Hemoglobin point-of-care testing in rural Gambia: Comparing accuracy of HemoCue and Aptus with an automated hematology analyzer

Stefan A. Nass; Ilias Hossain; Chilel Sanyang; Bakary Baldeh; Dora I. A. Pereira

doi:10.1371/journal.pone.0239931

Peer Review History

Original SubmissionFebruary 12, 2020
19 May 2020 Decision Letter - Simeon-Pierre Choukem, Editor PONE-D-20-03905 Hemoglobin point-of-care testing in rural Gambia: Comparison of HemoCue® and Aptus™ with an automated hematology analyzer PLOS ONE Dear Mr. Nass, 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 Jul 03 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. 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Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [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: Partly Reviewer #2: Yes ******** 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: 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 ****** 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 aimed to (1) compare Hb concentrations measured in venous blood by 2 PoCDs with an automated analyzer in young children with IDA in a rural setting (2) compare the Hb measurements provided by 2 PoCDs in capillary blood; (3) determine the usability of Aptus in these settings and 4) highlight potential improvements to the Aptus model used here before a wider global launch. 1) The method used for assessing the last two objectives are not well described in article under the "Materials and Method" section 2) The abstract does not include the last 2 aims in it's objectives, nor the results but seems to jump to a conclusion on the use of one PoCD 3) Statistical analysis: It is mentioned in the paper that "The Clinical Laboratory Improvement Amendments (CLIA) of 1988 postulate a ±7% deviance from the true value as acceptable for a device measuring hemoglobin." I think the limit of 7% is very large for hemoglobin measurements. I wish to suggest to the authors to use the total error allowable (TEa) based on Desirable Biological Variation Database specifications. For Hb, this is 4.19%.(https://www.westgard.com/biodatabase1.htm#de). This would be more fair method for comparing. 4) I wish to suggest the addition of ROC curves for the 2 PoCDs versus Lab measurements in addition to the agreement analysis 5) The manuscript should follow the Standards for Reporting of Diagnostic Accuracy studies - STARD statement (http://www.stard-statement.org/) for properly reporting this type of study. A STARD checklist should ideally accompany this manuscript. 6) I think the Conclusion on the usability of Aptus at the end of this manuscript is not fully supported by the results of this study. 7) This study included children. Please kindly specify whether consent was obtained from parents/legal guardians before study procedures Reviewer #2: The authors of this work present an interesting work which evaluates the performance of 2 Point-of-care devices (PoCDs), Aptus® and HemoCue® against an automated haematology analyser in children in a country with limited resources, The Gambia. These 2 devices showed similar level of agreement with the laboratory analyser but Aptus® showed slightly lower bias and wider limits of agreement than the HemoCue®. Both PoCDs were shown to overestimate Hb concentration. Then, Aptus® could represent an alternative to HemoCue® as standard for field settings in low resource areas. The study design is clear and the results well presented. I agree with the conclusions and recommendations of this work. However, some clarifications will help to improve the quality of this work. Introduction The introduction is clear but would benefit from being more concise. Table 1 (line 104): would it be possible to have an idea on the prices of these PoCDs, in order to be in agreement with the comment presented on line 369? Materials and methods Why the choice of 35 months as the upper limit for the recruitment of children, and not 36 months, even 59 months as in the WHO report (The Global Prevalence of Anaemia in 2011)? Children with severe anaemia were excluded from this study (line 124). For children between 6 and 59 months of age, WHO defines severe anaemia as <7.0 g / dL. Can you explain why in the basic characteristics of the participants in your study, the minimum haemoglobin level is 6.9 g / dL? (Table 2). Same as in Table 3 where the minimum Hb level for Medonic is 6.7 g / dL? Results Do you have climate data (particularly the temperature) at the time the blood samples were taken and the analysis of these samples was performed? Discussion The discussion is clear but would benefit from being more concise. ****** 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: Yes: Colette Sih Reviewer #2: Yes: Fernando KEMTA LEKPA [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. https://doi.org/10.1371/journal.pone.0239931.r001
Revision 1
26 Jun 2020 Author Response Dear editors, We would like to thank the reviewers for their work and have addressed their concerns in the manner described below. Reviewer #1: This study aimed to (1) compare Hb concentrations measured in venous blood by 2 PoCDs with an automated analyzer in young children with IDA in a rural setting (2) compare the Hb measurements provided by 2 PoCDs in capillary blood; (3) determine the usability of Aptus in these settings and 4) highlight potential improvements to the Aptus model used here before a wider global launch. 1) The method used for assessing the last two objectives are not well described in article under the "Materials and Method" section Clarification has been added in lines 98 – 102 2) The abstract does not include the last 2 aims in it's objectives, nor the results but seems to jump to a conclusion on the use of one PoCD Descriptions have been added to the abstract (lines 8, 11, 20,21,23-24) 3) Statistical analysis: It is mentioned in the paper that "The Clinical Laboratory Improvement Amendments (CLIA) of 1988 postulate a ±7% deviance from the true value as acceptable for a device measuring hemoglobin." I think the limit of 7% is very large for hemoglobin measurements. I wish to suggest to the authors to use the total error allowable (TEa) based on Desirable Biological Variation Database specifications. For Hb, this is 4.19%.(https://www.westgard.com/biodatabase1.htm#de). This would be more fair method for comparing. The CLIA method has been replaced with the proposed TEa method (lines 292-295) 4) I wish to suggest the addition of ROC curves for the 2 PoCDs versus Lab measurements in addition to the agreement analysis A ROC analysis was added with absence of anemia (Hb ≥ 11g/dl) as binary outcome variable (lines 316 – 326). As explained in the text, severe and moderate anemia were not suitable for comparison due to the low prevalence. 5) The manuscript should follow the Standards for Reporting of Diagnostic Accuracy studies - STARD statement (http://www.stard-statement.org/) for properly reporting this type of study. A STARD checklist should ideally accompany this manuscript. Aspects of the text have been adapted to follow STARD guidelines and the checklist has been uploaded separately. We stress, however, that this was an exploratory comparative study and as such the intention was not to exhaustively determine the diagnostic accuracy of the PoCDs. Furthermore, the ancillary nature of this study necessitated adherence to IHAT-GUT study protocol, which was not planned as a comparative study between the devices and as such did not always represent the optimal study design for such a study. 6) I think the Conclusion on the usability of Aptus at the end of this manuscript is not fully supported by the results of this study. In order to address this, the usage experience with the Aptus device has been moved from the Discussion to the Results section (lines 353-373), and the Discussion adapted to more clearly highlight the combination of statistical analysis and user experience that our conclusion is based on. 7) This study included children. Please kindly specify whether consent was obtained from parents/legal guardians before study procedures Consent details have been specified (lines 132-143) Reviewer #2: The authors of this work present an interesting work which evaluates the performance of 2 Point-of-care devices (PoCDs), Aptus® and HemoCue® against an automated haematology analyser in children in a country with limited resources, The Gambia. These 2 devices showed similar level of agreement with the laboratory analyser but Aptus® showed slightly lower bias and wider limits of agreement than the HemoCue®. Both PoCDs were shown to overestimate Hb concentration. Then, Aptus® could represent an alternative to HemoCue® as standard for field settings in low resource areas. The study design is clear and the results well presented. I agree with the conclusions and recommendations of this work. However, some clarifications will help to improve the quality of this work. Introduction 1) The introduction is clear but would benefit from being more concise. Parts of the Introduction have been reformulated in a more concise way, see tracked changes. 2) Table 1 (line 104): would it be possible to have an idea on the prices of these PoCDs, in order to be in agreement with the comment presented on line 369? Prices have been added to the last row of table 1 (line 104). Materials and methods 3) Why the choice of 35 months as the upper limit for the recruitment of children, and not 36 months, even 59 months as in the WHO report (The Global Prevalence of Anaemia in 2011)? Use of 35 months cut-off (inclusive, we could also write 6 to <36 months) is because this inclusion criteria was for children under the age of 3 years old which has been the group used in the iron supplementation trials conducted in sub-Saharan Africa showing a potential detrimental effect of iron supplementation in infection and diarrhea. We could have used the under 5s as defined by WHO (up to 59 months) but the trials with iron have been focusing on under 35months. Furthermore, after 3 years the microbiome changes too close to an adult-like microbiome and impact of iron on microbiome was an important endpoint of IHAT-GUT and the hypothesis behind IHAT. You can reference: https://pubmed.ncbi.nlm.nih.gov/16413877/ and https://www.sciencedirect.com/science/article/pii/S0966842X19302148 4) Children with severe anaemia were excluded from this study (line 124). For children between 6 and 59 months of age, WHO defines severe anaemia as <7.0 g / dL. Can you explain why in the basic characteristics of the participants in your study, the minimum haemoglobin level is 6.9 g / dL? (Table 2). Same as in Table 3 where the minimum Hb level for Medonic is 6.7 g / dL? Children had Hb ≥7 g/dL measured by the Medonic at the time of screening and enrolment in the study. The data presented in this manuscript was collected from study day 57 onwards, at which point some children had shown a drop of Hb to below the severe anemia cut-off. These children were subsequently discontinued of the study supplementation, as per IHAT-GUT study protocol, and given standard of care iron drops according to national guidelines in The Gambia. As this clinical consequence does not interfere with the methodological comparison of the measuring devices, these measurements were not excluded in the present study. For clarification, this explanation was added to the Methods section (lines 170-179, 217-222) Results 5) Do you have climate data (particularly the temperature) at the time the blood samples were taken and the analysis of these samples was performed? Temperature and humidity averages added (line 110,111). Discussion 6) The discussion is clear but would benefit from being more concise. Parts of the Discussion have been reformulated in a more concise way, see tracked changes. Furthermore, the description of the Aptus in-field usage has been moved to the Results section (lines 353-373), thereby significantly shortening the Discussion. Academic Reviewer 1. PLOS ONE's style requirements, including those for file naming. File names have been amended, Panels in figures 2-4 combined into planes, line numbers added to the title page and minor formatting issues fixed in the main text. 2. Competing interests and funding statements Competing interests and funding statements have been amended and clarified as per the feedback received. 3. Figures All figure files have been checked with Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool. We believe the manuscript is now suitable for publication in your journal. Kind regards, Stefan Nass On behalf of all the authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0239931.r002
28 Jul 2020 Decision Letter - Simeon-Pierre Choukem, Editor PONE-D-20-03905R1 Hemoglobin point-of-care testing in rural Gambia: Comparing accuracy of HemoCue® and Aptus™ with an automated hematology analyzer PLOS ONE Dear Dr. Nass, 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. ============================== ACADEMIC EDITOR: The manuscript will be accepted once you have carried out the minor revisions required by reviewer 1 Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact. ============================== Please submit your revised manuscript by Sep 11 2020 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 We look forward to receiving your revised manuscript. Kind regards, Simeon-Pierre Choukem Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] 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: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: No Reviewer #2: Yes ****** 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 ****** 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: The aim of this study was to (1) compare Hb concentrations measured in venous blood by 2 PoCDs with an automated analyzer in young children with IDA in a rural setting (2) compare the Hb measurements provided by 2 PoCDs in capillary blood; (3) determine the usability of Aptus in these settings and 4) highlight potential improvements to the Aptus model used here before a wider global launch. 1) A considerable amount of grammatical errors noted with additional "the", "a", sentences which are too long making their comprehension difficult Reviewer #2: Dear Editor, We have read the new version of the article submitted for our review by Nass S. et al on “ Hemoglobin point-of-care testing in rural Gambia: Comparing accuracy of HemoCue® and Aptus™ with an automated hematology analyzer”. The authors have taken all of my comments into consideration. We have no new comments. Best regards fkl ****** 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: Yes: Colette Sih Reviewer #2: Yes:** Fernando Kemta Lekpa [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.0239931.r003
Revision 2
28 Aug 2020 Author Response Dear editors, We would like to thank the reviewers for their work and have addressed their concerns in the manner described below. Reviewer #1: 1) A considerable amount of grammatical errors noted with additional "the", "a", sentences which are too long making their comprehension difficult The manuscript has been reviewed again by three native speakers. For the revisions, see tracked changes. 4. Have the authors made all data underlying the findings in their manuscript fully available? Answer: No The reviewer has not further specified which data they are referring to. All data pertaining to this analysis is presented in the manuscript. The demographic and endpoint data for the IHAT-GUT trial will be published separately and the full database for the IHAT-GUT trial will be made available upon publication of the primary and secondary endpoints. We trust that this is sufficient with regards to the data policy. We believe the manuscript is now suitable for publication in your journal. Kind regards, Stefan Nass On behalf of all the authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0239931.r004
16 Sep 2020 Decision Letter - Simeon-Pierre Choukem, Editor Hemoglobin point-of-care testing in rural Gambia: Comparing accuracy of HemoCue® and Aptus™ with an automated hematology analyzer PONE-D-20-03905R2 Dear Dr. Nass, 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, Simeon-Pierre Choukem Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0239931.r005
Formally Accepted
21 Sep 2020 Acceptance Letter - Simeon-Pierre Choukem, Editor PONE-D-20-03905R2 Hemoglobin point-of-care testing in rural Gambia: Comparing accuracy of HemoCue and Aptus with an automated hematology analyzer Dear Dr. Nass: 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 Dr. Simeon-Pierre Choukem Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0239931.r006

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