Reviewer ’s report  
 
Title: The Enhanced Liver Fibrosis test is associated  with liver -related outcomes in 
postmenopausal women with risk factors for liver disease  
 
Version: 0 Date: 04 Sep 2019  
 
Reviewer: Giada  Sebastiani  
 
Reviewer's report:  
The study by Trembling and colleagues is aimed at evaluate the performance of ELF in 
predicting liver -related events in postmenopausal women with risk factors for liver disease. The 
researchers conducted a case -control study incl uding 173 participants with high alcohol use or 
BMI &gt;25 matched with 115 controls who did not develop liver -related events. The median 
follow -up time was 8.5 years. The authors found significant high hazard ratio for liver -related 
events with specific cu t-off values of the ELF.  
Given the burden of liver disease, there is certainly need to find prognostic scores to identify 
those patients at higher risk of liver -related events. The study is overall well written and the 
analysis plan detailed.  
 
Concerns  
1) My main concern is the rationale for this study and the target study population. In the 
background, the researchers should start by explaining the importance of identifying post -
menopausal women at higher risk for developing liver -related events. Instead, the background 
commence with the test used (ELF) instead of the outcome of interest. This is quite unusual and 
confusing for the reader.  
2) I also find confusing the definition of the main outcome (liver -related events): this is not 
defined only as decompe nsated liver disease (bleeding, decompensation, ascites, etc; or 
cirrhosis/transplantation), but rather includes also other liver -related diagnoses (chronic hepatitis, 
alcoholic liver disease, varices, fatty liver). In fact, the actual liver -related events  are only 6 or 7 
(there are other 4 but it seems in the same patients as they are hospital and outpatient clinics 
appointments for patients with liver transplantation). Although the numbers are obviously small 
and I understand the reason for extended crite ria to increase the number of outcomes, it would be 
still interesting to mention the results for those with true liver -related events. Moreover, on the 
basis of such consideration, the conclusions should be understated.  
3) The authors mention a "primary ca re setting" for this study, however this is not well specified 
in the methods.  
Confidence intervals of reported hazard ratios should be presented into the abstract. Again in the 
abstract, it is not completely clear to me what the researchers mean for "clinical utility models 
showed good diagnostic accuracy of ELF in this low prevalen ce setting". What low prevalence 
means? Does it refer to liver -related events? It seems to me that 58 cases over 173 is actually a 
high rate of liver -related events. This sentence should be rephrased and better explained.  
4) The authors state "elastography  is time consuming to perform compared to automated blood 
tests like ELF". I would disagree with this statement if we mean transient elastography. I instead 
agree if we refer to MR elastography. VCTE in fact is usually performed in less than 5 minutes 
(unless technical difficulties, such as morbid obesity or narrow intercostal spaces). I would 
definitively be more cautious in this sentence and explain in more details. A blood test, even if 
automated, requires anyway time to wait for the blood draw and time to wait for the result.  
I think it would be also important to state that transient elastography, as well as other serum 
biomarkers such as Fibrotest, have been widely validated by several research teams across the 
globe. How many independent validation stu dies were performed for ELF?  
Page 22, line 420: spell out Fib -4 here and not afterwards, as the is the first time in the paper this 
abbreviation appears.  
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of compet ing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financia l competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details be low. 
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any att achments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: The Enhanced Liver Fibrosis test is associated  with liver -related outcomes in 
postmenopausal women with risk factors for liver disease  
 
Version: 0 Date: 04 Sep 2019  
 
Reviewer: Giada  Sebastiani  
 
Reviewer's report:  
The study by Trembling and colleagues is aimed at evaluate the performance of ELF in 
predicting liver -related events in postmenopausal women with risk factors for liver disease. The 
researchers conducted a case -control study incl uding 173 participants with high alcohol use or 
BMI &gt;25 matched with 115 controls who did not develop liver -related events. The median 
follow -up time was 8.5 years. The authors found significant high hazard ratio for liver -related 
events with specific cu t-off values of the ELF.  
Given the burden of liver disease, there is certainly need to find prognostic scores to identify 
those patients at higher risk of liver -related events. The study is overall well written and the 
analysis plan detailed.  
 
Concerns  
1) My main concern is the rationale for this study and the target study population. In the 
background, the researchers should start by explaining the importance of identifying post -
menopausal women at higher risk for developing liver -related events. Instead, the background 
commence with the test used (ELF) instead of the outcome of interest. This is quite unusual and 
confusing for the reader.  
2) I also find confusing the definition of the main outcome (liver -related events): this is not 
defined only as decompe nsated liver disease (bleeding, decompensation, ascites, etc; or 
cirrhosis/transplantation), but rather includes also other liver -related diagnoses (chronic hepatitis, 
alcoholic liver disease, varices, fatty liver). In fact, the actual liver -related events  are only 6 or 7 
(there are other 4 but it seems in the same patients as they are hospital and outpatient clinics 
appointments for patients with liver transplantation). Although the numbers are obviously small 
and I understand the reason for extended crite ria to increase the number of outcomes, it would be 
still interesting to mention the results for those with true liver -related events. Moreover, on the 
basis of such consideration, the conclusions should be understated.  
3) The authors mention a "primary ca re setting" for this study, however this is not well specified 
in the methods.  
Confidence intervals of reported hazard ratios should be presented into the abstract. Again in the 
abstract, it is not completely clear to me what the researchers mean for "clinical utility models 
showed good diagnostic accuracy of ELF in this low prevalen ce setting". What low prevalence 
means? Does it refer to liver -related events? It seems to me that 58 cases over 173 is actually a 
high rate of liver -related events. This sentence should be rephrased and better explained.  
4) The authors state "elastography  is time consuming to perform compared to automated blood 
tests like ELF". I would disagree with this statement if we mean transient elastography. I instead 
agree if we refer to MR elastography. VCTE in fact is usually performed in less than 5 minutes 
(unless technical difficulties, such as morbid obesity or narrow intercostal spaces). I would 
definitively be more cautious in this sentence and explain in more details. A blood test, even if 
automated, requires anyway time to wait for the blood draw and time to wait for the result.  
I think it would be also important to state that transient elastography, as well as other serum 
biomarkers such as Fibrotest, have been widely validated by several research teams across the 
globe. How many independent validation stu dies were performed for ELF?  
Page 22, line 420: spell out Fib -4 here and not afterwards, as the is the first time in the paper this 
abbreviation appears.  
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of compet ing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financia l competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details be low. 
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any att achments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: The Enhanced Liver Fibrosis test is associated  with liver -related outcomes in 
postmenopausal women with risk factors for liver disease  
 
Version: 0 Date: 04 Sep 2019  
 
Reviewer: Giada  Sebastiani  
 
Reviewer's report:  
The study by Trembling and colleagues is aimed at evaluate the performance of ELF in 
predicting liver -related events in postmenopausal women with risk factors for liver disease. The 
researchers conducted a case -control study incl uding 173 participants with high alcohol use or 
BMI &gt;25 matched with 115 controls who did not develop liver -related events. The median 
follow -up time was 8.5 years. The authors found significant high hazard ratio for liver -related 
events with specific cu t-off values of the ELF.  
Given the burden of liver disease, there is certainly need to find prognostic scores to identify 
those patients at higher risk of liver -related events. The study is overall well written and the 
analysis plan detailed.  
 
Concerns  
1) My main concern is the rationale for this study and the target study population. In the 
background, the researchers should start by explaining the importance of identifying post -
menopausal women at higher risk for developing liver -related events. Instead, the background 
commence with the test used (ELF) instead of the outcome of interest. This is quite unusual and 
confusing for the reader.  
2) I also find confusing the definition of the main outcome (liver -related events): this is not 
defined only as decompe nsated liver disease (bleeding, decompensation, ascites, etc; or 
cirrhosis/transplantation), but rather includes also other liver -related diagnoses (chronic hepatitis, 
alcoholic liver disease, varices, fatty liver). In fact, the actual liver -related events  are only 6 or 7 
(there are other 4 but it seems in the same patients as they are hospital and outpatient clinics 
appointments for patients with liver transplantation). Although the numbers are obviously small 
and I understand the reason for extended crite ria to increase the number of outcomes, it would be 
still interesting to mention the results for those with true liver -related events. Moreover, on the 
basis of such consideration, the conclusions should be understated.  
3) The authors mention a "primary ca re setting" for this study, however this is not well specified 
in the methods.  
Confidence intervals of reported hazard ratios should be presented into the abstract. Again in the 
abstract, it is not completely clear to me what the researchers mean for "clinical utility models 
showed good diagnostic accuracy of ELF in this low prevalen ce setting". What low prevalence 
means? Does it refer to liver -related events? It seems to me that 58 cases over 173 is actually a 
high rate of liver -related events. This sentence should be rephrased and better explained.  
4) The authors state "elastography  is time consuming to perform compared to automated blood 
tests like ELF". I would disagree with this statement if we mean transient elastography. I instead 
agree if we refer to MR elastography. VCTE in fact is usually performed in less than 5 minutes 
(unless technical difficulties, such as morbid obesity or narrow intercostal spaces). I would 
definitively be more cautious in this sentence and explain in more details. A blood test, even if 
automated, requires anyway time to wait for the blood draw and time to wait for the result.  
I think it would be also important to state that transient elastography, as well as other serum 
biomarkers such as Fibrotest, have been widely validated by several research teams across the 
globe. How many independent validation stu dies were performed for ELF?  
Page 22, line 420: spell out Fib -4 here and not afterwards, as the is the first time in the paper this 
abbreviation appears.  
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of compet ing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financia l competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details be low. 
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any att achments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant