Title: Determining the sensitivity and specificity of the calculated fatty liver index in
comparison with ultrasound
Version: 1 Date: 04 Sep 2024
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS:
REQUESTED REVISIONS:
GENERAL COMMENT
The goal of the study is interesting, but the data analysis and the overall presentation must be
improved. I hope that my comments will contribute to achieving this objective.
SPECIFIC COMMENTS
Legend: P= Page; L = line; G = general COMMENT; m = minor comment; M = major comment.
GM — Please ensure that the syntax and grammar of the manuscript are correct. Some parts
are very difficult to understand.
GM – Please check the references carefully. For example, the FLI original paper is quoted three
times (refs. 17, 21 and 37).
GM – The Youden index is a *discouraged* measure of classification for clinical tests. An
excellent description of its limitations is given here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975285/
(I am of course aware of its widespread usage in literature. However, this does not indicate its
correct utilization.) The authors of the FLI and some researchers (ref. 19) who validated it used
a different approach, which is more useful from a clinical viewpoint. They chose two values of
FLI, one to rule in and the other to rule out fatty liver. A diagnostic test will *always* have a
gray zone, which in the case of FLI original paper was supposed to be between 30 and 60. The
Youden index simply does not take this into account.
GM – The best way to validate a diagnostic or prognostic index according to the TRIPOD
guidelines is to evaluate 1) discrimination (C-statistic which, for a binary outcome, is the same
as the AUC ROC); 2) calibration (three levels) and 3) utility (e.g. net benefit).
www.tripod-statement.org/
Following such an approach, at least for points (1) and (2), would increase greatly the value of
this manuscript. The Authors of the FLI have recently evaluated points (1) and (2) to compare
different indexes of fatty liver.
https://www.mdpi.com/2077-0383/10/3/520
GM – Please report the 95% confidence intervals of metrics where appropriate, e.g., for
sensitivity and specificity.
GM – please make reference to *current* guidelines for metabolically associated steatotic liver
disease (MASLD), e.g.,:
https://www.uptodate.com/contents/management-of-metabolic-dysfunction-associated-
steatotic-liver-disease-nonalcoholic-fatty-liver-disease-in-adults
P4 L75 m Why were legal guardians involved in taking a consensus on adults over 35 years old?
G m: I would avoid dichotomizing fatty liver in grade 1 vs. grades 2 and 3 because there will be
a lower effective sample size. Whatever the case, please make clear how FLI was supposed to
separate different levels of fatty liver. This is important because FLI was not designed to detect
the degree of fatty liver.
P5 L109 M –  the “e” notation should be followed by a superscript.
P6 126 m – Table 1 Please report the FLI and its 4 components as continuous variables in Table
1. Specify the employed statistical tests in the legend of Table 1.
P7 L132 M Table 2 – This table uses the original cut-points of the FLI. It is not clear how they
were used in the MS, which seems to base its conclusions on the Youden index. Please see the
above comment on the Youden index.
GM – How were the between-sex comparisons of sensitivity, specificity, and the ROC curve
performed? Please specify.
P11 L193 M – please note that some differences between the studies can be simply explained
by different choices based even on same the Youden index. Please see the above comment on
the Youden index.
Title: Determining the sensitivity and specificity of the calculated fatty liver index in
comparison with ultrasound
Version: 1 Date: 04 Sep 2024
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS:
REQUESTED REVISIONS:
GENERAL COMMENT
The goal of the study is interesting, but the data analysis and the overall presentation must be
improved. I hope that my comments will contribute to achieving this objective.
SPECIFIC COMMENTS
Legend: P= Page; L = line; G = general COMMENT; m = minor comment; M = major comment.
GM — Please ensure that the syntax and grammar of the manuscript are correct. Some parts
are very difficult to understand.
GM – Please check the references carefully. For example, the FLI original paper is quoted three
times (refs. 17, 21 and 37).
GM – The Youden index is a *discouraged* measure of classification for clinical tests. An
excellent description of its limitations is given here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975285/
(I am of course aware of its widespread usage in literature. However, this does not indicate its
correct utilization.) The authors of the FLI and some researchers (ref. 19) who validated it used
a different approach, which is more useful from a clinical viewpoint. They chose two values of
FLI, one to rule in and the other to rule out fatty liver. A diagnostic test will *always* have a
gray zone, which in the case of FLI original paper was supposed to be between 30 and 60. The
Youden index simply does not take this into account.
GM – The best way to validate a diagnostic or prognostic index according to the TRIPOD
guidelines is to evaluate 1) discrimination (C-statistic which, for a binary outcome, is the same
as the AUC ROC); 2) calibration (three levels) and 3) utility (e.g. net benefit).
www.tripod-statement.org/
Following such an approach, at least for points (1) and (2), would increase greatly the value of
this manuscript. The Authors of the FLI have recently evaluated points (1) and (2) to compare
different indexes of fatty liver.
https://www.mdpi.com/2077-0383/10/3/520
GM – Please report the 95% confidence intervals of metrics where appropriate, e.g., for
sensitivity and specificity.
