Reviewer's report
Title:Applicability and precautions of use of liver injury biomarker FibroTest. A
reappraisal at 7 years of age.
Version: 4Date:26 January 2011
Reviewer: jerome boursier
Reviewer's report:
Authors evaluated the frequency of Fibrotest with high risk of false positive or
negative result (RFPN) in a very large cohort of 346.000 patients. They showed
that Fibrotest has a high applicability with a rate of RFPN ranging from only
0.51% to 1.97% according to the population studied. They also identified the
variations of Fibrotest components responsible for RFPN and determined their
respective risk factors and causes. This study is of interest because it determines
rules for interpretation of Fibrotest results in clinical practice, in order to limit
misdiagnoses of liver fibrosis. However, this paper deserves several comments.
MAJOR COMPULSORY REVISIONS
Authors defined RFPN as a substantial variation of a Fibrotest component
responsible for a #0.30 variation in Fibrotest result. A #0.30 variation was chosen
because it corresponds to a #1.5 variation in METAVIR F stage. 331 RFPN were
reviewed in population 4 (Table S4). Despite RFPN correspond to a significant
variation in Fibrotest result, it is surprising that only 126/331 RFPN really induced
a false positive or negative result.
Moreover, despite their abnormal value (beyond the 98% percentile of the normal
distribution), Table S4 show that low apolipoprotein A1, high apolipoprotein A1,
low alpha-2 macroglobulin, and high alpha-2macroglobulin had finally very few
impact on the accuracy of Fibrotest with, respectively, 2/17, 3/38, 5/32, and 0/24
(total: 10/111) false negative or positive results induced.
Finally, the rules used to determine failure of FT seem inappropriate because
authors have only considered a binary diagnosis of fibrosis (advanced fibrosis or
not), and not the individual stages of liver fibrosis. For example: a patient has a
8.2 kPa Fibroscan result and a RFPN profile for Fibrotest whom value is
corrected from 0.92 to 0.57 by replacing the value of the abnormal component by
its median value. Despite the significant change in F stage given by Fibrotest
(from F4 to F2 according to Poynard et al, Comp Hepatol 2004), RFPN is
considered as having no impact because the reference (Fibroscan result)
indicates F#2 result.
There is no ideal rule for the identification of non invasive fibrosis tests failure,
but the methodology used in this study has induced an underestimation of the
impact of RFPN on the diagnosis of liver fibrosis by Fibrotest.
MINOR ESSENTIAL REVISIONS
Authors evaluated the risk factors for RFPN in the population 3 and suggest that
high risk populations for RFPN were sub-saharian origin subjects, HIV patients,
and reference tertiary centre. However, despite a significant increase in risk, the
prevalence of RFPN remained very low in these 3 populations (<2.7%). Thus,
these risk factors will not modify the use of Fibrotest in clinical practice:
physicians will continue to perform Fibrotest in sub-saharian and HIV patients
consulting in a tertiary center. Finally, the most important is to determine the
profiles and the causes of RFPN to precisely identify the clinical situations where
Fibrotest result must be interpreted with high caution.
Rules used to indentify FT failure must be better assessed:
- “Biopsy was the reference if performed less than 5 years apart”: did authors
take into consideration the quality of the biopsy, especially its length (Poynard,
Clin Chem 2004; Bedossa, Hepatology 2003)?
- “When no biopsy had been performed but an LSM was interpretable (…)”:
please specify what is an interpretable LSM
- Authors chose 7.1 kPa as diagnostic cut-off for advanced fibrosis with LSM.
However, a large meta-analysis suggested 7.65 kPa (Friedrich-Rust 2008)
- Why oesophageal varices or ascites were interpreted as advanced fibrosis and
not as cirrhosis?
Page 10: 38 RFPN were indentify in population 2 but the sum of patients with
abnormal components is 40 (31 low haptoglobin, 5 high ApoA1, 2 high GGT, 1
low APoA1, 1 high bilirubin)
There are some discrepancies between the results presented in the paragraph
“factors associated with RFPN” and those presented in Table S3
Page 15: reference center was not associated with false positive RFPN result
(Table S3)
Figure 1: Population 1: 5/954 RFPN; population 4: 1.97% RFPN
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:Applicability and precautions of use of liver injury biomarker FibroTest. A
reappraisal at 7 years of age.
