poynard du 2014 biomarqueurs
TRANSCRIPT
7 févr. 2012
LiverCenter
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
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Biopsy=
Gold Standard
Biopsy=
0% False Positive0% False Negative
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Serum Biomarker Imaging Biomarker
Geno-FibroTest
Choice Hepatologist
EpidemiologistGP
Aixplorer
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Viral necrosisActivity
Fibrosis Steatosis
AlcoholAsh
Nash
Liver Injury
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Too many subjects at risk of chronic liver disease (1.5 billions)
Serious adverse events of biopsy
Non-invasive alternatives to biopsy for staging
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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 C1 Million Chronic Hepatitis B
IVS 2004mardi 14 janvier 14
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 Million0.25 Million Chronic Hepatitis C0.25 Million Chronic Hepatitis B
IVS 2004mardi 14 janvier 14
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Fibrosis biomarkers: 23 years history
SJG 2008
n=100
n=1 million
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Cirrhosis defined using biopsy or FibroTest score of more than 0.75
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Haptoglobin
Alpha2Macroglobulin
Apolipoprotein A1
Total Bilirubin
Gamma GT
In Situ In Serum: FibroTest
Imbert-Bismut, Lancet 2001
Liver Injury
Activated Stellate CellsFibrotic Matrix
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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: sensitive marker of early Fibrosis
• No transaminases: 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
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FibroMAX: HCV-HBV-ALD-NAFLD
ActiTest
FibroTest SteatoTest
AshTest
NashTest
FibroMAX
7
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Fouad et al Int J Gen Med
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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 ?
1. La biopsie se trompe moins d’une fois sur 4, pour l’estimation du stade de fibrose METAVIR
2. La biopsie a une meilleure performance que le FibroTest pour le diagnostic de fibrose intermédiaire (Stade F2 vs F1)
3. Une Aire sous la courbe ROC doit être supéreure a 0.80 pour un test diagnostique cliniquement interessant
4
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Period 1: 1991-2004 Optimistic
Looking for a fibrosis biomarker with accuracy > 90%
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Liver Injury
Serum biomarker Imaging biomarker
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
Hemorrhage Liver failure Cancer
FibroTest OK AUROC >80%
FibroTest OK FibroScan OKAUROC >80%
«Gray Zone»: Biopsy
Imbert Bismut 2001, Castera 2005mardi 14 janvier 14
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Period 2: 2005-2009: Sceptic
Standard statistical methods were inappropriate
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•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
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7 Key methodological issues:Biopsy is no more a perfect gold standard
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Sampling error:AUROCs (F1 vs F2) of Biopsy vs Whole Liver according to length
Bedossa Hepatology 2003
AUROC 15 mm = 0.82AUROC 25 mm = 0.89
«We showed that with 25-mm long biopsy specimens, only 75% were scored correctly»
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0
0,2250
0,4500
0,6750
0,9000
0,52
0,39 0,38 0,35
0,87
Kappa
F0 F1 F2 F3 F4
Inter-Observers variability:Biopsy has lower inter-observers concordance for intermediate stages
Rousselet, Hepatology 2005
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Discordances studies: independent endpoints
• 537 prospective cases
• 154 (29%) discordances FibroTest/Biopsy
• Error attributable
• To FibroTest: 2%
• To Biopsy: 18%
25
Poynard Clin Chem 2004, Halfon AJG 2006
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Meta-analysis of prognostic studies in different diseases7 publications and 21 assessmentsFibroTest (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
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Meta-analysis of the prognostic value of biomarkers vs biopsy
Survival without liver deaths
Poynard Gastroenterol Hepatol 2011
Only FibroTest has same prognostic value than biopsy
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5 years prognostic value in chronic hepatitis B
de Ledinghen APT 2013mardi 14 janvier 14
Liver stiffness FibroTest
5 years prognostic value in chronic hepatitis C
Vergniol Gastroenterology 2011mardi 14 janvier 14
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•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
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3/7 key methodological issues not well understoodBiopsy is no more a perfect gold standard
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
DANA=4
DANA=Difference between Advanced and non-advanced fibrosis stages
Obuchowski measure=AUROCs Pair-wise comparison between all stages
Black and White Spectrum
FibroTest AUROC=0.98
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
DANA=1
DANA=Difference between Advanced and non-advanced fibrosis stages
Obuchowski measure=AUROCs Pair-wise comparison between all stages
Gray Spectrum
FibroTest AUROC=0.67
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
DANA=2.5
