Reviewer's report
Title:Comparison of ELF, FibroTest and FibroScan for the non-invasive
assessment of liver fibrosis
Version: 2Date:4 May 2010
Reviewer: Mona Munteanu
Reviewer's report:
Review Report
In the present study the authors directly compared the diagnostic accuracy of
three different methods (FibroTest, FT, Enhanced Liver Fibrosis test, ELF, and
transient elastography, TE, by Fibroscan) for the non-invasive staging of fibrosis
with biopsy as reference.
Authors explained the choice of tested biomarkers as related to theirs different
scientific rationales: two panels of fibrosis serum markers, one of indirect
markers, FT, and another direct markers, ELF, and an ultrasonic method, TE.
The present study is the first direct comparison of diagnostic values by AUROC
and adjusted AUROC of these methods for advanced fibrosis and for cirrhosis
and of the respective correlations between methods and reference. The
population included subjects with chronic hepatitis C and B and with primary
biliary cirrhosis (PBC).
The authors did not found significant difference between methods for the
diagnostic values for advanced fibrosis and for cirrhosis (all p values were n.s.);
authors found that TE was less informative as only 66/74 (89%) were reliable
measurements.
Major comments:
The authors should be congratulated for this direct comparison of three different
methods; moreover the study included a population of 28 PBC patients with
biopsy permitting a first validation in this population for one of the biomarkers
(FT).
Abstract
1. In the Background: Alfa2 macroglobulin is a direct marker of fibrosis (more
specific of liver than hyaluronic acid) and therefore the terminology direct and
indirect markers is misleading and must be avoided, as well as the suggestion
that only ELF reflects extracellular matrix metabolism. Both tests included
components that reflect in the serum what’s happen in the liver. We suggest a
descriptive sentence:
"FibroTest (FT) is the most frequently used serum fibrosis marker and consists of
an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoprotein A1,
haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of
an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal
propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).”
Introduction
2. Delete as in the abstract the too commercial descriptions of the tests, one that
would be direct and the other one indirect. Just describe: "FibroTest (FT) is the
most frequently used serum fibrosis marker and consists of an algorithm of five
fibrosis markers (alfa2-macroglobulin, apolipoprotein A1, haptoglobin, GGT,
bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of
three fibrosis markers (hyaluronic acid, amino-terminal
propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).”
3. Delete "which reflect alteration in liver function" which is unfair. Rational exist
for all the components of these two tests. The components of ELF are not
organ-specific which is not mentioned.
Results
4. In the Table 1 (The patients characteristics), it is more suitable to give the
means and the medians for biochemical parameters (AST, ALT and GGT) in the
absolute value (units: IU/L) and not in number of the upper limit of normal (ULN),
as the ULN for each parameter is dependent on the laboratory. (Ferard et al Clin
Chem Lab Med 2005;43:549–553. and Ferard et al. Clin Chem Lab Med
2006;44:400–406)
Discussion
5. Delete in the 1st paragraph: "which demonstrated excellent diagnostic
accuracies for the diagnosis and exclusion of liver cirrhosis, but only moderate
diagnostic accuracies for discriminating mild (F0-1) from significant fibrosis
(F2-4)." This sentence is a methodological error repeated for years when the
spectrum effect and the absence of true gold standard are not taken into
account. The differences in unadjusted AUROCs are a mathematical
consequence of the spectrum effect (Poynard et al Clin Chem 2008).
Furthermore biopsy even of 25 mm has the same spectrum effect versus the true
gold standard the large surgical biopsy (Bedossa et al Hepatology 2003).
Therefore, relatively to biopsy the performance between adjacent stages are
equivalent than between extreme stages.
6. In the 4th paragraph: the same remark as above the sentence "One study (23)
has compared the FibroTest as an algorithm of indirect fibrosis markers with ELF
as an algorithm of extracellular matrix metabolism...." is too commercial. The
words indirect and extracellular matrix metabolism must be deleted.
7. In the 8th paragraph: Authors cited the studies conducted with biomarkers in
order to prove their prognostic value in terms of mortality and morbidity. The
authors cited for the ELF score, the 6-years prognostic value evaluated in PBC
patients and in a mixed etiology cohort and for FT, the 5-years prognostic value
in HCV patients. It is fair to cite also the evaluations of the 4-years prognostic
value of FT in HBV patients (Ngo et al. PLoS One. 2008; 3:e2573) and of the
10-years prognostic value of FT in patients with alcoholic liver disease (Naveau
et al. Hepatology. 2009;49:97-105).
