Reviewer’s report
Title: VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma
Version: 1 Date: 21 Feb 2019
Reviewer: Ryosuke Tateishi
Reviewer's report:
The authors investigated serum levels of von Willebrand factor antigen (VWF:Ag) and ADAMTS13
activity  (ADAMTS13:AC)  in  patients  with  hepatocellular  carcinoma  (HCC)  who  underwent
radiofrequency ablation. Liver cirrhotic patients without HCC were enrolled as a control.
They found that VWF:Ag/ADAMTS13:AC ratio was significantly higher in those with HCC than those
without. The diagnostic accuracy of the ration was comparable to AFPL-L3%. They concluded that the
VWF:Ag/ADAMTS13:AC ratio may be a useful biomarker for the early detection of HCC.
The reviewer would like to raise several concerns as addressed below.
Point-to-point comments
Introduction
1.The reviewer would wonder if VWF or ADAMTS13 are comparable to AFP or AFP-L3%.
Since AFP was produced by HCC cells, AFP ordinarily elevates according to tumor growth. On the
other hand, VWF or ADAMTS13 reflects a liver parenchymal status that indicates a high risk of
hepatocarcinogenesis. In that sense, VWF or ADAMTS13 are comparable to platelet count or fibrosis
markers.  Is  there  any  data  regarding  chronological  change  in  VWF  or  ADAMTS13  in  cirrhotic
patients?
Methods
2.This study seems to be a retrospective study using stored sera. What type of informed consent
did the authors obtain? And when? This point should be clarified. 
Results
3.In Table 2, the authors treated AFP and DCP as continuous variables. Since the two markers
show a skewed distribution, to apply a linear regression model is inappropriate. Please note that the
logistic regression model is a kind of generalized linear regression model. Please consider logarithmical
transformation or categorization for factors that do not follow the normal distribution. 
4.The authors suggested that lower platelet count in those with lower VWF:Ag/ADAMTS13:AC
ratio indicated hyperaggregability of the platelet. Lower platelet count is considered to be related to
splenomegaly  and  portal  hypertension,  and  not  hyperaggregability  of  the  platelet.  Is  there  any
additional evidence to support this assumption?
5.The authors applied logistic regression analysis to assess the diagnostic accuracy of various
factors.  However,  it  is  somewhat  unusual  since  logistic  regression  assumes  a  linear  relationship
between a factor and the risk. On the other hand, ROC analysis is a nonparametric method and does not
need the normal distribution of the variable and linear relationship. 
6.The  authors  concluded  that  elevated  VWF:Ag/ADAMTS13:AC  may  be  related  to  the
angiogenic process mediated by VEGF. However, this statement is too speculative that the authors
found only a correlation between the two factors.
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.
No
Are you able to assess any statistics in the manuscript or would you recommend an
additional statistical review?
If an additional statistical 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:
Acceptable
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  or  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 manuscript?
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 reply is yes to any, please give details below.
I have nothing to disclose regarding this manuscript.
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: VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma
Version: 1 Date: 21 Feb 2019
Reviewer: Ryosuke Tateishi
Reviewer's report:
The authors investigated serum levels of von Willebrand factor antigen (VWF:Ag) and ADAMTS13
activity  (ADAMTS13:AC)  in  patients  with  hepatocellular  carcinoma  (HCC)  who  underwent
radiofrequency ablation. Liver cirrhotic patients without HCC were enrolled as a control.
They found that VWF:Ag/ADAMTS13:AC ratio was significantly higher in those with HCC than those
without. The diagnostic accuracy of the ration was comparable to AFPL-L3%. They concluded that the
VWF:Ag/ADAMTS13:AC ratio may be a useful biomarker for the early detection of HCC.
The reviewer would like to raise several concerns as addressed below.
Point-to-point comments
Introduction
1.The reviewer would wonder if VWF or ADAMTS13 are comparable to AFP or AFP-L3%.
Since AFP was produced by HCC cells, AFP ordinarily elevates according to tumor growth. On the
other hand, VWF or ADAMTS13 reflects a liver parenchymal status that indicates a high risk of
hepatocarcinogenesis. In that sense, VWF or ADAMTS13 are comparable to platelet count or fibrosis
markers.  Is  there  any  data  regarding  chronological  change  in  VWF  or  ADAMTS13  in  cirrhotic
patients?
Methods
2.This study seems to be a retrospective study using stored sera. What type of informed consent
did the authors obtain? And when? This point should be clarified. 
