Call Girls Electronic City Just Call 7001305949 Top Class Call Girl Service A...
Poynard du 2014 biomarqueurs
1. 7 févr. 2012
Marqueurs sanguins des lésions hépatiques
Thierry Poynard
+
AP-HP Groupe Hospitalier Pitié Salpêtrière,
UPMC Liver Center, Université Paris 6,
INSERM UMR S 938, Biopredictive France
LiverCenter
mardi 14 janvier 14
5. 7 févr. 2012
Too many subjects at risk of chronic liver disease (1.5 billions)
Serious adverse events of biopsy
Non-invasive alternatives to biopsy for staging
mardi 14 janvier 14
6. USA FIBROSIS ICEBERG
IN 4 MILLIONS CHRONIC HEPATITIS C AND B
Biopsy: 1% (50 000 /yr)
FibroTest: 1% (50 000 /yr)
No-biopsy: 99%
3 Millions Chronic Hepatitis C
1 Million Chronic Hepatitis B
IVS
2004
mardi 14 janvier 14
7. FRANCE FIBROSIS ICEBERG
IN 0.5 MILLION CHRONIC HEPATITIS C AND B
Biopsy: 2% (8 000 /yr)
FibroTest: 10% (50 000/yr)
No-biopsy: 99% 0.5 Million
0.25 Million Chronic Hepatitis C
0.25 Million Chronic Hepatitis B
IVS
2004
mardi 14 janvier 14
8. 7 févr. 2012
Fibrosis biomarkers: 23 years history
SJG 2008
n=100
n=1 million
mardi 14 janvier 14
10. 7 févr. 2012
In Situ
In Serum: FibroTest
Alpha2Macroglobulin
Liver Injury
Total Bilirubin
Gamma GT
Apolipoprotein A1
Fibrotic Matrix
Activated Stellate Cells
Haptoglobin
Imbert-Bismut, Lancet 2001
mardi 14 janvier 14
11. 7 févr. 2012
Rational of FibroTest:
• Alpha 2 macroglobulin:
key protein for Collagenase metabolism
• Apolipoprotein A1
key protein for Collagen trapping
• Haptoglobin:
key protein for binding Free Hemoglobin oxidant
• Total Bilirubin:
specific marker of severe late Fibrosis
• Gamma Glutamyl Transpeptidase:
• No transaminases:
sensitive marker of early Fibrosis
to prevent inflammatory necrosis confusion (ActiTest)
• Proteomic has blindly proved the major diagnostic value of
• Apolipoprotein A1, A2M
• Haptoglobin
Paradis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996, Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010
mardi 14 janvier 14
13. Fouad et al Int J Gen Med
13
mardi 14 janvier 14
14. 7 févr. 2012
But: savoir répondre à ce QCM:
Parmi les propositions suivantes concernant les performances de la biopsie (25
mm) pour le diagnostic de fibrose, lesquelles sont vraies ?
La biopsie se trompe moins d’une fois sur 4, pour l’estimation du stade de
fibrose METAVIR
1.
La biopsie a une meilleure performance que le FibroTest pour le diagnostic de
fibrose intermédiaire (Stade F2 vs F1)
2.
Une Aire sous la courbe ROC doit être supéreure a 0.80 pour un test
diagnostique cliniquement interessant
3.