Version: 4Date:26 January 2011
Reviewer: jerome boursier
Reviewer's report:
Authors evaluated the frequency of Fibrotest with high risk of false positive or
negative result (RFPN) in a very large cohort of 346.000 patients. They showed
that Fibrotest has a high applicability with a rate of RFPN ranging from only
0.51% to 1.97% according to the population studied. They also identified the
variations of Fibrotest components responsible for RFPN and determined their
respective risk factors and causes. This study is of interest because it determines
rules for interpretation of Fibrotest results in clinical practice, in order to limit
misdiagnoses of liver fibrosis. However, this paper deserves several comments.
MAJOR COMPULSORY REVISIONS
Authors defined RFPN as a substantial variation of a Fibrotest component
responsible for a #0.30 variation in Fibrotest result. A #0.30 variation was chosen
because it corresponds to a #1.5 variation in METAVIR F stage. 331 RFPN were
reviewed in population 4 (Table S4). Despite RFPN correspond to a significant
variation in Fibrotest result, it is surprising that only 126/331 RFPN really induced
a false positive or negative result.
Moreover, despite their abnormal value (beyond the 98% percentile of the normal
distribution), Table S4 show that low apolipoprotein A1, high apolipoprotein A1,
low alpha-2 macroglobulin, and high alpha-2macroglobulin had finally very few
impact on the accuracy of Fibrotest with, respectively, 2/17, 3/38, 5/32, and 0/24
(total: 10/111) false negative or positive results induced.
Finally, the rules used to determine failure of FT seem inappropriate because
authors have only considered a binary diagnosis of fibrosis (advanced fibrosis or
not), and not the individual stages of liver fibrosis. For example: a patient has a
8.2 kPa Fibroscan result and a RFPN profile for Fibrotest whom value is
corrected from 0.92 to 0.57 by replacing the value of the abnormal component by
its median value. Despite the significant change in F stage given by Fibrotest
(from F4 to F2 according to Poynard et al, Comp Hepatol 2004), RFPN is
considered as having no impact because the reference (Fibroscan result)
indicates F#2 result.
There is no ideal rule for the identification of non invasive fibrosis tests failure,
but the methodology used in this study has induced an underestimation of the
impact of RFPN on the diagnosis of liver fibrosis by Fibrotest.
MINOR ESSENTIAL REVISIONS
Authors evaluated the risk factors for RFPN in the population 3 and suggest that
high risk populations for RFPN were sub-saharian origin subjects, HIV patients,
and reference tertiary centre. However, despite a significant increase in risk, the
prevalence of RFPN remained very low in these 3 populations (<2.7%). Thus,
these risk factors will not modify the use of Fibrotest in clinical practice:
physicians will continue to perform Fibrotest in sub-saharian and HIV patients
consulting in a tertiary center. Finally, the most important is to determine the
profiles and the causes of RFPN to precisely identify the clinical situations where
Fibrotest result must be interpreted with high caution.
Rules used to indentify FT failure must be better assessed:
- “Biopsy was the reference if performed less than 5 years apart”: did authors
take into consideration the quality of the biopsy, especially its length (Poynard,
Clin Chem 2004; Bedossa, Hepatology 2003)?
- “When no biopsy had been performed but an LSM was interpretable (…)”:
please specify what is an interpretable LSM
- Authors chose 7.1 kPa as diagnostic cut-off for advanced fibrosis with LSM.
However, a large meta-analysis suggested 7.65 kPa (Friedrich-Rust 2008)
- Why oesophageal varices or ascites were interpreted as advanced fibrosis and
not as cirrhosis?
Page 10: 38 RFPN were indentify in population 2 but the sum of patients with
abnormal components is 40 (31 low haptoglobin, 5 high ApoA1, 2 high GGT, 1
low APoA1, 1 high bilirubin)
There are some discrepancies between the results presented in the paragraph
“factors associated with RFPN” and those presented in Table S3
Page 15: reference center was not associated with false positive RFPN result
(Table S3)
Figure 1: Population 1: 5/954 RFPN; population 4: 1.97% RFPN
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:Applicability and precautions of use of liver injury biomarker FibroTest. A
reappraisal at 7 years of age.