Results
3.In Table 2, the authors treated AFP and DCP as continuous variables. Since the two markers
show a skewed distribution, to apply a linear regression model is inappropriate. Please note that the
logistic regression model is a kind of generalized linear regression model. Please consider logarithmical
transformation or categorization for factors that do not follow the normal distribution. 
4.The authors suggested that lower platelet count in those with lower VWF:Ag/ADAMTS13:AC
ratio indicated hyperaggregability of the platelet. Lower platelet count is considered to be related to
splenomegaly  and  portal  hypertension,  and  not  hyperaggregability  of  the  platelet.  Is  there  any
additional evidence to support this assumption?
5.The authors applied logistic regression analysis to assess the diagnostic accuracy of various
factors.  However,  it  is  somewhat  unusual  since  logistic  regression  assumes  a  linear  relationship
between a factor and the risk. On the other hand, ROC analysis is a nonparametric method and does not
need the normal distribution of the variable and linear relationship. 
6.The  authors  concluded  that  elevated  VWF:Ag/ADAMTS13:AC  may  be  related  to  the
angiogenic process mediated by VEGF. However, this statement is too speculative that the authors
found only a correlation between the two factors.
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.
No
Are you able to assess any statistics in the manuscript or would you recommend an
additional statistical review?
If an additional statistical 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:
Acceptable
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  or  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 manuscript?
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 reply is yes to any, please give details below.
I have nothing to disclose regarding this manuscript.
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: VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma
Version: 1 Date: 21 Feb 2019
Reviewer: Ryosuke Tateishi
Reviewer's report:
The authors investigated serum levels of von Willebrand factor antigen (VWF:Ag) and ADAMTS13
activity  (ADAMTS13:AC)  in  patients  with  hepatocellular  carcinoma  (HCC)  who  underwent
radiofrequency ablation. Liver cirrhotic patients without HCC were enrolled as a control.
They found that VWF:Ag/ADAMTS13:AC ratio was significantly higher in those with HCC than those
without. The diagnostic accuracy of the ration was comparable to AFPL-L3%. They concluded that the
VWF:Ag/ADAMTS13:AC ratio may be a useful biomarker for the early detection of HCC.
The reviewer would like to raise several concerns as addressed below.
Point-to-point comments
Introduction
1.The reviewer would wonder if VWF or ADAMTS13 are comparable to AFP or AFP-L3%.
Since AFP was produced by HCC cells, AFP ordinarily elevates according to tumor growth. On the
other hand, VWF or ADAMTS13 reflects a liver parenchymal status that indicates a high risk of
hepatocarcinogenesis. In that sense, VWF or ADAMTS13 are comparable to platelet count or fibrosis
markers.  Is  there  any  data  regarding  chronological  change  in  VWF  or  ADAMTS13  in  cirrhotic
patients?
Methods
2.This study seems to be a retrospective study using stored sera. What type of informed consent
did the authors obtain? And when? This point should be clarified. 
Results
3.In Table 2, the authors treated AFP and DCP as continuous variables. Since the two markers
show a skewed distribution, to apply a linear regression model is inappropriate. Please note that the
logistic regression model is a kind of generalized linear regression model. Please consider logarithmical
transformation or categorization for factors that do not follow the normal distribution. 
4.The authors suggested that lower platelet count in those with lower VWF:Ag/ADAMTS13:AC
ratio indicated hyperaggregability of the platelet. Lower platelet count is considered to be related to
splenomegaly  and  portal  hypertension,  and  not  hyperaggregability  of  the  platelet.  Is  there  any
additional evidence to support this assumption?
5.The authors applied logistic regression analysis to assess the diagnostic accuracy of various
factors.  However,  it  is  somewhat  unusual  since  logistic  regression  assumes  a  linear  relationship
between a factor and the risk. On the other hand, ROC analysis is a nonparametric method and does not
need the normal distribution of the variable and linear relationship. 
6.The  authors  concluded  that  elevated  VWF:Ag/ADAMTS13:AC  may  be  related  to  the
angiogenic process mediated by VEGF. However, this statement is too speculative that the authors
found only a correlation between the two factors.
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.
No
Are you able to assess any statistics in the manuscript or would you recommend an
additional statistical review?
If an additional statistical 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:
Acceptable
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  or  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 manuscript?
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 reply is yes to any, please give details below.
I have nothing to disclose regarding this manuscript.
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