144
mardi 14 janvier 14
15. 7 févr. 2012
Period 1: 1991-2004 Optimistic
Looking for a fibrosis biomarker with accuracy > 90%
mardi 14 janvier 14
17. Fibrotic Liver
Disease
FibroTest OK
AUROC >80%
F0
F1
«Gray Zone»: Biopsy
F2
F3
FibroTest OK
FibroScan OK
AUROC >80%
F4
Hemorrhage
Liver failure
Cancer
Imbert Bismut 2001, Castera 2005
mardi 14 janvier 14
18. 7 févr. 2012
Period 2: 2005-2009: Sceptic
Standard statistical methods were inappropriate
mardi 14 janvier 14
19. 7 févr. 2012
7 Key methodological issues:
Biopsy is no more a perfect gold standard
• Sampling error
Bedossa 2003
• Inter-observers variability
Rousselet 2005
• Discordance studies
Poynard 2004, Halfon 2006
• Prognostic studies
Ngo 2006, Vergniol 2011
• Spectrum effect
Poynard 2007, Lambert 2008
• Exceeding limits of biopsy
• Biopsy has a gray zone
Metha 2009
Poynard 2012
19
22
mardi 14 janvier 14
20. Sampling error:
AUROCs (F1 vs F2) of Biopsy vs Whole Liver according to length
AUROC 15 mm = 0.82
AUROC 25 mm = 0.89
«We showed that with 25-mm long
biopsy specimens, only 75% were
scored correctly»
Bedossa Hepatology 2003
mardi 14 janvier 14
21. 7 févr. 2012
Inter-Observers variability:
Biopsy has lower inter-observers concordance for intermediate stages
F0
F1
F2
F3
F4
0,9000
0,87
0,6750
0,52
0,4500
0,39
0,38
0,35
0,2250
0
Kappa
Rousselet, Hepatology 2005
mardi 14 janvier 14
23. 7 févr. 2012
Meta-analysis of prognostic studies in different diseases
7 publications and 21 assessments
FibroTest (5 studies), APRI (5 studies), FIB4 (3 studies)
First author, year Disease Biomarker assessed with area under the ROC curve
Ngo, 2006
HCV
FibroTest, APRI, Biopsy
Ngo, 2008
HBV
FibroTest, APRI, Biopsy
Naveau, 2009
ALD
FibroTest, APRI, FIB4, HepaScore, FibroMeter, Biopsy
Nunes, 2010
HCV
APRI, FIB4
Parkes, 2010
Mixed
ELF, Biopsy
Vergniol, 2011
HCV
FibroTest, APRI, FibroScan, FIB4, Biopsy
de Ledinghen, 2013 HBV
FibroTest, FibroScan, Biopsy
Poynard, Gastroenterol Hepatol 2011
mardi 14 janvier 14
24. Meta-analysis of the prognostic value of biomarkers vs biopsy
Survival without liver deaths
Only FibroTest has same
prognostic value than biopsy
Poynard Gastroenterol Hepatol 2011
mardi 14 janvier 14
25. 5 years prognostic value in chronic hepatitis B
de Ledinghen APT 2013
mardi 14 janvier 14
26. 5 years prognostic value in chronic hepatitis C
Liver stiffness
FibroTest
Vergniol Gastroenterology 2011
mardi 14 janvier 14
27. 7 févr. 2012
3/7 key methodological issues not well understood
Biopsy is no more a perfect gold standard
• Sampling error
Bedossa 2003
• Inter-observers variability
Rousselet 2005
• Discordance studies
Poynard 2004, Halfon 2006
• Prognostic studies
Ngo 2006, Vergniol 2011
• Spectrum effect
Poynard 2007, Lambert 2008
• Exceeding limits of biopsy
• Biopsy has a gray zone
Metha 2009
Poynard 2012
27
29
mardi 14 janvier 14
28. DANA=Difference between Advanced and non-advanced fibrosis stages
Black and White Spectrum
Fibrotic Liver
Disease
F0
DANA=4
FibroTest AUROC=0.98
F1
F2
F3
F4
Obuchowski measure=AUROCs Pair-wise comparison between all stages
mardi 14 janvier 14
29. DANA=Difference between Advanced and non-advanced fibrosis stages
Fibrotic Liver
Disease
F0
Gray Spectrum
F1
DANA=1
F2
FibroTest AUROC=0.67
F3
F4
Obuchowski measure=AUROCs Pair-wise comparison between all stages
mardi 14 janvier 14
30. DANA=Difference between Advanced and non-advanced fibrosis stages
Fibrotic Liver
Disease
Standard Spectrum
F0
F1
DANA=2.5
F2
F3
FibroTest AUROC=0.85
F4
Obuchowski measure=AUROCs Pair-wise comparison between all stages
mardi 14 janvier 14
31. 7 févr. 2012
Hazardous Tables due to Spectrum Effect (1)
Interpretation of AUROC
AUROC
Score*
Biopsy length
FibroTest and Spectrum
0.90-1
Excellent
0.80-0.90
Good
25 mm F1 vs F2
F01 vs F234
0.70-0.80
Fair
5 mm F1 vs F2
F0 vs F2
0.60-0.70
Poor
5 mm F0 vs F1
F1 vs F2
0.50-0.60
Fail
F0 vs F4
*Sebastiani CCLM 2011, Bedossa Hepatology 2003, Poynard Clin Chem 2007
mardi 14 janvier 14
32. 7 févr. 2012
Hazardous Tables due to Spectrum Effect (October 2012)
Real-time tissue elastography cut-off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using
these cut-off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%-96.0% in all stages.
The area under the receiver operating characteristic curve of elastic ratio better correlated than
serum fibrosis markers in both early and advanced fibrosis stages.
Conclusion: Real-time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD. (HEPATOLOGY 2012;1271-1278)
Ochi Hepatology 2012
mardi 14 janvier 14
33. 7 févr. 2012
3/7 key methodological issues not well understood
Biopsy is no more a perfect gold standard
• Sampling error
Bedossa 2003
• Inter-observers variability
Rousselet 2005
• Discordance studies
Poynard 2004, Halfon 2006
• Prognostic studies
Ngo 2006, Vergniol 2011
• Spectrum effect
Poynard 2007, Lambert 2008
• Exceeding limits of biopsy
Metha 2009
• Biopsy has a gray zone
Poynard 2012
33
29
mardi 14 janvier 14
34. Using 25 mm liver biopsy a perfect market cannot be validated
Metha J Hepatol 2009
Black shading represents the set of conditions under which the AUROC values exceed what has already been observed
mardi 14 janvier 14
35. 7 févr. 2012
Exceeding limits of biopsy:
>90% accuracy is impossible for advanced fibrosis
«Comparison of 8 diagnostic algorithms for liver
fibrosis in hepatitis C: New algorithms are more
precise and entirely non-invasive».
Boursier et al, Hepatology 2012
35
35
mardi 14 janvier 14
36. 7 févr. 2012
Misleading presentation using biopsy as Gold-Standard
Mathematically impossible with biopsy as «Gold Standard
Boursier Hepatology 2012
mardi 14 janvier 14
37. 7 févr. 2012
3/7 key methodological issues not well understood
Biopsy is no more a perfect gold standard
• Sampling error
Bedossa 2003
• Inter-observers variability
Rousselet 2005
• Discordance studies
Poynard 2004, Halfon 2006
• Prognostic studies
Ngo 2006, Vergniol 2011
• Spectrum effect
Poynard 2007, Lambert 2008
• Exceeding limits of biopsy
Metha 2009
• Biopsy has a gray zone
Poynard 2012
37
29
mardi 14 janvier 14
38. 7 févr. 2012
Review of tests by Gebo, Hepatology 2002
« These panels of tests may have the greatest
value in predicting fibrosis or cirrhosis »
« Biochemical tests were best at predicting no or
minimal fibrosis, or at predicting advanced fibrosis/
cirrhosis, and were poor at predicting intermediate
levels of fibrosis »
38
37
mardi 14 janvier 14
42. 7 févr. 2012
Review of fibrosis tests by Nguyen, Hepatology 2011
42
41
mardi 14 janvier 14
43. 7 févr. 2012
Liver Biopsy Analysis Has a Low Level of Performance
for Diagnosis of Intermediate
Stages of Fibrosis
The gray anatomy of 27,869 virtual biopsies and 6,500
patients
Poynard Clin Gastro Hepatol 2012
Poynard, BMC 2005, J Hepatol 2011
mardi 14 janvier 14
44. 7 févr. 2012
The gray zone of liver biopsy: 27,864 virtual biopsies
25 mm Liver Biopsies
Area
Fibrosis
(Log)
Poynard Clin Gastro Hepatol 2012
mardi 14 janvier 14
45. 7 févr. 2012
The gray zone of liver biopsy: 27,864 virtual biopsies
25 mm Liver Biopsies
Area
Fibrosis
(Log)
Poynard Clin Gastro Hepatol 2012
mardi 14 janvier 14
46. Lower gray zone of FibroTest relative to biopsy
Biopsy
n=27,864
Lower gray zone F2vsF1 for FibroTest vs Biopsy
58% lower F2vsF1 vs F1vsF0
41% lower F2vsF1 vs F4vsF3.
Fibrotest
n=6500
Poynard Clin Gastro Hepatol 2012
mardi 14 janvier 14
47. 7 févr. 2012
Biopsy is no more a perfect gold standard
FibroTest and Elastography have similar performance
2006: Approval Markers French Health Authorities HCV
2011: Guidelines EASL 2011
mardi 14 janvier 14
48. 14 janv. 2014
Biomarkers' recommendations
at least FibroTest-Elastography in Guidelines
APASL
EASL
Canada
AASLD
CHC
yes
yes
yes
no
CHB
yes
yes
yes
no
NAFLD
yes
yes
-
no
ALD
yes
no
-
no
Reference
All; Liv Int 2009
J Hepatol 2011/
Hepatology
CJG 2012/2012
2012/ 2011/ 2012
2009/2004/2003/2010
mardi 14 janvier 14
49. 14 janv. 2014
Performances for cirrhosis diagnosis
FibroTest Fibrosure
Transient
elastography
AUROC
0.86 (0.71-0.92)
0.94 (0.93-0.95)
Applicability
>95%
80 %
Afdhal, JVH Nov 2013
Chou, Ann Int Med 2013
mardi 14 janvier 14
50. Benefit/Risk must be evaluated for each change in the formula:
It takes time for one stable formula: the example of 360,000 FibroTest
(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission
mardi 14 janvier 14
51. FibroTest Global Quality Estimates
High Risk
False Positive Negative
5/954 (0.52%)
High Risk
False Positive Negative
38/7494 (0.51%)
FibroScan (Roulot et al 2008)
>7.1 kPa= 12.6%: False Positives ?
