Additional material

(1)

A single blood test adjusted for different liver fibrosis targets improves fibrosis staging especially cirrhosis diagnosis

: Additional material

This material reports p values for comparisons within FibroMeter family tests for population

#1 (1012 patients) in Table A1, for population #2 (641patients) in Table A2 or for combined populations #1 to #4 (3809 patients) in Table A3; and for comparisons between FibroMeter family tests with Hepascore and Zeng score for combined populations #2 to #4 (2797

patients) in Table A4 or with Fibrotest for combined populations #2 and #3 (1461 patients) in Table A5 or with VCTE for combined populations #2 to #4 (1746 patients) in Table A6.

Tables A7 to A15 report data on other blood tests outside the FibroMeter family, some of them reporting extended data compared to FibroMeter family tests already presented in Supplemental material.

Source: http://okina.univ-angers.fr/publications/ua15610

(2)

Table A1a. Primary objective for Multi-FibroMeters. Comparison of AUROCs for significant fibrosis of all test pairs of the FibroMeter family in the CHC derivation population #1 (1012 patients, Table 3) by Delong test.

FM2G CM2G MFM2 FM3G CM3G MFM3G

FibroMeter^V2G - <0.0001 0.5757 0.4632 <0.0001 0.7970 CirrhoMeter^V2G - <0.0001 <0.0001 0.3211 <0.0001

Multi-FibroMeter^V2G - 0.3395 <0.0001 0.2829

FibroMeter^V3G - <0.0001 0.7762

CirrhoMeter^V3G - <0.0001

Multi-FibroMeter^V3G -

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, FM^3G:

FibroMeter^V3G, CM^3G: CirrhoMeter^V2G, MFM^3G: Multi-FibroMeter^V3G. Significant differences are shown in bold. Main objective is indicated by a green background when reached and a blue background when overreached. Red characters indicate a significant gain of multi- FibroMeter vs FibroMeter.

(3)

Table A1b. Comparison of AUROCs for cirrhosis of all test pairs of the FibroMeter family in the CHC derivation population #1 (1012 patients, Table 3) by Delong test.

FM^2G CM^2G MFM^2G FM^3G CM^3G MFM^3G

FibroMeter^V2G - 0.2316 <0.0001 0.0039 0.6764 0.0296

CirrhoMeter^V2G - 0.1088 0.0280 0.0978 0.6587

Multi-FibroMeter^V2G - <0.0001 0.0216 0.1321

FibroMeter^V3G - 0.0945 <0.0001

CirrhoMeter^V3G - 0.1468

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V3G, MFM^3G: Multi-FibroMeter^V3G

Significant differences are indicated in bold. Primary objective criterion is indicated by a green background when reached and a blue background when overreached. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter or CirrhoMeter.

(4)

Table A1c. Comparison of Obuchowski indices of all test pairs of the FibroMeter family in the CHC derivation population #1 (1012 patients, Table 3) by z test.

FM^2G CM^2G MFMF^2G FM^3G CM^3G MFMF^3G

FibroMeter^V2G - 0.0004 0.0022 0.0344 0.0003 0.0892

CirrhoMeter^V2G - <0.0001 0.0068 0.6657 <0.0001

Multi-FibroMeter^V2G - 0.0004 <0.0001 0.0904

FibroMeter^V3G - 0.0018 0.0014

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^v2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V3G, MFM^3G: Multi-FibroMeter^V3G

Significant differences are indicated in bold. Primary objective criterion is indicated by a green background when reached and a blue background when overreached. Red characters indicate a significant gain of Multi-FibroMeter vs FibroMeter.

(5)

Table A2a. Comparison of AUROCs for significant fibrosis of all test pairs of the FibroMeter family in the CHC validation population #2 (641patients, Table 4) by Delong test.

FM2G CM2G MFM2 FM3G CM3G MFM3G

FibroMeter^V2G - 0.0147 0.7982 0.0096 0.0007 0.3843

CirrhoMeter^V2G - 0.0032 0.2918 0.0288 0.0465

Multi-FibroMeter^V2G - 0.0298 <0.0001 0.1037

FibroMeter^V3G - 0.0103 0.2322

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^v2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V3G, MFM^3G: Multi-FibroMeter^V3G

Significant differences are indicated in bold. Primary objective criterion is indicated by a green background when reached and a blue background when overreached. Red characters indicate a significant gain of Multi-FibroMeter vs FibroMeter.

