proof of concept" study since we know that neonates have a rightward axis. I don't think any information regarding CHD should be put in the paper, because it misleads the reader into thinking that there will be some information on the fetal electrical axis in CHD. Further comments: Previous edits are seen in the PDF, which made it challenging to review. ****** 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: Yes:** Ulrike Herberg Reviewer #3: 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.] 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0256115.r002
Revision 1
20 May 2021 Author Response 5. Review Comments to the Author Reviewer #1: This study examined the electrical axis of the fetal heart between 18 and 24 weeks gestation in a cohort study. This was a normative study in fetuses shown to have a normal fetal echo at a mean of 20 weeks gestation. Utilizing a non-invasive method with NEMO technology resulted in 6 dipolar electrodes in a standardized array on the maternal abdomen. Fetal echo orientation of the body position allowed the generation of a fetal vectorcardiogram from which a mean frontal fetal cardiac electric axis was generated equaling 123 degrees with 90% PI of 26 – 271 degrees. They concluded that this is consistent with the expected rightward electrical axis of the normal fetus and that they have generated reference values. While there is indeed a great need to perfect non-invasive fetal ecg’s for research and clinical purposes, and the authors are making a great contribution to science by developing this technology, unfortunately, the very wide confidence intervals of the mean value, even with such a large cohort, implies that this particular parameter is not clinically useful as is, and this is acknowledged by the authors. However, they are encouraged to continue to explore the utility of this technique. In fact, they have included a copy of their large long-term pilot study of fetal non-invasive electrocardiograms, of which this project is a small part. It was unexpected that the electrical axis turned out to be so variable in this study. I posit that the greatest source of error is in their estimation of the fetal chest position. The mean frontal electric cardiac axis is very dependent on the orientation of the heart in relation to the 3-dimensional thorax. Postnatally, our electrode arrays are oriented to the usual levocardia, can be corrected for dextrocardia, and are known to vary with altered positional anatomy of the heart (eg, mesocardia) and the thorax (eg, scoliosis). The study’s method of having trainees periodically assess the fetal lie during the ecg, while the fetus may be moving, is the probable source of error. It is neither accurate nor precise. I would humbly suggest that they try this again, but next time carefully correct the vectorcardiogram for a fixed, anatomically and easily identified landmark, such as diaphragm, or even spine. Shortening the length of study might also reduce error due to fetal movement. A few questions and comments: Was this a convenience sample, or all consecutive normal fetal echos? The technical success rate was remarkable in that only 5 of 281 eligible fetuses could not be analyzed. The Title and Abstract are good. The Introduction is long, but clear and informative. The Methods are adequate, and while they mostly refer to their previous publications, these and the Research Protocol are all readily available. The Results are straightforward. The Discussion is a bit lengthy, but complete, including strengths, weaknesses, and future directions. The text is clear and well written, but still needs careful proofreading. This group has many prior publications in this field, which is supportive. The References are comprehensive and relevant. The Figures and Tables are good. Overall, the science appears to be valid, technically believable and thus reproducible. The results are unique. Again, I encourage the authors to improve their correction for fetal thorax orientation. Specific Comments: The copy of the manuscript provided to me somehow included all of the preceding editorial markups and corrections. In addition, the text version I accessed included prior assessments by 3 previous reviewers. However, I generated my review before reading the other opinions. Reference 30 is a book and appears incomplete without the name and location of the publisher. The word “data” is always plural. The sentence on lines 163-165 is unclear to me. Answer: Thank you for your thorough reading of the paper and your feedback. We want to apologize for having submitted a version with editorial markups and assessments from previous reviewers. We admit that the determination of the fetal orientation is a limitation of this study. The fetal orientation was determined following a protocol in which the spine was taken as an identifiable landmark. The ultrasound probe was held only in a horizontal and vertical position for it to be reproducible and annotations were made about the position of the probe. A few factors can contribute to inaccuracies in the correction for the fetal orientation: inaccuracies in the correction for fetal movement and inaccurate assessment of the fetal orientation and the time at which this assessment was made. To minimize these inaccuracies, we have used the ECG data that was recorded around the time that the fetal orientation assessment was done. Possible cumulative errors in the correction for movement will therefore be limited. As an extra check, we did determine the fetal orientation multiple times per recording. Within a single patient, the correct ECGs/VCGs are compared to verify their consistency, which can act as an indirect evaluation of the accuracy of our orientation correction. We have modified the manuscript to include this extra check. With regard to the question regarding the samples that we used in our study. All measurements were taken of healthy fetuses after the 20 week anomaly scan, so these were all consecutive normal echos Answer: Reference 30 has been completed. Answer: Lines 163-165 have been adjusted for more clarification. Reviewer #2: Thank you for the opportunity to read this interesting paper about fetal ECG´s performed in normal pregnancies. The authors conclude, that the range of a normal fetal heart axis is wide and the fetal heart axis alone is not suitable for screening of CHD due to the wide prediction interval. I agree to the comments of the three previous reviewers. The comments of the authors and their changes within the text improved the paper. In conclusion, the authors showed that despite an optimal setting (study setting, optimal time window) the fetal heart axis is wide [and its use not applicable for screening of CHD]. Although they did not include fetuses with CHD als reference group, it many be reasonable to draw the above mentioned conclusions. This should be published. comment to the revision: lines 292 to 299: The statement that the heart axis has been shown to rotate in a fetus with aortic stenosis or critical pulmonary stenosis is an assumption that has not yet been proven. A fetal echo has a significantly greater significance here. I recommend deleting this section. Answer: Thank you for your positive comments regarding the manuscript. We agree with the suggestion on lines 292 to 299 and have deleted these. Reviewer #3: Lempersz et al performed a prospective study to evaluate the normal cardiac axis in fetuses. Abstract: This study does not evaluate electrical heart axis in CHD, it only evaluates normal fetuses. Please do not put in the discussion anything regarding the electrical axis in CHD screening. Answer: Thank you for the time taken to read the manuscript and to provide valuable feedback. We have adjusted the discussion section of the abstract by deleting the sentence about CHD screening. Introduction: Please cite: NI-fECG enables the production of a 12-lead electrocardiogram by means of a standardized method. Answer: We have added a reference (no 14) for this. Methods: Study population, how do doctors evaluate cardiac health? Do they do echocardiograms? I find this paragraph from 124-130 confusing. Either describe the protocol in full or leave it out. Answer: Before women were included in the study, they all underwent the fetal anomaly scan in which, amongst others, fetal cardiac health was assessed. Women could enter the study if the fetal anomaly scan showed a healthy fetus. The Paragraph (lines 124-130) has been changed for clarification. Postnatal check-ups consist of physical examination and auscultation of the heart. Results/conclusions: I think the major limitation of this study is the utility of this information. I think using this information to then compare to patients with CHD should be the next step and would make this a much more robust and useful study. Otherwise, the study should be reframed as a "proof of concept" study since we know that neonates have a rightward axis. I don't think any information regarding CHD should be put in the paper, because it misleads the reader into thinking that there will be some information on the fetal electrical axis in CHD. Answer: Thank you for the useful feedback. We agree with this comment, that was also raised by one of the other reviewers. We have omitted the paragraph regarding CHD. Further comments: Previous edits are seen in the PDF, which made it challenging to review. Answer: We apologize for having submitted the wrong version. Attachments Attachment Submitted filename: respons to reviewers Plos final.docx https://doi.org/10.1371/journal.pone.0256115.r003
11 Jun 2021 Decision Letter - Gabor Erdoes, Editor PONE-D-21-02858R1 The electrical heart axis of the fetus between 18 and 24 weeks of gestation: a cohort study. PLOS ONE Dear Dr. Lempersz, 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. Please address the issues raised by the statistical reviewer. Thank you. Please submit your revised manuscript by Jul 26 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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. 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). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Gabor Erdoes, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. 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 Reviewer #4: (No Response) ******** 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: Yes Reviewer #4: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #4: No ****** 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: Yes Reviewer #4: No ****** 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: Yes Reviewer #4: Yes ****** 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: (No Response) Reviewer #2: No further comments The authors responded to all questions raised. The manuscript has been reviewed an corrected. Reviewer #4: PONE-D-21-02858R1: statistical review SUMMARY. In this study, the electrical heart axis is proposed as a predictor of healthy fetuses around 20 weeks of gestation. The statistical analysis is based on a sample of frontal angles. Although the methods seem correct and the results are sound, some statistical computations are nonstandard because they belong to circular statistics. As such, these methods deserve a larger description than that one given by this version of the paper: see the specific issues below. SPECIFIC ISSUES 1. The average frontal axis is a circular mean. Was it computed by the traditional ratio of trigonometric moments? Please clarify. 2. It seems that the confidence interval of the average frontal axis has been computed by assuming that the data are sampled from a von Mises distribution. Please provide the value of the concentration parameter of the von Mises distribution that has been used for computing the confidence interval. 3. Please clarify whether the von Mises parameters have been estimated by maximum likelihood methods. In this case, please clarify if the bias of the maximum likelihood estimate of the concentration parameter has been corrected or not. 3. The von Mises density is just one of the possible distributions that one can choose for circular data modelling. Without asking for a formal test of goodness of fit, could the authors at least overlap the estimated density on the empirical rose diagram of the data? This will show whether the von Mises provides a reasonable fit in this case study. ****** 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: Yes:** Ulrike Herberg Reviewer #4: 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.] 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. 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23 Jul 2021 Author Response AUTHOR’s RESPONSE: Reviewer #4: PONE-D-21-02858R1: statistical review SUMMARY. In this study, the electrical heart axis is proposed as a predictor of healthy fetuses around 20 weeks of gestation. The statistical analysis is based on a sample of frontal angles. Although the methods seem correct and the results are sound, some statistical computations are nonstandard because they belong to circular statistics. As such, these methods deserve a larger description than that one given by this version of the paper: see the specific issues below. SPECIFIC ISSUES 1. The average frontal axis is a circular mean. Was it computed by the traditional ratio of trigonometric moments? Please clarify. Yes, we took the maximum likelihood estimate (mle) of the mean direction parameter μ of a von Mises distribution as the average frontal axis which is the same as the first sample trigonometric moment: θ ̅="atan2"(S ̅/C ̅), where C ̅=1/n ∑_(j=1)^n▒cos⁡〖θ_j 〗 and S ̅=1/n ∑_(j=1)^n▒sin⁡〖θ_j 〗⁡ . The praragraph has been adjusted in the manuscript (lines 176-179). 2. It seems that the confidence interval of the average frontal axis has been computed by assuming that the data are sampled from a von Mises distribution. Please provide the value of the concentration parameter of the von Mises distribution that has been used for computing the confidence interval. 3. Please clarify whether the von Mises parameters have been estimated by maximum likelihood methods. In this case, please clarify if the bias of the maximum likelihood estimate of the concentration parameter has been corrected or not. We would like to answer the reviewer’s comments 2-3 together since they are related to each other. First, we would like to mention that we computed the prediction interval for the frontal axis rather than the confidence interval. Nevertheless, reviewer 4’s comments regarding the bias of the concentration parameter κ are still valid. Indeed, we used the mle of the κ without bias corrections for the calculation of the prediction interval. Albeit the fact that the correction method proposed by Best and Fisher (1981) is still biased for small values of κ when the sample size is not large, we were able to verify that prediction interval based on the uncorrected κ ̂ has close-to-nominal coverage probability via simulations (see Table 1 below). In this simulation study, for each simulation run, we drew 281 independent random samples from a von Mises distribution with parameter μ=4.142 and κ=0.526 (these values are also parameter estimates of the real data which the reviewer requested) and estimated the parameters using maximum likelihood. Based on the estimated parameters, we computed the corresponding quantiles of the von Mises distribution as our prediction interval. Thereafter, an independent sample was again drawn from the same distribution as a “future” observation. Across 10000 simulation runs, we calculated how often the prediction intervals contained the “future” observations. Prediction interval Coverage probabilities 99% 98.95% 98% 98.02% 97% 96.72% 96% 96.06% 95% 95.11% 94% 93.98% 93% 93.05% 92% 91.46% 91% 90.37% 90% 90.33% 4. The von Mises density is just one of the possible distributions that one can choose for circular data modelling. Without asking for a formal test of goodness of fit, could the authors at least overlap the estimated density on the empirical rose diagram of the data? This will show whether the von Mises provides a reasonable fit in this case study. We agree with the reviewer that the von Mises distribution is just one of many possible distributions. We hereby provide the plot of the estimated density superimposed on the circular diagram. (diagram can be found in the 'response to reviewer' file) Attachments Attachment Submitted filename: Response-reviewer-4.docx https://doi.org/10.1371/journal.pone.0256115.r005
2 Aug 2021 Decision Letter - Gabor Erdoes, Editor The electrical heart axis of the fetus between 18 and 24 weeks of gestation: a cohort study. PONE-D-21-02858R2 Dear Dr. Lempersz, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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 help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- 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. Kind regards, Gabor Erdoes, M.D., Ph.D. Academic Editor PLOS ONE 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 #4: 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 #4: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #4: (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 #4: (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 #4: (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 #4: (No Response) ****** 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 #4: No https://doi.org/10.1371/journal.pone.0256115.r006
Formally Accepted
7 Dec 2021 Acceptance Letter - Gabor Erdoes, Editor PONE-D-21-02858R2 The electrical heart axis of the fetus between 18 and 24 weeks of gestation: a cohort study. Dear Dr. Lempersz: I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Dr. Dr. Gabor Erdoes Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0256115.r007

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