Reviewer ’s report  
 
Title:  Diagnostic accuracy of controlled attenuation parameter (CAP) as a non -invasive test for 
steatosis in suspected non alcoholic fatty liver disease: a systematic review and meta -analysis  
 
Version: 0 Date: 19 Sep 2018 
 
Reviewer:  Luca  Valenti  
 
Reviewer’s report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be incl uded in a text format.  
 
Please overwrite this text when adding your comments to the authors.  
 
In this study, Ke Pu and coworkers examined the diagnostic accuracy of CAP evaluation by 
Fibroscan in determining the presence and severity of hepatic steatosis in patients with suspected 
NAFLD, as compared to liver biopsy, by performing a meta -analysis of  9 papers considering 
1,297 patients.  
 
They found that CAP has a good diagnostic accuracy for detecting NAFLD, while the 
performance in detecting moderate and severe steatosis was moderate and poor, respectively. 
There was a significant heterogeneity in the  ability to detect moderate steatosis, which may be 
explained by differences in cutoff used, geographic regions, age, and BMI. They conclude that 
CAP should be cautiously considered as a non -invasive substitute for liver biopsy.  
 
This is a timely study tha t addresses a very important and hot topic, that is noninvasive 
assessment of hepatic fat by approaches that can be implemented in routine clinical practice (as 
opposed to Mir -Based techniques that are more suitable for research).  
 
 
I have the following com ments to further improve the manuscript, that I think should be 
addressed before the manuscript can be considered for publication:  
 
* Authors should specify more clearly in the title, the abstract and the conclusions that the 
reference standard for steatosi s evaluation was histologically assessment by a pathologist of liver 
biopsy, which is subject to sampling variability, inter individual disagreement and is a qualitative 
/ semiquantitative approach. Studies are now also available for comparison with MRI -PDFF (it 
would be good to discuss them)  
 
* Another major limitation that needs to be discussed is related to the lack of availability of 
individual patient data, which might have allowed to discriminate better the sources of 
heterogeneity and to propose more robust thresholds for the diagnosis and staging of steatosis, 
with adjustment for confounders (as proposed by Karlas et al. in liver diseases overall). Did the 
Authors contact Authors of the studies to check whether at least part of them was willing to sha re 
the data for such an analysis? Even if performed in a subgroup, this would increase the value of 
the manuscript.  
 
* Authors should specify throughout the manuscript that studies were conducted in patients with 
"suspected NAFLD", as apparently histologica l steatosis was not detected in a fraction of 
evaluated individuals. Otherwise it would have been impossible to evaluate the performance in 
detecting the presence of NAFLD. In this regard, since this is a very selected population in which 
apparently other liver diseases were ruled out and pre -test probability of NAFLD was very high, 
we submit that the diagnostic accuracy of CAP for evaluation of steatosis presence is over -
inflated. Authors should specify that this may be much lower in the general population . 
 
*Sensitivity analyses: I would present an analysis by removing the two studies at high risk of 
bias. 
 
* Minor: it would be useful to stress the importance of the assessment of hepatic fat content as a 
possible driver of liver disease progression in patien ts with NAFLD, see e.g. Dongiovanni, J 
Inter Med 2018  
 
Are the metho ds 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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional st atistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain o r lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that 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 man uscript?  
 
5. Do you have any other financial 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 repl y is yes to any, please give details below.  
 
I have no relevant conflict of interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments 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 included 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:  Diagnostic accuracy of controlled attenuation parameter (CAP) as a non -invasive test for 
steatosis in suspected non alcoholic fatty liver disease: a systematic review and meta -analysis  
 
Version: 0 Date: 19 Sep 2018 
 
Reviewer:  Luca  Valenti  
 
Reviewer’s report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be incl uded in a text format.  
 
Please overwrite this text when adding your comments to the authors.  
 
In this study, Ke Pu and coworkers examined the diagnostic accuracy of CAP evaluation by 
Fibroscan in determining the presence and severity of hepatic steatosis in patients with suspected 
NAFLD, as compared to liver biopsy, by performing a meta -analysis of  9 papers considering 
1,297 patients.  
 
They found that CAP has a good diagnostic accuracy for detecting NAFLD, while the 
performance in detecting moderate and severe steatosis was moderate and poor, respectively. 
There was a significant heterogeneity in the  ability to detect moderate steatosis, which may be 
explained by differences in cutoff used, geographic regions, age, and BMI. They conclude that 
CAP should be cautiously considered as a non -invasive substitute for liver biopsy.  
 
This is a timely study tha t addresses a very important and hot topic, that is noninvasive 
assessment of hepatic fat by approaches that can be implemented in routine clinical practice (as 
opposed to Mir -Based techniques that are more suitable for research).  
 