(6)

Table A2b. Comparison of AUROCs for cirrhosis of all test pairs of the FibroMeter family in the CHC validation population #2 (641 patients, Table 4) by Delong test.

FibroMeter^V2G - 0.7738 0.0154 0.0123 0.2037 0.5536

CirrhoMeter^V2G - 0.0135 0.4313 0.0174 0.4153

Multi-FibroMeter^V2G - 0.0006 0.0008 0.0629

FibroMeter^V3G - 0.8236 0.0201

CirrhoMeter^V3G - 0.0199

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V2G, MFM^3G: Multi-FibroMeter^V3G, FT: Fibrotest, HS:

Hepascore, VCTE: vibration controlled transient elastography (by Fibroscan). Significant differences are shown in bold. Primary objective criterion is indicated by a green background when reached and a blue background when overreached. Red characters indicate a significant gain of Multi-FibroMeter vs FibroMeter or CirrhoMeter.

(7)

Table A2c. Comparison of Obuchowski indices of all test pairs of the FibroMeter family in the CHC validation population #2 (641 patients, Table 4) by z test.

FibroMeter^V2G - 0.0032 0.3083 0.0024 <0.0001 0.2731

CirrhoMeter^V2G - 0.0005 0.1482 0.0033 0.0214

Multi-FibroMeter^V2G - 0.0026 <0.0001 0.0087

FibroMeter^V3G - 0.0011 0.2041

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V2G, MFM^3G: Multi-FibroMeter^V3G, FT: Fibrotest, HS:

Hepascore, VCTE: vibration controlled transient elastography (by Fibroscan). Significant differences are shown in bold. Primary objective criterion is indicated by a green background when reached and a blue background when overreached. Red characters indicate a significant gain of Multi-FibroMeter vs FibroMeter.

(8)

Table A3a. Primary objective for Multi-FibroMeters. Comparison of AUROCs for significant fibrosis of all test pairs of the FibroMeter family in the combined populations #1 to #4 (3809 patients, Table 5) by Delong test: p value for bilateral test.

FibroMeter^V2G CirrhoMeter^V2G Multi-FibroMeter^V2G FibroMeter^V3G CirrhoMeter^V3G Multi-FibroMeter^V3G

FibroMeter^V2G - <0.0001 0.7308 (0.3657)^a <0.0001 <0.0001 0.0012

CirrhoMeter^V2G - <0.0001 <0.0001 <0.0001 <0.0001

Multi-FibroMeter^V2G - <0.0001 <0.0001 <0.0001

FibroMeter^V3G - <0.0001 0.7898 (0.3952) ^a

Significant differences are shown in bold. Primary objective (AUROC Multi-FibroMeter ≥ AUROC FibroMeter) is indicated by a green background when reached.

a p value for unilateral test in brackets. Non-inferiority test was also evaluated: Multi-FibroMeter was not inferior to corresponding FibroMeter with a margin of 0.005 at 5% significance level (Analyse-it Software Ltd.).

(9)

Table A3b. Primary objective for Multi-FibroMeters. Comparison of AUROCs for cirrhosis of all test pairs of the FibroMeter family in the combined populations #1 to #4 (3809 patients, Table 5) by Delong test: p value for bilateral test.

FibroMeter^V2G - 0.0002 <0.0001 <0.0001 0.8004 0.0671

CirrhoMeter^V2G - 0.0277 (0.0138)^a <0.0001 <0.0001 <0.0001

Multi-FibroMeter^V2G - <0.0001 <0.0001 <0.0001

FibroMeter^V3G - <0.0001 <0.0001

CirrhoMeter^V3G - 0.1032 (0.0516)^a

Significant differences are shown in bold. Primary objective (AUROC Multi-FibroMeter > AUROC FibroMeter or ≥ AUROC CirrhoMeter) is indicated by a green background when reached and a blue background when overreached.

a p value for unilateral test in brackets. Non-inferiority test was also evaluated: Multi-FibroMeter was not inferior to corresponding CirrhoMeter with a margin of 0.001 (0.015 for V3G) at 5% significance level (Analyse-it Software Ltd.).

