PONE-D-24-06919Mortality and predictors among HIV/TB co-infected patients in Ethiopia: A Systematic Review and Meta-analysis.PLOS ONE

Dear Dr. Wondie,

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.

 This paper was reviewed by an expert statistician who has made comprehensive comments on the statistical methodology including the construction of the funnel plots with respect to the presence of outliers and the expression of p values. The reviewers also expressed concern with the selection of the MeSH terms which must be fully explained. Please submit your revised manuscript by Jul 27 2024 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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Reviewers' comments:

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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: No

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: Yes

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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

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Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

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Reviewer #1: Abstract

Cochrane’s I2 is a secondary confirmation, it does not provide a p-value. Use tau-squared;

I2 should be stated as Cochrane’s I^2

Pooled proportion is 18.35 (95% CI: 14.89-21.81) calculated as follows:

18.35+1.96σ x (s/√n) = 18.35+1.96.(10.73/√37) =21.81 upper limit

18.35-1.96σ x (s/√n) = 18.35-1.96.(10.73/√37) =14.89 lower limit

s = sample standard deviation; n = 37

α = 0.025 x 37 = 0.925 ≈ 1.

This means that your funnel plot should not have more than 1 observation outside the left pseudo 95% limit and not more than 1 outside the right pseudo limit. You have 7 outside the left limit and 16 outside the right limit. This shows your distribution is highly non-normal, and that the parameters of a normal distribution do not apply. The funnel plot does not indicate that an Egger’s trim and fill has been done because the number of papers remains at 37, and the left half of the funnel is relatively empty. The funnel plot is thus unacceptable in all details.

You have used STATA 14.2 for your meta-analysis, which is an add-in using the meta command. This uses the DerSimonian and Laird approach (DL) for the pooled effects and the diamond. You have overall DL at p<0.000 and I^2 =97.1%. This does not show the detailed tests for heterogeneity such as Tau-squared, H-squared and Q (see Borenstein below). STATA 16 onwards incorporates meta-analysis in its suite. I would recommend you use the latest version (STATA 18). Read also the STATA manual on meta-analysis. Note that funnel plots are rarely successful (Borenstein et.al. (2009)) mainly because of incomplete spread of publications.

Consult the paper: Michael Borenstein (8 November, 2023) https://doi.org/10.1002/jrsm.1678 Avoiding common mistakes in meta-analysis: Understanding the distinct roles of Q, I-squared, tau-squared, and the prediction interval in reporting heterogeneity (Wiley)

Figure 2 Forest plot of pooled mortality. Although the random effects model applies, and publications therefore have similar weights, the effects confirm the funnel plot’s conclusion of a very non-normal distribution. The top 5 effect means are: Habtamu 80.48; Palme et.al. 37.93; Birhan et.al. 35.39; Gebreyes 29.48; Belayneh et.al. 25.7. The bottom 5 effect means are: Ifa 4.40; Seyoum et.al. 4.45; Alemu et.al. 5.63; Balcha et.al. 6.15; Tola et.al. 7.70. Using the upper limit equation above 18.35+1.96*(10.73/√37) =21.81 upper limit and 18.35-1.96*(10.73/√37) =14.89 lower limit. In the top and bottom studies, Habtamu and Ifa respectively, we have:

The Habtamu mean has a z=35.2 above the mean, that is: 18.35+35.2*(10.73306/37^0.5) ≈ 80.48

The Ifa mean has a z=7.9 below the mean, that is 18.35-7.9*(10.73306/37^0.5) ≈ 4.40.

Applying these to the other 8 studies highlights the problems of the outliers in the funnel plot.

The conclusion on this forest plot is that the 37 studies constitute a highly non-normal distribution and that the 18.35% prevalence is invalid as a measure for Ethiopia as a whole.