GM – please make reference to *current* guidelines for metabolically associated steatotic liver
disease (MASLD), e.g.,:
https://www.uptodate.com/contents/management-of-metabolic-dysfunction-associated-
steatotic-liver-disease-nonalcoholic-fatty-liver-disease-in-adults
P4 L75 m Why were legal guardians involved in taking a consensus on adults over 35 years old?
G m: I would avoid dichotomizing fatty liver in grade 1 vs. grades 2 and 3 because there will be
a lower effective sample size. Whatever the case, please make clear how FLI was supposed to
separate different levels of fatty liver. This is important because FLI was not designed to detect
the degree of fatty liver.
P5 L109 M –  the “e” notation should be followed by a superscript.
P6 126 m – Table 1 Please report the FLI and its 4 components as continuous variables in Table
1. Specify the employed statistical tests in the legend of Table 1.
P7 L132 M Table 2 – This table uses the original cut-points of the FLI. It is not clear how they
were used in the MS, which seems to base its conclusions on the Youden index. Please see the
above comment on the Youden index.
GM – How were the between-sex comparisons of sensitivity, specificity, and the ROC curve
performed? Please specify.
P11 L193 M – please note that some differences between the studies can be simply explained
by different choices based even on same the Youden index. Please see the above comment on
the Youden index.
Please review this paper.
user
Title: Determining the sensitivity and specificity of the calculated fatty liver index in
comparison with ultrasound
Version: 1 Date: 04 Sep 2024
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS:
REQUESTED REVISIONS:
GENERAL COMMENT
The goal of the study is interesting, but the data analysis and the overall presentation must be
improved. I hope that my comments will contribute to achieving this objective.
SPECIFIC COMMENTS
Legend: P= Page; L = line; G = general COMMENT; m = minor comment; M = major comment.
GM — Please ensure that the syntax and grammar of the manuscript are correct. Some parts
are very difficult to understand.
GM – Please check the references carefully. For example, the FLI original paper is quoted three
times (refs. 17, 21 and 37).
GM – The Youden index is a *discouraged* measure of classification for clinical tests. An
excellent description of its limitations is given here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975285/
(I am of course aware of its widespread usage in literature. However, this does not indicate its
correct utilization.) The authors of the FLI and some researchers (ref. 19) who validated it used
a different approach, which is more useful from a clinical viewpoint. They chose two values of
FLI, one to rule in and the other to rule out fatty liver. A diagnostic test will *always* have a
gray zone, which in the case of FLI original paper was supposed to be between 30 and 60. The
Youden index simply does not take this into account.
GM – The best way to validate a diagnostic or prognostic index according to the TRIPOD
guidelines is to evaluate 1) discrimination (C-statistic which, for a binary outcome, is the same
as the AUC ROC); 2) calibration (three levels) and 3) utility (e.g. net benefit).
www.tripod-statement.org/
Following such an approach, at least for points (1) and (2), would increase greatly the value of
this manuscript. The Authors of the FLI have recently evaluated points (1) and (2) to compare
different indexes of fatty liver.
https://www.mdpi.com/2077-0383/10/3/520
GM – Please report the 95% confidence intervals of metrics where appropriate, e.g., for
sensitivity and specificity.
GM – please make reference to *current* guidelines for metabolically associated steatotic liver
disease (MASLD), e.g.,:
https://www.uptodate.com/contents/management-of-metabolic-dysfunction-associated-
steatotic-liver-disease-nonalcoholic-fatty-liver-disease-in-adults
P4 L75 m Why were legal guardians involved in taking a consensus on adults over 35 years old?
G m: I would avoid dichotomizing fatty liver in grade 1 vs. grades 2 and 3 because there will be
a lower effective sample size. Whatever the case, please make clear how FLI was supposed to
separate different levels of fatty liver. This is important because FLI was not designed to detect
the degree of fatty liver.
P5 L109 M –  the “e” notation should be followed by a superscript.
P6 126 m – Table 1 Please report the FLI and its 4 components as continuous variables in Table
1. Specify the employed statistical tests in the legend of Table 1.
P7 L132 M Table 2 – This table uses the original cut-points of the FLI. It is not clear how they
were used in the MS, which seems to base its conclusions on the Youden index. Please see the
above comment on the Youden index.
GM – How were the between-sex comparisons of sensitivity, specificity, and the ROC curve
performed? Please specify.
P11 L193 M – please note that some differences between the studies can be simply explained
by different choices based even on same the Youden index. Please see the above comment on
the Youden index.
assistant