DANA=Difference between Advanced and non-advanced fibrosis stages
Obuchowski measure=AUROCs Pair-wise comparison between all stages
FibroTest AUROC=0.85
Standard Spectrum
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Hazardous Tables due to Spectrum Effect (1)
Interpretation of AUROC Interpretation of AUROC Interpretation of AUROC
AUROC Score* Biopsy length FibroTest and Spectrum
0.90-1 Excellent F0 vs F4
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
*Sebastiani CCLM 2011, Bedossa Hepatology 2003, Poynard Clin Chem 2007mardi 14 janvier 14
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Hazardous Tables due to Spectrum Effect (October 2012)
Ochi Hepatology 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. Usingthese 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)
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•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
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3/7 key methodological issues not well understoodBiopsy is no more a perfect gold standard
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Using 25 mm liver biopsy a perfect market cannot be validated
Black shading represents the set of conditions under which the AUROC values exceed what has already been observed
Metha J Hepatol 2009
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Exceeding limits of biopsy: >90% accuracy is impossible for advanced fibrosis
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«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
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Misleading presentation using biopsy as Gold-Standard
Boursier Hepatology 2012
Mathematically impossible with biopsy as «Gold Standard
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•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
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3/7 key methodological issues not well understoodBiopsy is no more a perfect gold standard
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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 »
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FibroTest/FibroSure has a Gray Zone
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Biopsy has a Gray Zone
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Review of fibrosis tests by Nguyen, Hepatology 2011
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Liver Biopsy Analysis Has a Low Level of Performance for Diagnosis of IntermediateStages of Fibrosis
The gray anatomy of 27,869 virtual biopsies and 6,500 patients
Poynard Clin Gastro Hepatol 2012Poynard, BMC 2005, J Hepatol 2011
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The gray zone of liver biopsy: 27,864 virtual biopsies
Area Fibrosis (Log)
25 mm Liver Biopsies
Poynard Clin Gastro Hepatol 2012
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The gray zone of liver biopsy: 27,864 virtual biopsies
Poynard Clin Gastro Hepatol 2012
Area Fibrosis (Log)
25 mm Liver Biopsies
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Lower gray zone of FibroTest relative to biopsy
Lower gray zone F2vsF1 for FibroTest vs Biopsy
58% lower F2vsF1 vs F1vsF0 41% lower F2vsF1 vs F4vsF3.
Biopsyn=27,864
Fibrotestn=6500
Poynard Clin Gastro Hepatol 2012mardi 14 janvier 14
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Biopsy is no more a perfect gold standard
FibroTest and Elastography have similar performance
2006: Approval Markers French Health Authorities HCV2011: Guidelines EASL 2011
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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/ 2012/ 2011/ 2012 CJG 2012/2012 Hepatology
2009/2004/2003/2010
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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 2013Chou, Ann Int Med 2013
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(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission
Benefit/Risk must be evaluated for each change in the formula:
It takes time for one stable formula: the example of 360,000 FibroTest
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High Risk False Positive Negative
5/954 (0.52%)
High Risk False Positive Negative
38/7494 (0.51%)
FibroTest Global Quality Estimates
High Risk False Positive Negative3349/345,695 (0.97%)
High Risk False Positive Negative
491/24,872 (1.97%)
FibroScan (Roulot et al 2008)>7.1 kPa= 12.6%: False Positives ?
Poynard BMC Gastro 2011, Roulot J Hepatol 2008
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(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission
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%
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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
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Biopsy vs Serum markerMain 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 2011mardi 14 janvier 14
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Period 3: 2010-----
Welcome in a world without perfect Gold Standard
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Gold Standard
25 mm Biopsy 0%False PositiveFalse Negative
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Truth in the Absence of
Gold Standard
25 mm Biopsy 25%False PositiveFalse Negative
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Area of fibrosis estimated by biopsy according to its length (mm) in subjects scoring METAVIR F0 (no fibrosis) on large surgical section.
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.
