Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Round 1

Reviewer 1 Report

This systematic literature review by Revel-Vilk, Fuller and Zimran evaluates the utility of lyso-Gb1 as a biomarker for the diagnosis, prognosis and disease/treatment monitoring in patients with Gaucher Disease, concluding that circulating lyso-Gb1 level is a selective and sensitive biomarker of Gaucher Disease as a diagnostic and pharmacodynamic biomarker; while further research is required to elucidate its utility as a prognosis and disease-monitoring biomarker.

I would like to congratulate the authors, who are world-wide authorities in Gaucher Disease, for their thorough work in this paper.

The systematic review has been conducted and reported in line with PRISMA-P recommendations. The review is very complete and includes all the relevant references from 1974 to 2019. Besides, important papers related to this issue which appeared after 2019 are commented in the Discussion section.

I believe that this review will be of interest to the readers and to the medical community which treats patients with Gaucher Disease.

As this is an outstanding well written paper I don´t have any additional comments for the authors.

Author Response

This systematic literature review by Revel-Vilk, Fuller and Zimran evaluates the utility of lyso-Gb1 as a biomarker for the diagnosis, prognosis and disease/treatment monitoring in patients with Gaucher Disease, concluding that circulating lyso-Gb1 level is a selective and sensitive biomarker of Gaucher Disease as a diagnostic and pharmacodynamic biomarker; while further research is required to elucidate its utility as a prognosis and disease-monitoring biomarker.

I would like to congratulate the authors, who are world-wide authorities in Gaucher Disease, for their thorough work in this paper.

The systematic review has been conducted and reported in line with PRISMA-P recommendations. The review is very complete and includes all the relevant references from 1974 to 2019. Besides, important papers related to this issue which appeared after 2019 are commented in the Discussion section.

I believe that this review will be of interest to the readers and to the medical community which treats patients with Gaucher Disease.

As this is an outstanding well written paper I don´t have any additional comments for the authors.

Response: We thank the reviewer for the kind words and support for publication of our review.

Reviewer 2 Report

It is a good review on the value of lyso-Gb1 in Gaucher disease. The methodology is impeccable. Some considerations:

- Title: Instead of utility I would use the term value, it has a greater meaning for the subject of this article

- Method: Better use the word article than paper to refer to the bibliography used for the review.

- In data-analysis: The two main categories were as follows: (1) lyso-Gb1 involvement in the pathology of GD, and (2) evidence on lyso-Gb1 level as a biomarker in GD. The exact meaning of the first is not well understood.

- In table 4: easier to read since all the studies were in plasma or RBC, do not repeat the word plasma so much.

- Figure 2 is of little relevance to the article and may be better as a supplementary material.

- It would be positive if the results of the bias analysis were reflected in a section. Also comment more specifically in the discussion

- In discussion: “Although lyso-Gb1, chitotriosidase, and CCL18 correlate well with each other in patients with GD, lyso-Gb1 is more sensitive and specific than the other two biomarkers, irrespective of chitotriosidase genotype”. This must be argued with a bibliographic reference.

-In discussion: Since Lyso GB1 is a diagnostic marker that can be performed on a paper blood sample, it would be positive to comment in more detail on newborn screening in this pathology.

Author Response

Reviewer 2

It is a good review on the value of lyso-Gb1 in Gaucher disease. The methodology is impeccable. Some considerations:

- Title: Instead of utility I would use the term value, it has a greater meaning for the subject of this article

Response: This has been amended in the Title, Section 3.4.1 and the Discussion.

- Method: Better use the word article than paper to refer to the bibliography used for the review.

Response: As the word article is already defined in that sentence – with reference to all articles – we have replaced the word “paper” by restricting the sentence in the Abstract and have replaced “papers” with “articles” in the Methods.

- In data-analysis: The two main categories were as follows: (1) lyso-Gb1 involvement in the pathology of GD, and (2) evidence on lyso-Gb1 level as a biomarker in GD. The exact meaning of the first is not well understood.

Response: We have revised this sentence to improve clarity: “The two main categories were as follows: (1) involvement of lyso-Gb1 in the pathophysiology of GD, and (2) evidence of lyso-Gb1 as a biomarker in GD.”

- In table 4: easier to read since all the studies were in plasma or RBC, do not repeat the word plasma so much.

Response: On reflection of Table 4 it appears that the word “plasma” only appears once for each reference we feel that it is needed for clarity as whether RBC, plasma or urine were used. It also highlights that plasma is the more common sample type. However, we have removed the word “plasma” in many places in the associated text.

- Figure 2 is of little relevance to the article and may be better as a supplementary material.

Response: We respectfully disagree with the reviewer and believe that Figure 2 nicely depicts an important timeline highlighting just how long lyso-Gb1 has been around for and that the molecule is clearly not new.

- It would be positive if the results of the bias analysis were reflected in a section. Also comment more specifically in the discussion.

Response: we have included the results of the bias analysis in the supplementary appendix (three additional tables A1, A2 and A3), and commented on the risk of bias in the discussion, lines 567-570.

- In discussion: “Although lyso-Gb1, chitotriosidase, and CCL18 correlate well with each other in patients with GD, lyso-Gb1 is more sensitive and specific than the other two biomarkers, irrespective of chitotriosidase genotype”. This must be argued with a bibliographic reference.

Response: This statement has been supported with two references: #45 and #54.

-In discussion: Since Lyso GB1 is a diagnostic marker that can be performed on a paper blood sample, it would be positive to comment in more detail on newborn screening in this pathology.

Response: We have added more information in the discussion (lines 472-480) about the use of lyso-Gb1 in newborn screening, which is supported by the references #124 (Polo et al, 2019, which has been replaced by a full publication), #125 (Burlina et al, 2019) and #126 (Bender et al, 2020).