Poynard BMC Gastro 2011, Roulot J Hepatol 2008
mardi 14 janvier 14
High Risk
False Positive Negative
3349/345,695 (0.97%)
High Risk
False Positive Negative
491/24,872 (1.97%)
52. One Test, One formula
360,000 FibroTest for Quality Control
Risk of False positive/negative of FibroTest
• Tertiary center: 1.97%
• HIV co-infection: 1.77%
• Sub-Saharan origin: 2.61%
(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission
mardi 14 janvier 14
53. 7 févr. 2012
Which Fibrometer for patients with Hepatitis C ?
Too many variants = Risk of false positive
FibroMeter Variant
Year
Components
FM-1G
2005
PLT, PI, AST, A2M, HA, Urea, Age
FM-2G V*
2008
+ Gender
FM-3G
2008
Switch GGT/HA
FM-3G+ (CirrhoMeter)
2009
New formula for cirrhosis
FM-HICV
2010
AST, A2M, PI
CSF-Index
2011
Combined with LSM
SF-Index
2011
Combined with LSM
C-Index
2011
Combined with LSM
*ONLY one ( FM-2G V) is approved by Haute Autorité de Santé
PLT: platelet counts, PI prothrombin index, AST aspartate amino transferase, A2M alpha2 macroglobulin, HA hyaluronic acid
mardi 14 janvier 14
55. 7 févr. 2012
Biopsy vs Serum marker
Main advantages/disadvantages
Serum Marker
FibroTest
Less accurate for intermediate
stages
No grey zone relatively to
biopsy
Fibrosis only
ActiTest/SteatoTest
Delays result proprietary tests
1-48h
False positive/hemolysis/
inflammation/Gilbert
Yes but 0.97% (3349/345695;
0.94-1.00)
Nguyen Hepatology, 2011 Poynard BMC Gastro 2011
mardi 14 janvier 14
56. 7 févr. 2012
Period 3: 2010----Welcome in a world without perfect Gold Standard
mardi 14 janvier 14
57. 7 févr. 2012
Gold Standard
25 mm Biopsy 0%
False Positive
False Negative
mardi 14 janvier 14
58. 7 févr. 2012
Truth in the
Absence of
Gold Standard
25 mm Biopsy 25%
False Positive
False Negative
mardi 14 janvier 14
59. 7 févr. 2012
Area of fibrosis estimated by biopsy according to its length (mm) in subjects
scoring METAVIR F0 (no fibrosis) on large surgical section.
Cirrhosis
Advanced fibrosis
Area of fibrosis >5.3%: 16.3% false positives 20mm biopsy for diagnosis of advanced fibrosis
>16.5%: 0.3% false positives 20mm biopsy for diagnosis of cirrhosis.
Poynard J Hepatol 2012
mardi 14 janvier 14
60. 7 févr. 2012
5-30 mm Biopsy
FibroTest
FibroScan
Truth
ALT
Poynard J Hepatol 2011
mardi 14 janvier 14
61. 7 févr. 2012
Distribution of 1893 subjects according to the 16 possible combinations of
the 4 tests' results: presumed advanced fibrosis (present=1) or not (=0)
16 combinations of 4 tests results
Number of subjects
FibroTest
LSM
ALT
Biopsy
Observed
Expected
by model
0
0
0
0
621
615.5
0
0
0
1
186
191.1
1
1
1
276
277.0
...