On the subgroup analysis, Tigray region has the highest mortality 31.86% (95% CI 8.83-54.88). The abstract does not give the region with the lowest mortality and Figure 4 forest plot of subgroup analysis by region is not readable nor is the click download for Figure 4 readable so I cannot comment on this. The CI spread of 8.83 – 54.88 for Tigray indicates that this region must have a mixture of very high and very low prevalences. The conclusion is that Ethiopia does not have a consistent monitoring, recording, treatment, and health system, and an overall 18.35% prevalence is misleading because of the extreme outliers and imbalance in the regions.

Hazard ratios: the abstract should indicate that hazard ratios have been used and the various ratios for predictors like HR, for example:

In the AHR region poor adherence to ART should indicate HR 2.50(95% CI: 1.28-4.91) also for the other HRs.

Hazard ratios are computed in the underlying papers and are the ratios between treatment curves (HIV/TB) and curves for corresponding curves for controls (non-HIV/TB). A problem is that the curves in the underlying papers have different time periods, and this may affect comparability. Hazard ratio curves are often linearized by using log HR or log RR. The various graphs for predictors use The DL method and show the overall DL heterogeneity measure but not the component measures (see DerSimonian and Laird approach (DL) comment above).

MeSH has been used to search and select papers on the basis of key words and phrases. Only 37 out of 886 studies qualified. There is no test that the key words selected satisfy the relationship between the dependent variable mortality and the independent variables like anaemia, poor ART adherence and lack of co-trimoxazole therapy. Independent variables such as low CD4 count, poor nutritional status, male sex, female sex worker, early initiation of ART for TB patients in various papers have not been included in this paper and have not been included in the MeSH search.

The same independent variables have been applied across categories but would vary between children and adults. A logistic regression should be done to ensure that the independent variables demarcate mortality and non-mortality and that these independent variables are included in the MeSH search and model.

The logistic regression has the form P=(e^(a +bx))/(1+e^(a+bx)); P takes on binary values

(1= mortality; 0= no-mortality) and b is the vector of independent variables that take continuous values.

Background gives WHO mortality rates, rates for Lesotho, Zambia, children, African region, and South East Asia. These would most likely have different predictors so they are not strictly comparable. For clarity of presentation they should be shown in a table.

Spelling and grammar: change ‘systemic’ to ‘systematic’, ‘Anemia’ to ‘anaemia’

Reviewer #2: • There are no page and line numbers used in the document- the authors did not follow PLOS instructions and makes it difficult to refer.

• According to The United States National Institutes of Health, the United Nations and its Children’s Fund (UNICEF), and the European Union pediatrics are defined as persons younger than 18 years. Which guidelines did the authors use to categorize pediatrics up to 15 years?

• Tabe 1: years must be corrected for ID 9 and 11.

• Reference the software used to analyse eg. Endnote version 9.

• The authors need to be consistency when referring to HIV-TB coinfection/TB-HIV co-infection/HIV/TB co-infection.

• P value should be written consistently throughout the manuscript with a symbol = or ≤.

• All the abbreviations must be written in full before abbreviation.

• Page 13: The authors referenced 6 studies but mentioned that five studies were included to examine the association between anemia and mortality.

• Page 14: Last sentence under “Poor adherence” should read “For this predictor publication bias was not performed due to small number of studies”.

• There are some spelling and grammatical errors on the manuscript that need to be corrected eg, page 14 under extrapulmonary tuberculosis: HIIV-TB should read HIV-TB.

• In the discussion, when comparing your studies with others, indicate the location of the systematic review and meta-analysis you are comparing too. Paragraph 2 and 6.

• Indicate when was the test-and treat strategy introduced globally and in Ethiopia?

• Discussion: The pecentages after the countries should be inside the brackets

Eg. This finding is in line with studies conducted in Sub-Saharan Africa (SSA) (18.1%) (1), Europe and Latin America (19%) (63), and systematic review and meta-analysis (15%) (64). However, this finding was lower than a study conducted in Eastern Europe (29%) (63), Brazil (27.4%) (65), and a systematic review and meta-analysis (33.56%)

• Discussion, paragraph 3 “This discrepancy may be related to limited access to appropriate therapy, …………...”- This statement is contrary to the above where the author mentioned that “The other possible justification is the study period, those studies were incorporated studies conducted before the commencement of the test-and-treat strategy, but in the present study, most of included studies were conducted after test and treat all strategy which is a proven strategy in reducing mortality.

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Reviewer #1: Yes: Anthony Leland Hamilton Mayne

Reviewer #2: No

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PONE-D-24-06919R1Mortality and predictors among HIV-TB co-infected patients in Ethiopia: A Systematic Review and Meta-analysis.PLOS ONE

Dear Dr. Wondie,

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.

The statistical reviewer still identifies significant concerns with the analysis here particularly, for example, with the construction of the forest plots. Since this is a systematic review, these plots are essential to the underlying analysis.

Please submit your revised manuscript by Oct 18 2024 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: https://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,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

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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: (No Response)

Reviewer #2: All comments have been addressed

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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: No

Reviewer #2: Yes

**********

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

Reviewer #1: No

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: Yes

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: No

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: PLoS One Mortality and predictors among HIV-TB co-infected patients in Ethiopia: A Systematic Review and Meta-analysis

Pone-D-24-06919R1

Lines

31 systematic.

38 Cochrane Q and I2 test statistics.

42 A total of 886 studies were identified, using database searches and keywords. Of these, 37 met the criteria for inclusion. (omit “and were included in this study”).

44-49 The APA style is 95% CI [4.32, 9.26]. Note that the STATA 18 forest plot style is 4.45[3.24, 5.66] effect size with 95% CI, which is also acceptable.

44-49 The APA style for hazard ratios is (HR=2.02, 95% CI [1.7, 2.5]).

44-49 APA style for p-values is p<.001 or p≤.05 not p=.00 i.e. state a limit. I know STATA 18 gives the form p=0.00 in the forest plots, but in a formal report, use the APA style (p=0.00 becomes p<.01).

50 Nearly one-fifth? How much? present the value, for example, 19.6%.

The introduction needs to be rewritten, please refer this to an experienced editor. What is the African region (line 69) and South-East Asian region, line (69). Line 70, what is WHO Africa region? These are vague.

73 high-HIV-TB burden countries like Ethiopia. This is vague.

74 $78, is this US dollars?

75 Several studies names 7 factors. Are these the only ones? Did all the studies deal with the same 7 factors? (what about NCDs, cancers?). (No in fact 20 were considered in line 265 – you need to disclose this fact here).

85 46% were getting ART. Does this apply to Ethiopia?

89 Different corners? State "Ethiopia"

96 Systematic.

123 Capitalisation of headings is inconsistent, for example, Eligibility Criteria, capitalises both words. Elsewhere only the first is capitalised.

124 Systematic.

127 Too many hyphens.

128 English (drop language).

130 P: HIV-TB etc.

143 Software eliminated duplication of studies.

144 Briggs (JBI) critical appraisal tools.

153 the pooled hazard ratios (PHR) with 95% confidence intervals…

158 A restricted maximum likelihood (REML) means a restricted conclusion. How does this affect your study?

159 Please read the Cochrane handbook 10.4.3.1 at Cochrane.org https://handbook-5-

1.cochrane.org/chapter_10/10_4_3_1_recommendations_on_testing_for_funnel_plot_asymmetry.htm Your details are

not clear and application of tests may not be valid. Tests for heterogeneity are only approximate too.

166 p≤.05 APA style.

168 PHR already defined in line 153.

194 Table 1. Style is inconsistent. Mortality % column studies should all use the same number of decimal points.

194 ID 6 remove “all over”. Stating “Ethiopia” is sufficient.

194 Some authors have initials, others do not.

194 ID 11 what is 2012S?

194 Line up follow-up period dates.

194 IDs 14, 17, 18, 19, 20, 22, 23, 24 … 37 have commas after name, others do not

199 (S3). ( ?