Minor comments:
Introduction
1. Delete “e” at the end of macroglobuline and bilirubine.
Materials and Methods
2. In the chapter on Blood Markers, the 2nd paragraph the reference 15 for the
high risk of false positive/negative results is wrong (I advice replacement with the
reference 29).
Results
3. In the 2nd paragraph, there is some confusion in the attribution of significance
(p value) quoted between brackets as p<0.0001; it is not clear if the p value is
related to the comparison of correlations of ELF and FT with histology or the p
value is related to the significance of correlation with histology of both ELF and
FT (all p<0.0001).
Discretionary Revisions
1. In the Table 2 (Results chapter), the adjusted AUROC is computed using an
algorithm combining the observed DANA of the study with the observed AUROC
for advanced fibrosis. The algorithm of calculation of adjusted AUROCs in order
to avoid spectrum bias was done for FT in HCV patients and published by
Poynard et al (reference 17). It is to be highlighted that the algorithm of Poynard
et al (reference 17) is applicable only in HCV patients and only for FT. Assuming
artificially that, using other methods (TE and ELF) and in other pathologies, the
spectrum bias have the same profile as for FT in HCV, authors extrapolated the
FT-specific algorithm to adjust all the AUROCs.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
Disclosure: Mona Munteanu is BioPredictive employee, the company marketing
FibroTest which patents belong to the French Public Organization (Assistance
Publique Hôpitaux de Paris -APHP).
Reviewer's report
Title:Comparison of ELF, FibroTest and FibroScan for the non-invasive
assessment of liver fibrosis
Version: 2Date:4 May 2010
Reviewer: Mona Munteanu
Reviewer's report:
Review Report
In the present study the authors directly compared the diagnostic accuracy of
three different methods (FibroTest, FT, Enhanced Liver Fibrosis test, ELF, and
transient elastography, TE, by Fibroscan) for the non-invasive staging of fibrosis
with biopsy as reference.
Authors explained the choice of tested biomarkers as related to theirs different
scientific rationales: two panels of fibrosis serum markers, one of indirect
markers, FT, and another direct markers, ELF, and an ultrasonic method, TE.
The present study is the first direct comparison of diagnostic values by AUROC
and adjusted AUROC of these methods for advanced fibrosis and for cirrhosis
and of the respective correlations between methods and reference. The
population included subjects with chronic hepatitis C and B and with primary
biliary cirrhosis (PBC).
The authors did not found significant difference between methods for the
diagnostic values for advanced fibrosis and for cirrhosis (all p values were n.s.);
authors found that TE was less informative as only 66/74 (89%) were reliable
measurements.
Major comments:
The authors should be congratulated for this direct comparison of three different
methods; moreover the study included a population of 28 PBC patients with
biopsy permitting a first validation in this population for one of the biomarkers
(FT).
Abstract
1. In the Background: Alfa2 macroglobulin is a direct marker of fibrosis (more
specific of liver than hyaluronic acid) and therefore the terminology direct and
indirect markers is misleading and must be avoided, as well as the suggestion
that only ELF reflects extracellular matrix metabolism. Both tests included
components that reflect in the serum what’s happen in the liver. We suggest a
descriptive sentence:
"FibroTest (FT) is the most frequently used serum fibrosis marker and consists of
an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoprotein A1,
haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of
an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal
propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).”
Introduction
2. Delete as in the abstract the too commercial descriptions of the tests, one that
would be direct and the other one indirect. Just describe: "FibroTest (FT) is the
most frequently used serum fibrosis marker and consists of an algorithm of five
fibrosis markers (alfa2-macroglobulin, apolipoprotein A1, haptoglobin, GGT,
bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of
three fibrosis markers (hyaluronic acid, amino-terminal
propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).”
3. Delete "which reflect alteration in liver function" which is unfair. Rational exist
for all the components of these two tests. The components of ELF are not
organ-specific which is not mentioned.
Results
4. In the Table 1 (The patients characteristics), it is more suitable to give the
means and the medians for biochemical parameters (AST, ALT and GGT) in the
absolute value (units: IU/L) and not in number of the upper limit of normal (ULN),
as the ULN for each parameter is dependent on the laboratory. (Ferard et al Clin
Chem Lab Med 2005;43:549–553. and Ferard et al. Clin Chem Lab Med
2006;44:400–406)
Discussion
5. Delete in the 1st paragraph: "which demonstrated excellent diagnostic
accuracies for the diagnosis and exclusion of liver cirrhosis, but only moderate
diagnostic accuracies for discriminating mild (F0-1) from significant fibrosis
(F2-4)." This sentence is a methodological error repeated for years when the
spectrum effect and the absence of true gold standard are not taken into
account. The differences in unadjusted AUROCs are a mathematical
consequence of the spectrum effect (Poynard et al Clin Chem 2008).
