Title: Methylated SEPT9 combined with AFP and PIVKA-II is effective for the detection of
HCC in high-risk population
Version: 1 Date: 21 Jun 2023
Reviewer:  Jin-Wook Kim
Reviewer's report:
1. The authors claim that this work assessed "screening" performonace of serum markers in
combination  on the ground that samples were collected a prior of HCC diagnosis, but I do
not agree for the following reason:  for the screeing performances, "all control cases" (HC in
this study) should be examed who visited the institution in the same period as HCC cases were
chosen,  not 1:1 sampling (the authors should also present the selection criteria of study HC
population from the entire HC cases who visited authors' institution), regardless of prospective or
retrospective sampling. Otherwise, this study may claim "diagnostic performance of combined
markers" in the current case-control setting.
2.  Regarding the "What is the proportion of comorbid cirrhosis in HCC?",  the authors should
responsd with the percentage of cirrhosis in HCC patients "in THIS study", because many
markers are influenced by the presence/absence of cirrhosis.
3. Regarding liver function, I guess some patients were Child Pugh class B. Present the
percentages of Child Pugh class, and also add additional analysis stage-specific performance for
Child A vs B, like Fig. 3.
4. Regarding comparison of ROC, present the methods.
5. "Response: We also checked the references regarding the performance of mSEPT9, AFP and
PIVKA-II in HBV, HCV and  alcoholic HCC, and we found similar performance of the markers
in HCC with different etiology": present them in Results section.
Title: Methylated SEPT9 combined with AFP and PIVKA-II is effective for the detection of
HCC in high-risk population
Version: 1 Date: 21 Jun 2023
Reviewer:  Jin-Wook Kim
Reviewer's report:
1. The authors claim that this work assessed "screening" performonace of serum markers in
combination  on the ground that samples were collected a prior of HCC diagnosis, but I do
not agree for the following reason:  for the screeing performances, "all control cases" (HC in
this study) should be examed who visited the institution in the same period as HCC cases were
chosen,  not 1:1 sampling (the authors should also present the selection criteria of study HC
population from the entire HC cases who visited authors' institution), regardless of prospective or
retrospective sampling. Otherwise, this study may claim "diagnostic performance of combined
markers" in the current case-control setting.
2.  Regarding the "What is the proportion of comorbid cirrhosis in HCC?",  the authors should
responsd with the percentage of cirrhosis in HCC patients "in THIS study", because many
markers are influenced by the presence/absence of cirrhosis.
3. Regarding liver function, I guess some patients were Child Pugh class B. Present the
percentages of Child Pugh class, and also add additional analysis stage-specific performance for
Child A vs B, like Fig. 3.
4. Regarding comparison of ROC, present the methods.
5. "Response: We also checked the references regarding the performance of mSEPT9, AFP and
PIVKA-II in HBV, HCV and  alcoholic HCC, and we found similar performance of the markers
in HCC with different etiology": present them in Results section.
Please review this paper.
user
Title: Methylated SEPT9 combined with AFP and PIVKA-II is effective for the detection of
HCC in high-risk population
Version: 1 Date: 21 Jun 2023
Reviewer:  Jin-Wook Kim
Reviewer's report:
1. The authors claim that this work assessed "screening" performonace of serum markers in
combination  on the ground that samples were collected a prior of HCC diagnosis, but I do
not agree for the following reason:  for the screeing performances, "all control cases" (HC in
this study) should be examed who visited the institution in the same period as HCC cases were
chosen,  not 1:1 sampling (the authors should also present the selection criteria of study HC
population from the entire HC cases who visited authors' institution), regardless of prospective or
retrospective sampling. Otherwise, this study may claim "diagnostic performance of combined
markers" in the current case-control setting.
2.  Regarding the "What is the proportion of comorbid cirrhosis in HCC?",  the authors should
responsd with the percentage of cirrhosis in HCC patients "in THIS study", because many
markers are influenced by the presence/absence of cirrhosis.
3. Regarding liver function, I guess some patients were Child Pugh class B. Present the
percentages of Child Pugh class, and also add additional analysis stage-specific performance for
Child A vs B, like Fig. 3.
4. Regarding comparison of ROC, present the methods.
5. "Response: We also checked the references regarding the performance of mSEPT9, AFP and
PIVKA-II in HBV, HCV and  alcoholic HCC, and we found similar performance of the markers
in HCC with different etiology": present them in Results section.
assistant