(10)

Table A3c. Primary objective for Multi-FibroMeters. Comparison of Obuchowski indices of all test pairs of the FibroMeter family in the combined populations #1 to #4 (3809 patients, Table 5) by z test.

FibroMeter^V2G - <0.0001 0.0590^a 0 0 0.0012

CirrhoMeter^V2G - <0.0001 0.0720 <0.0001 0.0003

Multi-FibroMeter^V2G - <0.0001 0 0

FibroMeter^V3G - <0.0001 0.0044

Significant differences are shown in bold. Primary objective (Obuchowski index Multi-FibroMeter > Obuchowski index FibroMeter) is indicated by a green background when reached.

a Borderline significance with superior value of Multi-FibroMeter

(11)

Table A3d. Comparison of correctly classified patient rate (%) in classification metric between Multi-FibroMeters as a function of Metavir fibrosis stages in the four combined populations #1 to #4 (3809 patients, Table 6).

Metavir fibrosis stage

F0 F1 F2 F3 F4 All F

Multi-FibroMeter^V2G 32.6 91.2 93.3 90.7 84.7 86.0

p ^a 1 <0.001 0.001 0.804 <0.001 0.938

a Paired McNemar test

Significant differences are shown in bold.Colour codes: accuracy (%) <60, 60-70, 70-80, 80-90, >90

(12)

Table A3e. Comparison of correctly classified patient rate (%) in classification metric within FibroMeter family as a function of cirrhosis in the combined populations #1 to #4 (3809 patients, Table 6).

F0 to F3 Cirrhosis (F4) p^a All F

FibroMeter^V2G 81.7 84.7 0.100 82.1

CirrhoMeter^V2G 80.6 89.4 <0.001 81.8

Multi-FibroMeter^V2G 86.2 84.7 0.347 86.0

Comparison (p ^b):

All tests <0.001 <0.001 - <0.001

FibroMeter^V2G vs CirrhoMeter^V2G 0.058 0.002 - 0.568

FibroMeter^V2G vs Multi-FibroMeter^V2G <0.001 1 - <0.001

CirrhoMeter^V2G vs Multi-FibroMeter^V2G <0.001 <0.001 - <0.001

FibroMeter^V3G 82.0 63.9 <0.001 79.5

CirrhoMeter^V3G 81.6 75.6 0.001 80.8

Multi-FibroMeter^V3G 87.6 76.2 <0.001 86.1

Comparison (p ^b):

All tests <0.001 <0.001 - <0.001

FibroMeter^V3G vs CirrhoMeter^V3G 0.499 <0.001 - 0.031

FibroMeter^V3G vs Multi-FibroMeter^V3G <0.001 <0.001 - <0.001

CirrhoMeter^V3G vs Multi-FibroMeter^V3G <0.001 0.743 - <0.001

Comparison V2G vs V3G (p^a):

FibroMeter 0.567 <0.001 - <0.001

CirrhoMeter 0.048 <0.001 - 0.034

Multi-FibroMeter <0.001 <0.001 - 0.938

Significant differences are shown in bold. Colour codes: accuracy (%) <60, 60-70, 70-80, 80-85, >85

a 2 test

b Paired Cochran test or McNemar test

(13)

Table A4a. Secondary objective for Multi-FibroMeters. Comparison of AUROCs for significant fibrosis of all test pairs in the combined validation populations #2 to #4 (2797 patients, Tables S5 and A11) by Delong test with emphasis on Hepascore and Zeng score.