200 Pooled proportion of mortality

202 Death rates of 4.4% …. to 80.45%.

202 to 205 A forest plot weights studies by relative sample size, which is not the same thing as prevalence, which is weighted on relative population size. If the 80.45% applies to 90% of the population of Ethiopia it has a different effect than if it applied to (say) only 10% of the overall population. In Table 3 on page 13, the 18.42% mortality for Ethiopia is weighted on sample sizes of included studies. Table 3 shows number of studies, event, and sample sizes. The discussion of Table 3 should disclose how weighting was applied, for example, did weighting include information in all three columns, or was it based, as I suspect, on sample size only. The 18.42% must be described as weighted on sample sizes (if this is the case), and that this is used as a best proxy for prevalence. Prevalence takes relative population sizes of regions into account. If you do not have these figures, you must qualify your statistic, otherwise your study is invalid.

(203 I know the Tigray region was weighted in the forest plot to get a weighted overall effect size and 95% CI. How have you done your weighting of Tigray and other regions to get to your 18.42% overall mortality for Ethiopia? (See comment above).

205-208 For p-value and CI disclosure, see APA style in lines 44-49.

213-216 See APA style for disclosure.

214 Fig 3 shows many studies outside the 95% CI lines, so the trim and fill exercise is unsuccessful. You need to discuss this or acknowledge the problem and state how you have overcome this. Your conclusion on the 18.42% must be qualified as having been based on a heterogeneous spread of papers. It may help to justify the 18.42% by basing it on population sizes and minimising the effect of the Tigray region’s outlier effect by stating, for example, that Tigray forms only 5% of the Ethiopian population. How have other countries arrived at their prevalence rates?

216 (Table 2). ( ?

219 Table 2 does not state a conclusion and is meaningless in terms of the problem in line 214.

223-226 See APA style for disclosure (see lines 44-49).

227 The sensitivity analysis to resolve the outliers in the Galbraith plot is unsuccessful because many studies lie outside the 95% CI bands. You need to explain why this is the case, if this is important, and how you have discounted this in your conclusion.

233 to 238 See APA disclosure of p-values and confidence intervals.

242-243 See the forest plot presentation of effect size and 95% CI used by STATA 18.

242-243 The 18.42[14.27, 22.57] for Ethiopia is based on sample size. Prevalence needs to be weighted by relative population size (see discussions above).

248 Remove furthermore.

250 Remove accordingly.

251-254 For effect size and CI, use STATA 18 forest plot form, for formal disclosure p-value use the APA form.

265 20 predictors assessed. These are not mentioned in your abstract on page 2. Only the 7 significant ones are shown in lines 50-53. The abstract on page 2 is incomplete. You are concluding on something that has not been included in your opening statements of aims.

265-272 You cannot use a forest plot to assess which predictors are significant. A forest plot is a meta-analysis of a particular property in a set of publications. It is not a direct statistical model to assess individual significance in a set of multiple variables which are likely to be interdependent. This can only be done by regression models, ANOVA models or other multivariable statistical models. You need to design a matrix of dependent and independent variables and a regression analysis (for example a multiple linear regression, or preferably a logistic regression). You are attempting to gauge significance of individual variables by subgroup forest plots. The more subgroup analyses you do, the smaller is the sample size of data which you are testing, which may affect significance achieved, if sample sizes are too small. The testing of 20 variables as independent predictors is incorrect unless you can demonstrate they are independent. A correct test is to include these into a matrix with a column for the dependent variable (HIV1-TB) and to determine model fit (root mean square values), F statistics and p values and to remove variables with p values >.05

265-272 You cannot assess predictors singly. There will be some collinearity (dependence between one or more predictors) See comment above.

325-336 comparisons between countries. You need to justify why these are comparable. Were they done on the same basis as your analysis? Are they claiming prevalence or are they based on your sample weighting basis?

337 heterogeneity indicates to what extent studies do not come from a common source or population. The Tigray region is an outlier, and there are relatively few studies to do a test of more than a few predictors. This is a major issue, and a hazard ratio may not be significant because of this.

337 If there is interdependence between predictors, it may affect the significance of the hazard ratios you are computing as isolated predictors.

387 Strengths and limitations. This indicates major limitations, for example, high heterogeneity, unavailability of studies and inconsistent measurements. This means that the result of 18.42% proportion of mortality is in doubt and that your study has failed. This is a significant problem. You can circumvent this problem by qualifying your figure as based on a best proxy and justifying it by referring to other countries who have used the same basis.

Reviewer #2: The authors addressed all my comments to my satisfaction and the manuscripts is written in a scientific way.

**********

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: Anthony L.H. Mayne

Reviewer #2: No

**********

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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.

PONE-D-24-06919R2Mortality and predictors among HIV-TB co-infected patients in Ethiopia: A Systematic Review and Meta-analysis.PLOS ONE

Dear Dr. Wondie,

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.

 This manuscript was again sent for specialised statistical review and the statistician has made several comments which still need to be corrected. These include consistent reporting of results, the correct grouping (within and between groups) and some of the extrapolations of the data.

Please submit your revised manuscript by Dec 13 2024 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: https://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,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

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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: (No Response)

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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: Partly

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

Reviewer #1: No

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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

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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: No

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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: Lines

General: reporting of data especially p-values and 95% CLs is inconsistent. STATA shows exact p-values, p=0.00 so references to forest plots must show the exact values. Sometimes you adopt the STATA representation of CIs as in the square brackets in line 246 and sometimes your depiction with round brackets. A p-value gives the probability that a statistic like i^2 is a chance value. If (say) i^2=98.002, which indicates high heterogeneity, p=0.11 is not significant, because it is higher than p=0.05 and we cannot conclude that the i^2 is significant or not (a p-value is usually computed by a chi-square distribution, and a statistic such as i2 does not determine its own p-value).

45-46 the lowest pooled mortality was reported for two general studies in Ethiopia 11.95 (95% CI; 4.19-19.00).

51 … 18.42% (95% CI; 14.27-22.57), i2=98.02%. The lowest individual study mortality was 4.40 (95%CI; 1.21-7.50) and the highest, 80.48 (95%CI; 75.12-85.84), which indicated significant interstudy heterogeneity. This was confirmed by the funnel and Galbraith plots, where 22 out of the 37 studies lay outside the central pseudo-95% region. The tau-squared value of 160.41 indicated there was significant within study variability. In the subgroup analysis…

65 …which accounts for 30%...

164-167 (this is a conceptual section, not a results section). …to assess the presence of a small study effect, an Egger’s test was done. The trim and fill funnel plot analysis was confirmed by a Galbraith plot, and the studies lying inside and outside the central 95% pseudo-CI region was agreed to the distributional features in the pooled mortality forest plot in Fig 2.

205-207 rewrite this (note that p values in forest plots are exact in STATA forest plots).

205-207 significant heterogeneity was observed between studies with a Q=123.16; and i^2 =98.02 and H^2 =50.46; P=0.00. Tau-squared=160.41 indicated significant heterogeneity within studies.

211-226 I suggest a rewrite of these lines as follows -

211-215 An Egger’s test value, P<0.001, indicated a significant publication bias, and highly non-normal distribution. A funnel plot confirmed both the bias and the non-normal distribution, but the non-parametric trim and fill analysis failed to resolve the bias because 22 of the 37 studies and the 3 imputed studies remained outside the pseudo 95% CIs. Standard errors to effect size (mortality) varied between 6.5 standard errors and 0.5 standard errors before and after the three imputed studies. A Galbraith plot confirmed the results of the funnel plot.

216 Fig 3: Non-parametric funnel plot with fill and trim analysis

217 Fig 4: Galbraith plot

218-226 Handling heterogeneity

Because of the high heterogeneity between and within the 37 studies, a forest plot was prepared using the REML method to show the pooled mortality for the 37 studies (Fig 2). This confirmed the significant heterogeneity of the Egger’s test and the significant bias of the funnel plot, and identified the 22 studies falling outside the 95% pseudo-CI region of the funnel plot. Although the pooled mortality in the forest plot was 18.42% (95% CI; 14.27-22.57), there was a significant range in mortality values for Ifa 2018, 4.40% (95% CI; 1.21-7.59), to Habtamu et.al. 2021, 80.48% (95% CI; 75.12-85.84). In view of the heterogeneity, subgroup and sensitivity analyses were performed by region (Fig 5), and by age (Fig 6).

227 Subgroup analysis

228-239 Some figures in 228 to 236 do not agree with the table in 239. For example, Addis Ababa and Amhara region and SNNPR.

233 to 236 Is incorrect. The subgroup analysis is between groups not within groups. Within group heterogeneity is significant (all i^2 are high) at p=0.00, which means that the heterogeneity values are not obtained by chance. The test of group differences, that is, the between group differences shows significant heterogeneity with i^2 = 98.02. However, p=0.30 for group differences, shows that there is a 30% chance that the heterogeneity values are incorrect, which is much higher than the benchmark p=0.05 and so are not significant (once again STATA gives exact p-values in the forest plots).

239 The table should show a column between Region and Proportion ((95% CI) for study size. For example, Addis Ababa| 3 | 20.36 (1.76-36.97)| 68.22| 97.82| 0.00| and for the rest of the rows. This emphasises that some areas have very low study sizes.

246-248 Is incorrect. The test for group differences had p=0.11 which is above p=0.05 and is not significant because there is a 11% chance that the high heterogeneity values are incorrect. The within group significant heterogeneity is significant at p=0.00 or p=0.01.

256 Add that the weights in Fig 2 are approximately equal and group around 100/37=2.70, which is satisfactory and shows that no study unduly influences the overall weighting.

258 …in this study, the pooled effect size of the 20 independent predictors was assessed.

297 Incorrect. A p-value is the chance that a test is by chance or incorrect. P=0.244 means one cannot accept the significance or non-significance of the test.

380-381 our studies had the following limitations: the significant heterogeneity in the pooled proportion of mortality of the 37 studies, remained in the subgroup and sensitivity analysis and within study analysis. The funnel plot and Galbraith plot analysis indicated significant bias which was not resolved in the fill and trim procedure in the case of the funnel plot. Nevertheless the paper has significant value in establishing benchmark values in the case of a country with significant diversity in its independent predictors.

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Reviewer #1: Yes: Anthony L H Mayne

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PONE-D-24-06919R3Mortality and predictors among HIV-TB co-infected patients in Ethiopia: A Systematic Review and Meta-analysis.PLOS ONE

Dear Dr. Wondie,

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 note there are several minor changes (including some grammar issues which need correction).

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Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

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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.

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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: (No Response)

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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

**********

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

Reviewer #1: 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: Yes

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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

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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: Please make these changes to items and use of capitals in the lines below

Lines

45 31.86% (95% CI: 7.69 - 56.03)

47-48 anaemia (HR = 2.25, 95% CI: 1.5 – 3.07)

49 co-trimoxazole preventive therapy (HR = 1.87, 95% CI: 1.28 – 2.73)

50 (HR = 1.23, 95% CI: 1.01 – 1.51)

66 [6]. (full stop)

107 Systematic

108 Systematic

153 predictors of mortality

236 31.86% (95% CI: 7.69 – 56.03)

237 20.73% (95% CI: 15.15 – 26.30)

237-238 20.36% (95% CI: 1.76 – 38.97)

238 15.19% (95% CI: 10.73 – 19.65) 13.66% (95% CI: 8.98 – 18.35)

239 13.74% (95% CI: 6.86 – 20.62)

240 11.95% (95% CI: 4.91 – 19.00)

242 (regions)

251 pediatrics

252 20.70% (95% CI: 14.29 – 27.11)

281 hazard ratio

290 hazard ratio

308 hazard ratio

313 co-infected

314-315 18.42% (95% CI: 14.27 – 22.57)

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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: Anthony Leland Hamilton Mayne

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[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.

Mortality and predictors among HIV-TB co-infected patients in Ethiopia: A Systematic Review and Meta-analysis.

PONE-D-24-06919R4

Dear Dr. Wondie,

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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Elizabeth S. Mayne, M.D.

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

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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

**********

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

Reviewer #1: 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: 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

**********

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)

**********

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: Anthony Leland Hamilton Mayne

**********