Furthermore biopsy even of 25 mm has the same spectrum effect versus the true
gold standard the large surgical biopsy (Bedossa et al Hepatology 2003).
Therefore, relatively to biopsy the performance between adjacent stages are
equivalent than between extreme stages.
6. In the 4th paragraph: the same remark as above the sentence "One study (23)
has compared the FibroTest as an algorithm of indirect fibrosis markers with ELF
as an algorithm of extracellular matrix metabolism...." is too commercial. The
words indirect and extracellular matrix metabolism must be deleted.
7. In the 8th paragraph: Authors cited the studies conducted with biomarkers in
order to prove their prognostic value in terms of mortality and morbidity. The
authors cited for the ELF score, the 6-years prognostic value evaluated in PBC
patients and in a mixed etiology cohort and for FT, the 5-years prognostic value
in HCV patients. It is fair to cite also the evaluations of the 4-years prognostic
value of FT in HBV patients (Ngo et al. PLoS One. 2008; 3:e2573) and of the
10-years prognostic value of FT in patients with alcoholic liver disease (Naveau
et al. Hepatology. 2009;49:97-105).
Minor comments:
Introduction
1. Delete “e” at the end of macroglobuline and bilirubine.
Materials and Methods
2. In the chapter on Blood Markers, the 2nd paragraph the reference 15 for the
high risk of false positive/negative results is wrong (I advice replacement with the
reference 29).
Results
3. In the 2nd paragraph, there is some confusion in the attribution of significance
(p value) quoted between brackets as p<0.0001; it is not clear if the p value is
related to the comparison of correlations of ELF and FT with histology or the p
value is related to the significance of correlation with histology of both ELF and
FT (all p<0.0001).
Discretionary Revisions
1. In the Table 2 (Results chapter), the adjusted AUROC is computed using an
algorithm combining the observed DANA of the study with the observed AUROC
for advanced fibrosis. The algorithm of calculation of adjusted AUROCs in order
to avoid spectrum bias was done for FT in HCV patients and published by
Poynard et al (reference 17). It is to be highlighted that the algorithm of Poynard
et al (reference 17) is applicable only in HCV patients and only for FT. Assuming
artificially that, using other methods (TE and ELF) and in other pathologies, the
spectrum bias have the same profile as for FT in HCV, authors extrapolated the
FT-specific algorithm to adjust all the AUROCs.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
Disclosure: Mona Munteanu is BioPredictive employee, the company marketing
FibroTest which patents belong to the French Public Organization (Assistance
Publique Hôpitaux de Paris -APHP).
Please review this paper.
user
Reviewer's report
Title:Comparison of ELF, FibroTest and FibroScan for the non-invasive
assessment of liver fibrosis
Version: 2Date:4 May 2010
Reviewer: Mona Munteanu
Reviewer's report:
Review Report
In the present study the authors directly compared the diagnostic accuracy of
three different methods (FibroTest, FT, Enhanced Liver Fibrosis test, ELF, and
transient elastography, TE, by Fibroscan) for the non-invasive staging of fibrosis
with biopsy as reference.
Authors explained the choice of tested biomarkers as related to theirs different
scientific rationales: two panels of fibrosis serum markers, one of indirect
markers, FT, and another direct markers, ELF, and an ultrasonic method, TE.
The present study is the first direct comparison of diagnostic values by AUROC
and adjusted AUROC of these methods for advanced fibrosis and for cirrhosis
and of the respective correlations between methods and reference. The
population included subjects with chronic hepatitis C and B and with primary
biliary cirrhosis (PBC).
The authors did not found significant difference between methods for the
diagnostic values for advanced fibrosis and for cirrhosis (all p values were n.s.);
authors found that TE was less informative as only 66/74 (89%) were reliable
measurements.
Major comments:
The authors should be congratulated for this direct comparison of three different
methods; moreover the study included a population of 28 PBC patients with
biopsy permitting a first validation in this population for one of the biomarkers
(FT).
Abstract
1. In the Background: Alfa2 macroglobulin is a direct marker of fibrosis (more
specific of liver than hyaluronic acid) and therefore the terminology direct and
indirect markers is misleading and must be avoided, as well as the suggestion
that only ELF reflects extracellular matrix metabolism. Both tests included
components that reflect in the serum what’s happen in the liver. We suggest a
descriptive sentence:
"FibroTest (FT) is the most frequently used serum fibrosis marker and consists of
an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoprotein A1,
haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of
an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal
propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).”
Introduction
2. Delete as in the abstract the too commercial descriptions of the tests, one that
would be direct and the other one indirect. Just describe: "FibroTest (FT) is the
most frequently used serum fibrosis marker and consists of an algorithm of five
fibrosis markers (alfa2-macroglobulin, apolipoprotein A1, haptoglobin, GGT,
bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of
three fibrosis markers (hyaluronic acid, amino-terminal
propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1).”
3. Delete "which reflect alteration in liver function" which is unfair. Rational exist
for all the components of these two tests. The components of ELF are not
organ-specific which is not mentioned.
Results
4. In the Table 1 (The patients characteristics), it is more suitable to give the
means and the medians for biochemical parameters (AST, ALT and GGT) in the
absolute value (units: IU/L) and not in number of the upper limit of normal (ULN),
as the ULN for each parameter is dependent on the laboratory. (Ferard et al Clin
Chem Lab Med 2005;43:549–553. and Ferard et al. Clin Chem Lab Med
2006;44:400–406)
Discussion
5. Delete in the 1st paragraph: "which demonstrated excellent diagnostic
accuracies for the diagnosis and exclusion of liver cirrhosis, but only moderate
diagnostic accuracies for discriminating mild (F0-1) from significant fibrosis
(F2-4)." This sentence is a methodological error repeated for years when the
spectrum effect and the absence of true gold standard are not taken into
account. The differences in unadjusted AUROCs are a mathematical
consequence of the spectrum effect (Poynard et al Clin Chem 2008).
Furthermore biopsy even of 25 mm has the same spectrum effect versus the true
gold standard the large surgical biopsy (Bedossa et al Hepatology 2003).
Therefore, relatively to biopsy the performance between adjacent stages are
equivalent than between extreme stages.
6. In the 4th paragraph: the same remark as above the sentence "One study (23)
has compared the FibroTest as an algorithm of indirect fibrosis markers with ELF
as an algorithm of extracellular matrix metabolism...." is too commercial. The
words indirect and extracellular matrix metabolism must be deleted.
7. In the 8th paragraph: Authors cited the studies conducted with biomarkers in
order to prove their prognostic value in terms of mortality and morbidity. The
authors cited for the ELF score, the 6-years prognostic value evaluated in PBC
patients and in a mixed etiology cohort and for FT, the 5-years prognostic value
in HCV patients. It is fair to cite also the evaluations of the 4-years prognostic
value of FT in HBV patients (Ngo et al. PLoS One. 2008; 3:e2573) and of the
10-years prognostic value of FT in patients with alcoholic liver disease (Naveau
et al. Hepatology. 2009;49:97-105).
Minor comments:
Introduction
1. Delete “e” at the end of macroglobuline and bilirubine.
Materials and Methods
2. In the chapter on Blood Markers, the 2nd paragraph the reference 15 for the
high risk of false positive/negative results is wrong (I advice replacement with the
reference 29).
Results
3. In the 2nd paragraph, there is some confusion in the attribution of significance
(p value) quoted between brackets as p<0.0001; it is not clear if the p value is
related to the comparison of correlations of ELF and FT with histology or the p
value is related to the significance of correlation with histology of both ELF and
FT (all p<0.0001).
Discretionary Revisions
1. In the Table 2 (Results chapter), the adjusted AUROC is computed using an
algorithm combining the observed DANA of the study with the observed AUROC
for advanced fibrosis. The algorithm of calculation of adjusted AUROCs in order
to avoid spectrum bias was done for FT in HCV patients and published by
Poynard et al (reference 17). It is to be highlighted that the algorithm of Poynard
et al (reference 17) is applicable only in HCV patients and only for FT. Assuming
artificially that, using other methods (TE and ELF) and in other pathologies, the
spectrum bias have the same profile as for FT in HCV, authors extrapolated the
FT-specific algorithm to adjust all the AUROCs.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
Disclosure: Mona Munteanu is BioPredictive employee, the company marketing
FibroTest which patents belong to the French Public Organization (Assistance
Publique Hôpitaux de Paris -APHP).
assistant