Volatile Organic Compound Identification-Based Tuberculosis Screening among TB Suspects: A Diagnostic Accuracy Study

Round 1

Reviewer 1 Report

Comments to the author:

This article interests clinicians because it suggests that VOC can be point-of-care testing for TB. As a whole, the article is well-written and logically structured. It should be published after the revisions regarding several recommendations to make the article more informative.

1) In the introduction section, the authors state, “The data suggest.....the hidden burden of the disease.” This sentence is somewhat unclear. Describe why the data suggest that around one in every three TB patients is undiagnosed.

2) In the second paragraph of the introduction section, describe in detail the “large diagnostic gap.”

3) In the third paragraph of the introduction section, provide references to the following two sentences: “Pulmonary tuberculosis may alter volatile organic compounds (VOCs) in breath because Mycobacteria and oxidative stress resulting from Mycobacterial infection both generate distinctive VOCs.” and “It is reported that several species of Mycobacteria produce VOC metabolites that act as chemical “fingerprints.”

4) In Table 3 of the results section, sensitivity and specificity values are relatively low in the age group (30−44). Consider discussing this reason.

5) In Table 3 of the results section, 70.8% of the age group (45−59) was negative for TB. This percentage is high compared to other groups. Additionally, the exclusion criterium is only derived from taking the previous history of TB. Generally, the older people are, the higher the prevalence rate of TB will be. Consider discussing this reason.

 

6) In the Figure of the results section, the authors state, “These graphs are chemical signatures to be deciphered only by artificial intelligence.” Does it mean that VOC’s accuracy will alter according to the development of AI?

7) Correct minor grammar errors (examples: an article, a capital/small letter, a comma, a conjunction, a hyphen, a period, a preposition, a space, an inappropriate number on behalf of a space, Etc.).

Author Response

To

The Editorial Board

Advance in Respiratory Medicine

We are grateful for the quick peer review process. We sincerely appreciate the editorial board and the reviewers for giving valuable comments and suggestion, which helped us in improving the quality of the manuscript.

We have addressed all your apt comments & suggestions which helped us to re-do the manuscript better. We hope you will find it in order and publication worthy.

Anticipating a positive response.

With best regards

Dr Richa Sinha

Corresponding Author

Point-by-point Response to Reviewer’s Comments

Report #1 by Anonymous Reviewer

We appreciate the reviewer for taking time to carefully review the manuscript and give detailed and constructive comments, which has greatly helped to improve this paper. Below is our point-by-point response to each comment.

Point -1

In the introduction section, the authors state, “The data suggest.....the hidden burden of the disease.” This sentence is somewhat unclear. Describe why the data suggest that around one in every three TB patients is undiagnosed.

Response: (Introduction: Para I, line 49-53)

Thank you for your suggestion. We have expanded the paragraph to include these details and highlighted it in revised manuscript as under:

Factors like lack of awareness & resources, poor infrastructure, poor notification, overall negligence including poverty, undernourishment & social stigma are major challenges for huge proportion of the cases remaining undiagnosed and increasing hidden burden of the disease in India.

Point -2

In the second paragraph of the introduction section, describe in detail the “large diagnostic gap.”

Response: (Second paragraph, line 63-66)

Thank you for your suggestion. We have expanded the paragraph to include these details as under:

The gaps in diagnostic testing were due to: non-availability of doctors/lab-technicians, inadequate knowledge about TB diagnostic tests among health care providers, reluctance of patients to undergo the TB diagnostic tests due to stigma/confidentiality issues and sub-optimal engagement of private health facilities for TB control

Point -3

In the third paragraph of the introduction section, provide references to the following two sentences: “Pulmonary tuberculosis may alter volatile organic compounds (VOCs) in breath because Mycobacteria and oxidative stress resulting from Mycobacterial infection both generate distinctive VOCs.” and “It is reported that several species of Mycobacteria produce VOC metabolites that act as chemical “fingerprints.”

Response: (third paragraph, line 71-75)

Thank you for pointing out, we have mentioned references at appropriate places.

There is a continuous search for more reliable & efficient techniques enabling effective management decision. A potential non-invasive technique is the analysis of Volatile Biomarkers in exhaled breath, namely, so called volatile organic compounds (VOCs). Pulmonary tuberculosis may alter volatile organic compounds (VOCs) in breath because Mycobacteria and oxidative stress resulting from Mycobacterial infection both generate distinctive VOCs[7]. It is reported that several species of Mycobacteria produce VOC metabolites that act as chemical “fingerprints”. Of several techniques in practice for collection, detection, and analysis of exhaled VOCs [8-11] use gas chromatography (GC).

 

Point -4 & Point -5

Point -4  In Table 3 of the results section, sensitivity and specificity values are relatively low in the age group (30−44). Consider discussing this reason.

Point -5 In Table 3 of the results section, 70.8% of the age group (45−59) was negative for TB. This percentage is high compared to other groups. Additionally, the exclusion criterium is only derived from taking the previous history of TB. Generally, the older people are, the higher the prevalence rate of TB will be. Consider discussing this reason.

 

Response for Point 4 & 5: (Table 3, line 168-172)

Thank you for your suggestion, we have tried to mention the reason-

However, the study analysis shows relatively low indicator status in age group 30-44 years and as much as 67.2% of age group 45-59 as negative for TB; the reasons may be patient characteristics of this age group including a difference in smoking, eating, or other habits influencing this difference.

Point-6

In the Figure of the results section, the authors state, “These graphs are chemical signatures to be deciphered only by artificial intelligence.” Does it mean that VOC’s accuracy will alter according to the development of AI?

Response: (Figure of result section, line 179-83)

 

Thank you for pointing this out. We have rephrased the line as follows:

The graphs are digital signatures deciphered by Artificial Intelligence. VOC's accuracy won't be altered or degraded by AI. Rather with more developments in new machine learning and deep learning algorithms, the interpretation will only grow for better. Future research can also bring neural network models to find deeper associations, allowing better risk stratification.

Point -7

Correct minor grammar errors (examples: an article, a capital/small letter, a comma, a conjunction, a hyphen, a period, a preposition, a space, an inappropriate number on behalf of a space, Etc.)

Respsonse:

Thanks for valuable suggestion, we have checked thoroughly.

 

Author Response File: Author Response.docx

Reviewer 2 Report

The studies are very interestingly designed, and their application would undoubtedly accelerate the diagnosis of tuberculosis patients, particularly as a screening test. However, in my opinion, these studies require a broader comparison with other microbiological methods, especially acid-fast bacillus smear and culture. There is doubt regarding the fact that the method does not detect compounds that are present in atypical mycobacteria (MOTT)

The text needs to be verified by a native speaker, which will definitely improve the clarity and communicativeness of the publication text

Author Response

To

The Editorial Board

Advance in Respiratory Medicine

We are grateful for the quick peer review process. We sincerely appreciate the editorial board and the reviewers for giving valuable comments and suggestion, which helped us in improving the quality of the manuscript.

We have addressed all your apt comments & suggestions which helped us to re-do the manuscript better. We hope you will find it in order and publication worthy.

Anticipating a positive response.

With best regards

Dr Richa Sinha

Corresponding Author

Report # Reviewer  2

 

Point-1

These studies require a broader comparison with other microbiological methods, especially acid-fast bacillus smear and culture. There is doubt regarding the fact that the method does not detect compounds that are present in atypical mycobacteria (MOTT)

Response: (limitations, 241-247)

Thank you for pointing out the discrepancy.

We completely agree with your concern. But we will like to reinforce that the current study was done as a pilot initiative with at a single tertiary institution with limited resources. We understand that comparison against gold standard (microbial culture and sputum microscopy) could have been rewarding, but with limited resources, we decided to compare it against a test of similar public health relevance allowing a simpler outcome analysis to justify further use and research for the evolving tools. The results indicate that future research can surely contrast it against these gold standard with large and diverse sample sizes and promote it's widespread usage. We also agree to the point raised about Atypical mycobacteria (MOTT). We feel that covering them was beyond the scope of this study.

We have added the following to future recommendations after discussion:

Future studies are warranted to contrast VOCs against the gold standard with large and diverse sample sizes  and find its relevance for Atypical mycobacteria (MOTT).

Author Response File: Author Response.docx