1
Poynard, J Hepatol 2011
mardi 14 janvier 14
62. 7 févr. 2012
Performance for Advanced Fibrosis: Sensitivity
FibroTest Se
LSM Se
Biopsie Se
100
100
75
50
68
66
48
63
45
25
0
Reference Biopsy
Reference Latent Class
The standard cutoffs: 0.48 FibroTest, 8.8 kPa Stiffness
Poynard, J Hepatol 2011
mardi 14 janvier 14
63. 7 févr. 2012
Performance for Advanced Fibrosis: Specificity
FibroTest Sp
LSM Sp
Biopsy Sp
100
100
93
96
89
85
75
67
50
25
0
Reference Biopsy
Reference Latent Class
The standard cutoffs: 0.48 FibroTest, 8.8 kPa Stiffness
Poynard, J Hepatol 2011
mardi 14 janvier 14
64. 7 févr. 2012
Performance for Cirrhosis: Sensitivity
FibroTest Se
LSM Se
Biopsie Se
100
100
75
68
65
51
50
41
39
25
0
Reference Biopsy
Reference Latent Class
The standard cutoffs: 0.74 FibroTest, 14.5 kPa Stiffness
Poynard, J Hepatol 2011
mardi 14 janvier 14
65. 7 févr. 2012
Performance for Cirrhosis: Specificity
FibroTest Sp
100
95
89
LSM Sp
Biopsy Sp
100
93
95
87
75
50
25
0
Reference Biopsy
Reference Latent Class
The standard cutoffs: for cirrhosis 0.74 for FibroTest, and 14.5 kilo-Pascal for stiffness (LSM)
Poynard, J Hepatol 2011
mardi 14 janvier 14
67. Performances for diagnosis of Cirrhosis (HCV, HBV, NAFLD, ALD)
of FibroTest, and Elastography: Transient M-XL probes and Share Wave
SWE
Fibrotest 1
TE-M
Fibrotest 2
TE-XL
FibroTest 3
n = 322 simultaneous reliable tests
99
100%
97
99
99
97
98
75%
61
64
61
54
47
50%
46
25%
0%
Specificity
Sensitivity
Latent Class Model: Best model for FibroTest with TE-XL or SWE (Likelihood ratio test 5.5, 6.9)
Poynard, J Hepatol 2013
mardi 14 janvier 14
7 févr. 2012
68. 7 févr. 2012
Period 3: 2010----Improving serum biomarker
mardi 14 janvier 14
79. 7 févr. 2012
Elasto-FibroTest®
• 1289 patients with CHC and 604 healthy volunteers
• Appropriate methods
• Obuchowski measures
• Methods without Gold Standard
Poynard, CRHG 2012
79
66
mardi 14 janvier 14
80. 7 févr. 2012
Elasto-FibroTest®
1289 patients with CHC and 604 healthy volunteers
•For the diagnosis of cirrhosis Elasto-FibroTest has
significantly higher performances than FibroTest
or Fibroscan alone.
•For the diagnosis of advanced fibrosis (F234) no
improvement in performance has been observed
vs FibroTest alone, when a method without gold
standard was used.
Poynard, CRHG 2012
80
67
mardi 14 janvier 14
82. 7 févr. 2012
Period 4: 2014----Simplifier le quotidien des cliniciens
mardi 14 janvier 14
83. 7 Stages
Presumed by Biomarkers
FibroTest
TE
F0
F1
0.48
7.1
F2
F3
0.74
9.5
F4.1
0.85
20
F4.2
Varices
0.95
50
F4.3
Decompensated
Poynard J Hepatol 2014
mardi 14 janvier 14
84. Anti-Fibrosis Platform
Consultation
BioChimie
Opérateur BAF
Borne
Salle Attente
L’opérateur du BAF, a
directement accès à la base
pendant le bilan.
FibroScan
Base BAF
Réseau BAF
Chercheur
BioPredictive
(c) BioPredictive 2012 - All Rights Reserved - No reproduction without written permission
mardi 14 janvier 14
AixPlorer
Bio
Predictive
88. 7 févr. 2012
1. La biopsie de 25 mm se trompe moins d’une fois sur 4,
pour l’estimation du stade de fibrose : Faux c’est bien 25%
«We showed that with 25-mm long biopsy specimens,
only 75% were scored correctly»
Bedossa, Hepatology 2003
884
mardi 14 janvier 14
89. 7 févr. 2012
2. La biopsie a une meilleure performance que le FibroTest pour le diagnostic de
fibrose intermédiaire (Stade F2 vs F1) : Faux
« Liver Biopsy Analysis Has a Low Level of Performance
for Diagnosis of Intermediate Stages of Fibrosis»
Poynard, CGH 2012
894
mardi 14 janvier 14
90. 7 févr. 2012
3. Une Aire sous la courbe ROC doit être supéreure a 0.80 pour un test diagnostique
cliniquement interessant Faux
« AUROC analysis led to discordant results depending on
how the fibrosis stages were grouped together.
We recommend the Obuchowski measure...»
Poynard, Clin Chem 2007,
Lambert, Clin Chem 2008
904
mardi 14 janvier 14
92. 7 févr. 2012
«Despite ductular proliferation vanishing and lobular zonation restoration,
portal inflammation and sinusoidal capillarization may not regress after
viral eradication. (HEPATOLOGY 2012;56:532-543)»
mardi 14 janvier 14