 
I have the following com ments to further improve the manuscript, that I think should be 
addressed before the manuscript can be considered for publication:  
 
* Authors should specify more clearly in the title, the abstract and the conclusions that the 
reference standard for steatosi s evaluation was histologically assessment by a pathologist of liver 
biopsy, which is subject to sampling variability, inter individual disagreement and is a qualitative 
/ semiquantitative approach. Studies are now also available for comparison with MRI -PDFF (it 
would be good to discuss them)  
 
* Another major limitation that needs to be discussed is related to the lack of availability of 
individual patient data, which might have allowed to discriminate better the sources of 
heterogeneity and to propose more robust thresholds for the diagnosis and staging of steatosis, 
with adjustment for confounders (as proposed by Karlas et al. in liver diseases overall). Did the 
Authors contact Authors of the studies to check whether at least part of them was willing to sha re 
the data for such an analysis? Even if performed in a subgroup, this would increase the value of 
the manuscript.  
 
* Authors should specify throughout the manuscript that studies were conducted in patients with 
"suspected NAFLD", as apparently histologica l steatosis was not detected in a fraction of 
evaluated individuals. Otherwise it would have been impossible to evaluate the performance in 
detecting the presence of NAFLD. In this regard, since this is a very selected population in which 
apparently other liver diseases were ruled out and pre -test probability of NAFLD was very high, 
we submit that the diagnostic accuracy of CAP for evaluation of steatosis presence is over -
inflated. Authors should specify that this may be much lower in the general population . 
 
*Sensitivity analyses: I would present an analysis by removing the two studies at high risk of 
bias. 
 
* Minor: it would be useful to stress the importance of the assessment of hepatic fat content as a 
possible driver of liver disease progression in patien ts with NAFLD, see e.g. Dongiovanni, J 
Inter Med 2018  
 
Are the metho ds 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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional st atistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain o r lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that 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 man uscript?  
 
5. Do you have any other financial 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 repl y is yes to any, please give details below.  
 
I have no relevant conflict of interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments 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 included 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:  Diagnostic accuracy of controlled attenuation parameter (CAP) as a non -invasive test for 
steatosis in suspected non alcoholic fatty liver disease: a systematic review and meta -analysis  
 
Version: 0 Date: 19 Sep 2018 
 
Reviewer:  Luca  Valenti  
 
Reviewer’s report:  
 
Please include all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be incl uded in a text format.  
 
Please overwrite this text when adding your comments to the authors.  
 
In this study, Ke Pu and coworkers examined the diagnostic accuracy of CAP evaluation by 
Fibroscan in determining the presence and severity of hepatic steatosis in patients with suspected 
NAFLD, as compared to liver biopsy, by performing a meta -analysis of  9 papers considering 
1,297 patients.  
 
They found that CAP has a good diagnostic accuracy for detecting NAFLD, while the 
performance in detecting moderate and severe steatosis was moderate and poor, respectively. 
There was a significant heterogeneity in the  ability to detect moderate steatosis, which may be 
explained by differences in cutoff used, geographic regions, age, and BMI. They conclude that 
CAP should be cautiously considered as a non -invasive substitute for liver biopsy.  
 
This is a timely study tha t addresses a very important and hot topic, that is noninvasive 
assessment of hepatic fat by approaches that can be implemented in routine clinical practice (as 
opposed to Mir -Based techniques that are more suitable for research).  
 
 
I have the following com ments to further improve the manuscript, that I think should be 
addressed before the manuscript can be considered for publication:  
 
* Authors should specify more clearly in the title, the abstract and the conclusions that the 
reference standard for steatosi s evaluation was histologically assessment by a pathologist of liver 
biopsy, which is subject to sampling variability, inter individual disagreement and is a qualitative 
/ semiquantitative approach. Studies are now also available for comparison with MRI -PDFF (it 
would be good to discuss them)  
 
* Another major limitation that needs to be discussed is related to the lack of availability of 
individual patient data, which might have allowed to discriminate better the sources of 
heterogeneity and to propose more robust thresholds for the diagnosis and staging of steatosis, 
with adjustment for confounders (as proposed by Karlas et al. in liver diseases overall). Did the 
Authors contact Authors of the studies to check whether at least part of them was willing to sha re 
the data for such an analysis? Even if performed in a subgroup, this would increase the value of 
the manuscript.  
 
* Authors should specify throughout the manuscript that studies were conducted in patients with 
"suspected NAFLD", as apparently histologica l steatosis was not detected in a fraction of 
evaluated individuals. Otherwise it would have been impossible to evaluate the performance in 
detecting the presence of NAFLD. In this regard, since this is a very selected population in which 
apparently other liver diseases were ruled out and pre -test probability of NAFLD was very high, 
we submit that the diagnostic accuracy of CAP for evaluation of steatosis presence is over -
inflated. Authors should specify that this may be much lower in the general population . 
 
*Sensitivity analyses: I would present an analysis by removing the two studies at high risk of 
bias. 
 
* Minor: it would be useful to stress the importance of the assessment of hepatic fat content as a 
possible driver of liver disease progression in patien ts with NAFLD, see e.g. Dongiovanni, J 
Inter Med 2018  
 
Are the metho ds 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.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional st atistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain o r lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that 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 man uscript?  
 
5. Do you have any other financial 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 repl y is yes to any, please give details below.  
 
I have no relevant conflict of interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments 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 included as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant