Du 2012 tp biomarkers

26 janv. 2012

LiverCenter

Measurement of Fibrosis

Serum markers of fibrosis: improvement of methods

Truth without A Gold Standard

Thierry Poynard+

AP-HP Groupe Hospitalier Pitié Salpêtrière,UPMC Liver Center, Université Paris 6, INSERM U680, Biopredictive France

jeudi 26 janvier 2012

26 janv. 2012

But: Savoir répondre à ce QCM:

2


26 janv. 2012


Parmi les 5 propositions suivantes concernant les performances relatives de la biopsie du foie (de 25 mm) par rapport à un marqueur noninvasif comme le FibroTest lesquelles sont vraies ?

2


26 janv. 2012



1. La biopsie se trompe moins d’une fois sur 4 pour l’estimation d’un stade de fibrose METAVIR

2


26 janv. 2012




2. La biopsie du foie a une meilleure performance que le FibroTest pour le diagnostic de fibrose intermédiaire (Stade F2 vs F1)

2


26 janv. 2012





3. Une biopsie de 25 mm peut avoir des faux négatifs pour le diagnostic de fibrose avancée (stades F2F3F4) mais très rarement des faux positifs.

2


26 janv. 2012






4. Le FibroTest a une meilleure valeur diagnostique pour le stade de cirrhose (F4) que pour le stade intermédiaire F2

2


26 janv. 2012







5. Pour une bonne estimation des performance d’un test il faut calculer les valeurs diagnostiques non seulement pour le diagnostic de cirrhose (F4) vs F0/F1/F2/F), mais aussi pour le diagnostic de F3/F4 vs F2/F1/F0, F2/F3/F4 vs F0/F1, et F1/F2/F3/F4 vs F0.

2


26 janv. 2012

Viral necrosisActivity

Fibrosis Steatosis

AlcoholAsh

Nash

Liver Injury


26 janv. 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


26 janv. 2012

FibroMAX: HCV-HBV-ALD-NAFLD

5


26 janv. 2012

FibroMAX: HCV-HBV-ALD-NAFLD

ActiTest

FibroTest SteatoTest

AshTest

NashTest

FibroMAX

5


26 janv. 2012

Imbert-Bismut, Lancet 2001jeudi 26 janvier 2012

26 janv. 2012

In Situ


26 janv. 2012

In Situ In Serum: FibroTest


26 janv. 2012


Imbert-Bismut, Lancet 2001

Liver Injury

Activated Stellate Cells

Fibrotic Matrix


26 janv. 2012

Alpha2Macroglobulin



Liver Injury


Fibrotic Matrix


26 janv. 2012

Alpha2Macroglobulin

Total Bilirubin



Liver Injury


Fibrotic Matrix


26 janv. 2012

Alpha2Macroglobulin

Total Bilirubin

Gamma GT



Liver Injury


Fibrotic Matrix


26 janv. 2012

Haptoglobin

Alpha2Macroglobulin

Total Bilirubin

Gamma GT



Liver Injury


Fibrotic Matrix


26 janv. 2012

Haptoglobin

Alpha2Macroglobulin

Apolipoprotein A1

Total Bilirubin

Gamma GT



Liver Injury


Fibrotic Matrix


26 janv. 2012

Rational of FibroTest:

Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010


26 janv. 2012


• Alpha 2 macroglobulin: key protein for Collagenase metabolism



26 janv. 2012



• Apolipoprotein A1 key protein for Collagen trapping



26 janv. 2012




• Haptoglobin: key protein for binding Free Hemoglobin oxidant



26 janv. 2012





• Total Bilirubin: specific marker of severe late Fibrosis



26 janv. 2012






• Gamma Glutamyl Transpeptidase: sensitive marker of early Fibrosis



26 janv. 2012







• No transaminases: to prevent inflammatory necrosis confusion (ActiTest)



26 janv. 2012








• Proteomic has blindly proved the major diagnostic value of



26 janv. 2012









• Apolipoprotein A, A2M



26 janv. 2012









• Apolipoprotein A, A2M

• HaptoglobinImbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010


26 janv. 2012

In Situ events: Fibrosis and serum ApoA1 decrease

Apo A1

Trapping

Down Regulation

Paradis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996.


26 janv. 2012

Haptoglobin Hemopexin


26 janv. 2012

Fibrosis biomarkers: 20 years history

SJG 2008


26 janv. 2012


SJG 2008

n=100


26 janv. 2012


SJG 2008

n=100

n=600,000


26 janv. 2012


Poynard SJG 2008


26 janv. 2012

Period 1: 1991-2004 Optimistic

Looking for a fibrosis biomarker with accuracy > 90%


26 janv. 2012

Biopsy=

Gold Standard

Biopsy=

0% False Positive0% False Negative


26 janv. 2012

Biopsy=

0% False Positive0% False Negative


26 janv. 2012

Liver Injury

Serum biomarker Imaging biomarker


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 2005jeudi 26 janvier 2012

26 janv. 2012

Period 2: 2005-2009: Sceptic

Standard statistical methods were inappropriate


26 janv. 2012

18

7 Key methodological issues:Biopsy is no more a perfect gold standard


26 janv. 2012

• Sampling error Bedossa 2003

18



26 janv. 2012


• Inter-observers variability Rousselet 2005

18



26 janv. 2012



• Discordance studies Poynard 2004, Halfon 2006

18



26 janv. 2012




• Prognostic studies Ngo 2006, Vergniol 2011

18



26 janv. 2012





• Spectrum effect Poynard 2007, Lambert 2008

18



26 janv. 2012






• Exceeding limits of biopsy Metha 2009

18



26 janv. 2012







• Biopsy has a gray zone Poynard 2012

18



Sampling error:AUROCs (F1 vs F2) of Biopsy vs Whole Liver according to length

Bedossa Hepatology 2003




AUROC 15 mm = 0.82

AUROC 25 mm = 0.89




AUROC 15 mm = 0.82

AUROC 25 mm = 0.89

«We showed that with 25-mm long biopsy specimens, only 75% were scored correctly»


26 janv. 2012

0

0,30

0,60

0,90

0,52

0,390,38

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


26 janv. 2012

Discordances studies: independent endpoints

• 537 prospective cases

• 154 (29%) discordances FibroTest/Biopsy

• Error attributable

• To FibroTest: 2%

• To Biopsy: 18%

21

Poynard Clin Chem 2004, Halfon AJG 2006


26 janv. 2012

Meta-analysis of prognostic studies: 6 publications and 21 assessmentsFibroTest (4 studies, 2396 patients), APRI (5 studies, 2422 patients), FIB4 (3 studies,1184 patients)

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

Poynard Gastroenterol Hepatol 2011


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


Liver stiffness FibroTest

5 years prognostic value in chronic hepatitis C

Vergniol Gastroenterology 2011jeudi 26 janvier 2012

26 janv. 2012







• Biopsy has a gray zone Poynard 2012

25

3/7 key methodological issues not well understoodBiopsy is no more a perfect gold standard


F4

F1

F0


F2

F3

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


F4

F1

F0


F2

F3

DANA=4



Black and White Spectrum



F4

F1

F0


F2

F3



Gray Spectrum



F4

F1

F0


F2

F3

DANA=1



Gray Spectrum



F4

F1

F0


F2

F3

DANA=2.5




Standard Spectrum


26 janv. 2012

Hazardous Tables due to Spectrum Effect (1)

*Sebastiani CCLM 2011, Bedossa Hepatology 2003, Poynard Clin Chem 2007


26 janv. 2012

Hazardous Tables due to Spectrum Effect (1)

Interpretation of Area Under ROC CurvesInterpretation of Area Under ROC CurvesInterpretation of Area Under ROC Curves

AUROC Score* Biopsy FibroTest

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 2007


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


26 janv. 2012

Exceeding limits of biopsy: >90% accuracy is impossible for advanced fibrosis

31

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


26 janv. 2012

Misleading presentation using biopsy as Gold-Standard

Boursier Hepatology 2012


26 janv. 2012

Misleading presentation using biopsy as Gold-Standard

Boursier Hepatology 2012

Mathematically impossible with biopsy as «Gold Standard


26 janv. 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 »

33


FibroTest/FibroSure has a Gray Zone


Biopsy has a Gray Zone


26 janv. 2012

Review of tests by Nguyen, Hepatology 2011

37


26 janv. 2012

0

0,30

0,60

0,90

0,52

0,390,38

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

The gray zone of liver biopsy (1)


26 janv. 2012

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 2012 in pressPoynard, BMC 2005, J Hepatol 2011


26 janv. 2012

The gray zone of liver biopsy: 27,864 virtual biopsies

Poynard Clin Gastro Hepatol 2012


The gray zone of liver biopsy: 27,864 virtual biopsies



The gray zone of FibroTest: 6,500 patients with biopsy



Lower gray zone of FibroTest relative to biopsy

Decrease FibroTest F2vsF1 58% lower compared with F1vsF0 41% lower compared with 4vsF3.

Biopsy

Fibrotest


Texte


26 janv. 2012

Biopsy is no more a perfect gold standard

FibroTest and Elastography have similar performance

2006: Approval Markers French Health Authorities HCV2011: Guidelines EASL 2011


26 janv. 2012

Period 3: 2010-----

Welcome in a world without perfect Gold Standard


26 janv. 2012

Truth in the Absence of

Gold Standard

25 mm Biopsy 25%

False PositiveFalse Negative


26 janv. 2012

Area of fibrosis estimated by biopsy according to its length (mm) in subjects scoring METAVIR F0 (no fibrosis) on large surgical section.

Poynard J Hepatol 2012jeudi 26 janvier 2012

26 janv. 2012

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 2012jeudi 26 janvier 2012

26 janv. 2012

Poynard J Hepatol 2011

Truth

FibroTest FibroScan

5-30 mm Biopsy

ALT


26 janv. 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 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

0 0 1 0 190 197.5

0 0 1 1 123 117.4

0 1 0 0 10 10.0

0 1 0 1 18 18.4

0 1 1 0 18 16.4

0 1 1 1 39 39.2

1 0 0 0 41 47.0

1 0 0 1 58 54.8

1 0 1 0 95 86.6

1 0 1 1 141 145.1

1 1 0 0 9 8.3

1 1 0 1 45 43.1

1 1 1 0 23 25.7

1 1 1 1 276 277.0

Poynard, J Hepatol 2011


26 janv. 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 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 ObservedExpected by model

0 0 0 0 621 615.5

0 0 0 1 186 191.1

...

1 1 1 1 276 277.0



26 janv. 2012

FibroTest Se LSM Se Biopsie Se

Performance for Advanced Fibrosis: Sensitivity

The standard cutoffs: 0.48 FibroTest, 8.8 kPa Stiffness



26 janv. 2012

0%

25%

50%

75%

100%

66%68%

48% 45%

100%

63%

Reference Biopsy

Reference Latent Class


Performance for Advanced Fibrosis: Sensitivity




26 janv. 2012

FibroTest Sp LSM Sp Biopsy Sp

Performance for Advanced Fibrosis: Specificity




26 janv. 2012

0%

25%

50%

75%

100%

85% 89%93% 96%

100%

67%

Reference Biopsy

Reference Latent Class


Performance for Advanced Fibrosis: Specificity




26 janv. 2012

0%

25%

50%

75%

100%

68%

41%

65%

39%

100%

51%

Reference BiopsyReference Latent Class


Performance for Cirrhosis: Sensitivity




26 janv. 2012

0%

25%

50%

75%

100% 89%87%

95%93%

100%

95%

Reference BiopsyReference Latent Class


Performance for Cirrhosis: Specificity

The standard cutoffs: for cirrhosis 0.74 for FibroTest, and 14.5 kilo-Pascal for stiffness (LSM)



26 janv. 2012

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

24-48h

False positive/hemolysis/inflammation/Gilbert

Yes but 0.97% (3349/345695; 0.94-1.00)

Nguyen Hepatology, 2011 Poynard BMC Gastro 2011jeudi 26 janvier 2012

Serum biomarker Imaging biomarker

Geno-FibroTest

FibroScanGPHepatologist

EpidemiologistChoice


A la ParisienneFibrotestFirst Line

If not interpretableBiopsy

FibroTest ActiTest

If not interpretableFibroscan

98%

<1%

2%

Prevalence


Serum biomarker

FibroTest

Imaging biomarker

FibroScan

Elasto-FibroTest


26 janv. 2012

Elasto-FibroTest®

• 1289 patients with CHC and 604 healthy volunteers

• Appropriate methods

• Obuchowski measures

• Methods without Gold Standard

59

Poynard, JFHOD 2012


26 janv. 2012

Elasto-FibroTest®

• 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.

60

Poynard, JFHOD 2012


26 janv. 2012

FibroTest validation in “difficult to diagnose patients”

• HIV-HCV: Myers 2003, Cacoub 2008

• Aged patients: Thabut 2006

• Children: de Ledinghen 2007, Friedrich 2008

• Renal insufficiency: Varaud 2005

• Vasculitis: Cacoub 2006

• Hemophiliac Mahor 2006

• Transplanted

• Kidney: Varaud 2006

• Liver: Hamelet 2008

• Normal ALT Poynard 2006, 2008, Castera 2006

61


26 janv. 2012ActiTest vs ALT accuracy for the diagnosis of necro-Inflammatory histological activity grade

in 1,250 patients with chronic hepatitis C

* m (se) One test for all grades pairwise area under the ROC curves comparisons


26 janv. 2012ActiTest vs ALT accuracy for the diagnosis of necro-Inflammatory histological activity grade

in 1,250 patients with chronic hepatitis C

ActiTest ALT Significance

Obuchowski* Measure 0.848 (0.005) 0.834 (0.006) P= 0.008

* m (se) One test for all grades pairwise area under the ROC curves comparisons


High Risk False Positive Negative

5/954 (0.52%)


38/7494 (0.51%)

FibroTest Global Quality Estimates

High Risk False Positive Negative3349/345,695 (0.97%)


491/24,872 (1.97%)

FibroScan (Roulot et al 2008)>7.1 kPa= 12.6%: False Positives ?

Poynard EASL 2010, Roulot J Hepatol 2008


(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


(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%


26 janv. 2012

3 major pitfalls of Fibrometers’ family

1. Transaminases in a fibrosis biomarker

• Too rapid decrease of a fibrosis biomarkers is a sign of confounding factor

• Need to associate fibrosis biomarker with a specific marker of steatosis (SteatoTest) or activity (ActiTest)

2. Benefit/Risk must be evaluated for each change in the formula of algorithms and there is 8 different formula...

3. The «new» CirrhoMeter is build on the false assumption that biopsy is a gold standard. To use only a test for»Cirrhosis» is less efficient than a quantitative estimate from F0 to F4. When the CirrhoTest is negative you must re-perform another test to see if the patient is F0 or F3....

66


26 janv. 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


26 janv. 2012

• 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

69

Elastography


26 janv. 2012

Oliveri WJG 2008


26 janv. 2012

Pitfalls of Fibroscan

3.1% Failures and Unreliable results 15.8%


26 janv. 2012

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 2008


26 janv. 2012

HCV n=92Mean Fibrotest and Actitest

0

0,20

0,40

0,60

0,80

1,00

FibrotestActitest

Baseline 12 weeks 24 weeks 48 weeks

D’Arondel et al JVH 2006

Fibrosis Activity


26 janv. 2012

HCV n=416Median % changes Fibrosis estimates (12-24 month)

-30%

-25%

-20%

-15%

-10%

-5%

0%

5%

10%

Control (n=304)NR (n=27)

SVR (n=70)

FibroTest Fibroscan

Vergniol et al JVH 2009


26 janv. 2012

HCV n=416Mean FibroTest (range 0.00-1.00)

0

0,12

0,24

0,36

0,48

0,60

Control (n=304)SVR (n=70)

Baseline 12mo/EOT 24mo/EOF


Slow increase = Sensitivity

Slow decrease = Not related to activity


26 janv. 2012

HCV n=416Mean Liver Stiffness Measurements (range 0-75 kPa )

0

3

6

9

12

15

Control (n=304)SVR (n=70)

Baseline 12mo/EOT 24mo/EOF


Too Early = necro-inflammatory activity

improvement ?

No treatment No increase = Lack of sensitivity ?


BioPredictive S.A.S - Capital social 40.000 Euros - SIRET 442349387 00013 - Code APE 7219Z - Numero TVA intracommunautaire FR00442349387

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HCV Geno-FibroTestInternal reference : TEST

Ref #123456

Patient

Birth date 1935-09-22

Sex Female

IL28B Genotype C/C

Biomarkers

Sample date 2009-05-06

Alpha2Macroglobulin 3.12 g/l

Apolipoprotein A1 1.82 g/l

Bilirubin 13.00 Ämol/l

Haptoglobin 1.18 g/l

Gamma GT 149.00 IU/l

ALT 47.00 IU/l

Hepatitis C

HCV Viral Load 250000

HCV Genotype Genotype 2

Tests resultsFibroTest ActiTest HCV Geno-FibroTest

FibroTest assesses thefibrosis of the liver

ActiTest assesses activity(inflammation in chronic

viral hepatitis C or B)

Chance of sustainedvirological response.

Score: 0.72(F3)

Score: 0.41(A1-A2)

Score: 0.14(SVR ++)

F3: advanced fibrosis A1-A2: minimal activity SVR ++: very goodresponse

Precautions of use and interpretabilityÅ The reliability of results is dependent on compliance with the preanalytical and analytical conditions recommended by BioPredictive.Å The Tests have to be deferred for: acute hemolysis, acute hepatitis, acute inflammation, extra hepatic cholestasis.Å The advice of a specialist should be sought for interpretation in chronic hemolysis and Gilbert's syndrome.Å The Test interpretation is not validated in liver transplant patients.Å Isolated extreme values of one of the components should lead to caution in interpreting the results.Å In case of discordance between a biopsy result and a Test, it is recommended to seek the advice of a specialist. The causes of these discordances could be due to a flaw of the Test or to a flawin the biopsy: i.e. a liver biopsy has a 33% variability rate for one fibrosis stageÅ FibroTest is interpretable for chronic hepatitis B and C, alcoholic and non alcoholic steatosis.Å ActiTest is interpretable for chronic hepatitis B and C.Å HCV Geno-FibroTest is interpretable when FibroTest is interpretable and when the IL28b genotype is interpretable. C/C : good response, C/T : intermediate response, T/T : poor response.


26 janv. 2012

HCV-GenoFibroTest: Liver injury, Virus Resistance, Host Genes for treatment Response and Tolerance

78

ActiTest

FibroTest SteatoTest

IL28B

HCV-GenoFibroTest

Viral Load

Viral Resistance

ITPA

UGT1A1

Genotype


26 janv. 2012

Conclusion for Biomarkers (1)

• Accept than a 25 mm biopsy can have 25% false positive/negative and that the risk of biopsy's error is greater between stage F2vsF1 than for the extreme stages F1vsF0 and F4vsF3.

• Dont use non-Evidence Based statements:

• «Gray Zone for intermediate stages»

• «Percentage of biopsies avoided»

• Avoid the presentation of sAUROCs of multiple stages combinations in a Table (i.e. F4vsF2F3F4; F4F3vsF2F1F0; F4F3F2vsF1F0) to prevent the spectrum effect.

• Apply appropriate methods:

• Obuchowski measures

• Methods without Gold Standard

79


26 janv. 2012

Conclusion for Biomarkers (2)

• Finally guidelines for the indications of fibrosis tests should take into consideration these evidence-based data.

• At least for FibroTest there is no scientific reason for recommending a biopsy for the diagnosis of intermediate fibrosis stages.

80


26 janv. 2012

Summary: Responses to Questions


26 janv. 2012


• Is the perfect fibrosis biomarker possible?


26 janv. 2012



• No as 25 mm has 25% False P/N


26 janv. 2012




• There is a "gray zone" or "inaccurate zone" between intermediate stages?


26 janv. 2012





• No as this is the same for 25 mm biopsy (Spectrum effect)


26 janv. 2012






• Is FibroTest better than non-patented biomarker?: ALT, Forns, APRI...


26 janv. 2012







• Yes higher performance and safety than ALT, Forns, APRI


26 janv. 2012








• Is liver biopsy still useful?


26 janv. 2012








• Is liver biopsy still useful?

• Yes but when everything else failed


26 janv. 2012



26 janv. 2012

• Performance of Fibrotest according to liver disease?



26 janv. 2012


• Similar diagnostic value for HCV, HBV, ALD, NAFLD, AIH



26 janv. 2012



• What is the prognostic value of FibroTest vs biopsy?



26 janv. 2012




• At least similar for HCV, HBV, ALD, preliminary for NAFLD



26 janv. 2012





• Fibrotest-ActiTest-SteatoTest-NashTest-AshTest better than FibroScan?



26 janv. 2012






• Yes: More sensitive in patients and more specific in general population



26 janv. 2012







• Yes: Less sensitive to Activity and Steatosis



26 janv. 2012








• Yes: FibroMax takes into account necrosis, inflammation and steatosis



26 janv. 2012









• Rational of FibroTest components?



26 janv. 2012









• Rational of FibroTest components?

• Yes: Key proteins, validated proteomics



26 janv. 2012

Anticipated Frequently Asked Questions


26 janv. 2012


• Are the authors credible due to their possible conflict of interest?


26 janv. 2012



• Yes: many independent validation studies and official guide lines


26 janv. 2012




• France


26 janv. 2012




• France

• Poland


26 janv. 2012




• France

• Poland

• Romania


26 janv. 2012




• France

• Poland

• Romania

• Israel


26 janv. 2012




• France

• Poland

• Romania

• Israel

• Turkey


26 janv. 2012




• France

• Poland

• Romania

• Israel

• Turkey

• EASL


26 janv. 2012


84


26 janv. 2012


Parmi les 5 propositions suivantes concernant les performances relatives de la biopsie du foie (de 25 mm) par rapport à un marqueur noninvasif comme le FibroTest lesquelles sont exactes ?

84


26 janv. 2012




84


26 janv. 2012




1.1. Faux c’est 1/4

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2.1. Faux Relativement au FibroTest la biopsie est plus handicapée pour F1vsF2

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3.1. Faux: 15% de Faux positif...

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4.1. Faux: Relativement a la biopsie la diminutionde performace est plus faible pour le FibroTest

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5.1. Faux exemple typique d’effet de spectre

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F4

F1

F0

France: 12,000,000 at Risk100%

5%

Death 15,000/year0.1%

Biomarker10% F2

F3


Du 2012 tp biomarkers

Health & Medicine

Transcript of Du 2012 tp biomarkers