Cirrhosis
Advanced fibrosis
Poynard J Hepatol 2012mardi 14 janvier 14
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Poynard J Hepatol 2011
Truth
FibroTest FibroScan
5-30 mm Biopsy
ALT
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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 results16 combinations of 4 tests results16 combinations of 4 tests results16 combinations of 4 tests results Number of subjectsNumber 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 1 276 277.0
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0
25
50
75
100
66 68
48 45
100
63
Reference Biopsy Reference Latent Class
FibroTest Se LSM Se Biopsie Se
Performance for Advanced Fibrosis: Sensitivity
The standard cutoffs: 0.48 FibroTest, 8.8 kPa Stiffness
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0
25
50
75
10085
8993 96
100
67
Reference Biopsy Reference Latent Class
FibroTest Sp LSM Sp Biopsy Sp
Performance for Advanced Fibrosis: Specificity
The standard cutoffs: 0.48 FibroTest, 8.8 kPa Stiffness
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0
25
50
75
100
68
41
65
39
100
51
Reference Biopsy Reference Latent Class
FibroTest Se LSM Se Biopsie Se
Performance for Cirrhosis: Sensitivity
The standard cutoffs: 0.74 FibroTest, 14.5 kPa Stiffness
Poynard, J Hepatol 2011 mardi 14 janvier 14
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0
25
50
75
10089 87
95 93100
95
Reference Biopsy Reference Latent Class
FibroTest Sp LSM Sp Biopsy Sp
Performance for Cirrhosis: Specificity
The standard cutoffs: for cirrhosis 0.74 for FibroTest, and 14.5 kilo-Pascal for stiffness (LSM)
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0%
25%
50%
75%
100%99
47
97
46
99
61
99
61
97
54
98
64
Specificity Sensitivity
SWE Fibrotest 1 TE-M Fibrotest 2 TE-XL FibroTest 3
Poynard, J Hepatol 2013
Performances for diagnosis of Cirrhosis (HCV, HBV, NAFLD, ALD)of FibroTest, and Elastography: Transient M-XL probes and Share Wave
Latent Class Model: Best model for FibroTest with TE-XL or SWE (Likelihood ratio test 5.5, 6.9)
n = 322 simultaneous reliable tests
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Period 3: 2010-----
Improving serum biomarker
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HCV-GenoFibroTest: Liver injury, Virus Resistance, Host Genes for treatment Response and Tolerance
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ActiTest
FibroTest SteatoTest
IL28B
HCV-GenoFibroTest
Viral Load
Viral Resistance
ITPA
UGT1A1
Genotype
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Period 3: 2010-----
Combining serum and imaging biomarkers
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• 11 Published studies
• n=2,260
• Standardized AUROC
• Advanced Fibrosis
• 0.89 (0.84-0.95)
Friedrich Rust et al Gastroenterology 2008, Poynard et al SJG 2008
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Elastography
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Oliveri WJG 2008
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Pitfalls of Fibroscan
3.1% Failures and Unreliable results 15.8%
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Choice of FibroScan Cutoffs
Castera 2005, Ketanneh 2007Roulot 2008
For F2: 7.1 or 8.8 kPa ? Patients: false negatives ?Low negative predictive value
Healthy volunteers: 7.1 kPa 12.6% false positives ?
For screening 7.1 kPa ?
For patients 8.8 kPa ?
No rationale for changing cutoff according to liver disease
F2 8.8 kPa F4 14.5 kPa
F4 0.73
F2 0.48
Poynard PlosOne 2008mardi 14 janvier 14
A la ParisienneFibrotestFirst Line
If not interpretableBiopsy
FibroTest ActiTest
If not interpretableFibroscan
98%
<1%
2%
Prevalence
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Serum biomarker
FibroTest
Imaging biomarker
FibroScan
Elasto-FibroTest
Poynard, CRHG 2012mardi 14 janvier 14
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Elasto-FibroTest®
•1289 patients with CHC and 604 healthy volunteers
•Appropriate methods
•Obuchowski measures
•Methods without Gold Standard
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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.
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Poynard, CRHG 2012mardi 14 janvier 14
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Period 4: 2014-----
Simplifier le quotidien des cliniciens
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F4.1
F1
F0
F2
F3
7 Stages Presumed by Biomarkers
Decompensated
F4.2
F4.3
Varices
FibroTest
0.48
0.74
0.850.95
TE
7.1
9.5
2050
Poynard J Hepatol 2014mardi 14 janvier 14
(c) BioPredictive 2012 - All Rights Reserved - No reproduction without written permission Bio Predictive
BioChimie
FibroScan
AixPlorer
Anti-Fibrosis Platform
Base BAF
Réseau BAF
Consultation
Borne Salle Attente
Chercheur
Opérateur BAFL’opérateur du BAF, a directement accès à la base pendant le bilan.
BioPredictive
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Epilogue Universitaire
Résultat du QCM
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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%
4
«We showed that with 25-mm long biopsy specimens, only 75% were scored correctly»
Bedossa, Hepatology 2003
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2. La biopsie a une meilleure performance que le FibroTest pour le diagnostic de fibrose intermédiaire (Stade F2 vs F1) : Faux
4
« Liver Biopsy Analysis Has a Low Level of Performance for Diagnosis of Intermediate Stages of Fibrosis»
Poynard, CGH 2012
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90
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3. Une Aire sous la courbe ROC doit être supéreure a 0.80 pour un test diagnostique cliniquement interessant Faux
4
« AUROC analysis led to discordant results depending onhow the fibrosis stages were grouped together.
We recommend the Obuchowski measure...»
Poynard, Clin Chem 2007, Lambert, Clin Chem 2008
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Epilogue de Recherche Clinique
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«Despite ductular proliferation vanishing and lobular zonation restoration, portal inflammation and sinusoidal capillarization may not regress after viral eradication. (HEPATOLOGY 2012;56:532-543)»
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F4
F1
F0
France: 12,000,000 at Risk100%
5%
Death 15,000/year0.1%
Biomarker10% F2
F3
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