Version: 4Date:26 January 2011
Reviewer: jerome boursier
Reviewer's report:
Authors evaluated the frequency of Fibrotest with high risk of false positive or
negative result (RFPN) in a very large cohort of 346.000 patients. They showed
that Fibrotest has a high applicability with a rate of RFPN ranging from only
0.51% to 1.97% according to the population studied. They also identified the
variations of Fibrotest components responsible for RFPN and determined their
respective risk factors and causes. This study is of interest because it determines
rules for interpretation of Fibrotest results in clinical practice, in order to limit
misdiagnoses of liver fibrosis. However, this paper deserves several comments.
MAJOR COMPULSORY REVISIONS
Authors defined RFPN as a substantial variation of a Fibrotest component
responsible for a #0.30 variation in Fibrotest result. A #0.30 variation was chosen
because it corresponds to a #1.5 variation in METAVIR F stage. 331 RFPN were
reviewed in population 4 (Table S4). Despite RFPN correspond to a significant
variation in Fibrotest result, it is surprising that only 126/331 RFPN really induced
a false positive or negative result.
Moreover, despite their abnormal value (beyond the 98% percentile of the normal
distribution), Table S4 show that low apolipoprotein A1, high apolipoprotein A1,
low alpha-2 macroglobulin, and high alpha-2macroglobulin had finally very few
impact on the accuracy of Fibrotest with, respectively, 2/17, 3/38, 5/32, and 0/24
(total: 10/111) false negative or positive results induced.
Finally, the rules used to determine failure of FT seem inappropriate because
authors have only considered a binary diagnosis of fibrosis (advanced fibrosis or
not), and not the individual stages of liver fibrosis. For example: a patient has a
8.2 kPa Fibroscan result and a RFPN profile for Fibrotest whom value is
corrected from 0.92 to 0.57 by replacing the value of the abnormal component by
its median value. Despite the significant change in F stage given by Fibrotest
(from F4 to F2 according to Poynard et al, Comp Hepatol 2004), RFPN is
considered as having no impact because the reference (Fibroscan result)
indicates F#2 result.
There is no ideal rule for the identification of non invasive fibrosis tests failure,
but the methodology used in this study has induced an underestimation of the
impact of RFPN on the diagnosis of liver fibrosis by Fibrotest.
MINOR ESSENTIAL REVISIONS
Authors evaluated the risk factors for RFPN in the population 3 and suggest that
high risk populations for RFPN were sub-saharian origin subjects, HIV patients,
and reference tertiary centre. However, despite a significant increase in risk, the
prevalence of RFPN remained very low in these 3 populations (<2.7%). Thus,
these risk factors will not modify the use of Fibrotest in clinical practice:
physicians will continue to perform Fibrotest in sub-saharian and HIV patients
consulting in a tertiary center. Finally, the most important is to determine the
profiles and the causes of RFPN to precisely identify the clinical situations where
Fibrotest result must be interpreted with high caution.
Rules used to indentify FT failure must be better assessed:
- “Biopsy was the reference if performed less than 5 years apart”: did authors
take into consideration the quality of the biopsy, especially its length (Poynard,
Clin Chem 2004; Bedossa, Hepatology 2003)?
- “When no biopsy had been performed but an LSM was interpretable (…)”:
please specify what is an interpretable LSM
- Authors chose 7.1 kPa as diagnostic cut-off for advanced fibrosis with LSM.
However, a large meta-analysis suggested 7.65 kPa (Friedrich-Rust 2008)
- Why oesophageal varices or ascites were interpreted as advanced fibrosis and
not as cirrhosis?
Page 10: 38 RFPN were indentify in population 2 but the sum of patients with
abnormal components is 40 (31 low haptoglobin, 5 high ApoA1, 2 high GGT, 1
low APoA1, 1 high bilirubin)
There are some discrepancies between the results presented in the paragraph
“factors associated with RFPN” and those presented in Table S3
Page 15: reference center was not associated with false positive RFPN result
(Table S3)
Figure 1: Population 1: 5/954 RFPN; population 4: 1.97% RFPN
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
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