FM2G CM2G MFM2G FM3G CM3G MFM3G APRI Fib4 HS Zeng FMA2G

FM2G - <0.0001 0.8852 <0.0001 <0.0001 0.0005 <0.0001 <0.0001 <0.0001 <0.0001 0.0001 CM2G - <0.0001 0.0024 <0.0001 0.0003 <0.0001 <0.0001 0.7436 0.3567 0.4188 MFM2G - <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

FM3G - <0.0001 0.7446 <0.0001 <0.0001 0.0123 0.0005 0.10539

CM3G - <0.0001 <0.0001 <0.0001 0.1965 0.5016 0.0079

MFM3G - <0.0001 <0.0001 0.0115 0.0009 0.0625

APRI - 0.0330 <0.0001 <0.0001 <0.0001

Fib4 - <0.0001 <0.0001 <0.0001

HS - 0.4445 0.2372

Zeng - 0.1132

FMA2G -

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V2G, MFM^3G: Multi- FibroMeter^V3G, FT: Fibrotest, HS: Hepascore, ZS: Zeng score, FMA2G: FibroMeter^ALD2G. Significant differences are shown in bold. Secondary objective (AUROC Multi-FibroMeter > AUROC Hepascore or Zeng score) is indicated by a green background when reached. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to other tests (outside FibroMeter family).

(14)

Table A4b. Secondary objective for Multi-FibroMeters. Comparison of AUROCs for cirrhosis of all test pairs in the combined validation populations #2 to #4 (2797 patients, Tables S5 and A11) by Delong test with emphasis on Hepascore and Zeng score.

FM2G - 0.0003 <0.0001 <0.0001 0.9718 0.3111 <0.0001 <0.0001 0.8557 0.4126 0.0080 CM2G - 0.1146 <0.0001 <0.0001 0.0059 <0.0001 <0.0001 0.0071 0.0021 0.7446 MFM2G - <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0001 <0.0001 0.1564

FM3G - <0.0001 <0.0001 <0.0001 0.0008 0.0093 0.0234 <0.0001

CM3G - 0.2780 <0.0001 <0.0001 0.8830 0.4962 0.0293

MFM3G - <0.0001 <0.0001 0.5065 0.2118 0.1087

APRI - <0.0001 <0.0001 <0.0001 <0.0001

Fib4 - <0.0001 <0.0001 <0.0001

HS - 0.5091 0.0005

Zeng - 0.0007

FMA2G -

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V2G, MFM^3G: Multi- FibroMeter^V3G, FT: Fibrotest, HS: Hepascore, ZS: Zeng score, FMA2G: FibroMeter^ALD2G. Significant differences are shown in bold. Secondary objective (AUROC Multi-FibroMeter > AUROC Hepascore or Zeng score) is indicated by a green background when reached and by a yellow background when not reached and without significant difference. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to other tests (outside FibroMeter family).

(15)

A4c. Secondary objective for Multi-FibroMeters. Comparison of Obuchowski indices of all test pairs in the combined validation populations #2 to #4 (2797 patients, Tables S5 and A11) by z test with emphasis on Hepascore and Zeng score.

FM2G - 0.2450 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0003 <0.0001 0.0017 CM2G - <0.0001 0.3288 <0.0001 <0.0001 <0.0001 <0.0001 0.7724 0.0181 0.3015 MFM2G - <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0001 <0.0001 0.0002

FM3G - <0.0001 0.0501 <0.0001 <0.0001 0.7187 0.0002 0.8986

CM3G - <0.0001 <0.0001 <0.0001 0.0109 0.9732 0.0002

MFM3G - <0.0001 <0.0001 0.2842 <0.0001 0.4739

APRI - 0.1258 <0.0001 <0.0001 <0.0001

Fib4 - <0.0001 <0.0001 <0.0001

HS - 0.0023 0.5514

Zeng - 0.0014

FMA2G -

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, FM^3G: FibroMeter^V3G, CM^3G: CirrhoMeter^V2G, MFM^3G: Multi- FibroMeter^V3G, FT: Fibrotest, HS: Hepascore, ZS: Zeng score, FMA2G: FibroMeter^ALD2G. Significant differences are shown in bold. Secondary objective (Obuchowski index Multi-FibroMeter > Obuchowski index Hepascore or Zeng score) is indicated by a green background when reached and by a yellow background when not reached and without significant difference. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to other tests (outside FibroMeter family).

(16)

Table A5a. Secondary objective for Multi-FibroMeters. Comparison of AUROCs for significant fibrosis of all test pairs between FibroMeter family tests and Fibrotest in the combined populations #2 and #3 (1461 patients, Table A14) by Delong test.

FibroMeter^V2G Multi-FibroMeter^V2G FibroMeter^V3G Multi-FibroMeter^V3G Fibrotest

FibroMeter^V2G - 0.5079 <0.0001 0.0075 <0.0001

Multi-FibroMeter^V2G - 0.0400 0.0014 <0.0001

FibroMeter^V3G - 0.9239 <0.0001

Multi-FibroMeter^V3G - <0.0001

Fibrotest -

Significant differences are shown in bold. Secondary objective (AUROC Multi-FibroMeter > AUROC Fibrotest) is indicated by a green background when reached. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to Fibrotest.

(17)

Table A5b. Secondary objective for Multi-FibroMeters. Comparison of AUROCs for cirrhosis of all test pairs between FibroMeter family tests and Fibrotest in the combined populations #2 and #3 (1461 patients, Table A14)) by Delong test.

FibroMeter^V2G - <0.0001 <0.0001 0.3486 0.0046

Multi-FibroMeter^V2G - <0.0001 0.0002 <0.0001

FibroMeter^V3G - 0.0001 0.3270

Multi-FibroMeter^V3G - 0.0034

Fibrotest -

Significant differences are shown in bold. Secondary objective (AUROC Multi-FibroMeter > AUROC Fibrotest) is indicated by a green background when reached. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to Fibrotest.

(18)

Table A5c. Secondary objective for Multi-FibroMeters. Comparison of Obuchowski indices of all test pairs between FibroMeter family tests and Fibrotest in the combined populations #2 and #3 (1461 patients, Table A14)) by z test.

FibroMeter^V2G - 0.8580 <0.0001 0.0006 <0.0001

Multi-FibroMeter^V2G - 0.0015 <0.0001 <0.0001

FibroMeter^V3G - 0.9700 <0.0001

Multi-FibroMeter^V3G - 0.0002

Fibrotest -

Significant differences are shown in bold. Secondary objective (Obuchowski index Multi-FibroMeter > Obuchowski index Fibrotest) is indicated by a green background when reached. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to

Fibrotest.

(19)

Table A6a. Secondary objective for Multi-FibroMeters. Comparison of AUROCs for significant fibrosis of all test pairs between FibroMeter family tests and VCTE in the combined populations #2 to #4 (1746 patients, Table S9) by Delong test.

FibroMeter^V2G Multi-FibroMeter^V2G FibroMeter^V3G Multi-FibroMeter^V3G VCTE

FibroMeter^V2G - 0.7966 <0.0001 0.0020 0.0165

Multi-FibroMeter^V2G - 0.0056 <0.0001 0.0188

FibroMeter^V3G - 0.6323 0.1555

Multi-FibroMeter^V3G - 0.1979

VCTE -

VCTE: vibration controlled transient elastography (by Fibroscan).Significant differences are shown in bold. Secondary objective (AUROC Multi-FibroMeter > AUROC VCTE) is indicated by a green background when reached and by a yellow background when not reached and without significant difference. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to VCTE.

(20)

Table A6b. Secondary objective for Multi-FibroMeters. Comparison of AUROCs for cirrhosis of all test pairs between FibroMeter family tests and VCTE in the combined populations #2 to #4 (1746 patients, Table S9) by Delong test: p value for bilateral test.

FibroMeter^V2G - <0.0001 <0.0001 0.6946 0.0078

Multi-FibroMeter^V2G - <0.0001 <0.0001 0.3954 (0.0336)^a

FibroMeter^V3G - <0.0001 <0.0001

Multi-FibroMeter^V3G - 0.0233 (0.4515)^a

VCTE -

VCTE: vibration controlled transient elastography (by Fibroscan).Significant differences of Delong test are shown in bold. Secondary objective (AUROC Multi-FibroMeter  AUROC VCTE) is indicated by a green background when reached and by a grey background for a significant limitation. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to VCTE.

a Equivalence test in brackets (H0 means non-equivalence with a margin of 0.04 at 5% significance level, Analyse-it Software Ltd.)

(21)

Table A6c. Secondary objective for Multi-FibroMeters. Comparison of Obuchowski indices of all test pairs between FibroMeter family tests and VCTE in the combined populations #2 to #4 (1746 patients, Table S9) by z test.

FibroMeter^V2G - 0.6609 <0.0001 0.0001 0.0637

Multi-FibroMeter^V2G - <0.0001 <0.0001 0.0455

FibroMeter^V3G - 0.7296 0.8052

Multi-FibroMeter^V3G - 0.7295

VCTE -

VCTE: vibration controlled transient elastography (by Fibroscan).Significant differences are shown in bold. Secondary objective (Obuchowski index Multi-FibroMeter > Obuchowski index VCTE) is indicated by a green background when reached and by a yellow background when not reached and without significant difference. Red characters indicate a significant gain of multi-FibroMeter vs FibroMeter in the comparison to VCTE.

(22)

Table A6d. Comparison of correctly classified patient rate (%) according to classification metric between Multi-FibroMeters, FibroMeters and VCTE in the 3 populations with VCTE (1746 patients, Table S9).

Population #2 CHC validation #3 non-CHC validation #4 Miscellaneous validation Combined #2 to #4 Rate (%) p vs VCTE^a Rate (%) p vs VCTE Rate (%) p vs VCTE Rate (%) p vs VCTE

FibroMeter^V2G 84.2 0.001 77.1 0.013 75.6 0.234 79.1 0.446

Multi-FibroMeter^V2G 88.3 0.762 76.1 0.024 82.1 0.023 83.0 0.004

VCTE 87.7^b - 70.7 - 77.9 - 80.0 -

p ^c 0.014 - 0.007 - <0.001 - <0.001 -

FibroMeter^V3G 81.7 0.001 70.5 1 72.1 0.003 75.7 <0.001

Multi-FibroMeter^V3G 88.9 0.475 76.6 0.013 80.5 0.173 82.7 0.013

VCTE 87.7 ^b - 70.7 - 77.9 - 80.0 -

p ^c <0.001 - 0.008 - <0.001 - <0.001 -

VCTE: vibration controlled transient elastography. Significant differences are shown in bold. Red characters indicate a significant gain of multi- FibroMeter vs FibroMeter in the comparison with VCTE. Colour codes: accuracy (%) <60, 60-70, 70-80, 80-90, >90

a Paired McNemar test

b Optimism bias

c Paired Cochran test

(23)

Tableau A6e. Comparison of correctly classified patient rate (%) in classification metric between Multi-FibroMeters and VCTE as a function of Metavir fibrosis stages in the 3 combined populations #2 to #4 with VCTE (1746 patients, Table S9).

Metavir fibrosis stage

F0 F1 F2 F3 F4 All F

p ^a 0.007 0.080 0.135 0.091 0.024 0.004

VCTE 13.8 87.7 92.9 83.5 88.1 80.0

p ^a 0.015 0.008 0.088 0.076 <0.001 0.013

a Paired McNemar test between each Multi-FibroMeter and VCTE Colour codes: accuracy (%) <60, 60-70, 70-80, 80-90, >90

Comparison between Multi-FibroMeters is reported in a larger population in Table S4.

(24)

Table A6f. Comparison of correctly classified patient rate (%) according to classification metric between Multi-FibroMeter^V2G and VCTE as a function of Metavir fibrosis stages in each of the three populations #2 to #4 with VCTE (1746 patients, Table S9).

Population Test F0 F1 F2 F3 F4 All F

#2 Multi-FibroMeter^V2G 25.0 88.7 96.3 92.4 84.1 88.3

VCTE^a 16.7 93.1 95.1 84.7 81.8 87.7

p ^b 0.727 0.117 0.774 0.078 0.804 0.762

#3 Multi-FibroMeter^V2G 13.9 96.0 96.1 91.1 70.8 76.1

VCTE 16.5 86.1 90.9 73.3 83.3 70.7

p ^b 0.832 0.003 0.219 0.039 0.508 0.024

#4 Multi-FibroMeter^V2G 35.9 90.4 94.6 85.6 76.5 82.1

VCTE 10.9 82.6 91.4 85.6 96.3 77.9

p ^b <0.001 0.027 0.307 1 <0.001 0.023

Combined #2 to #4 Multi-FibroMeter^V2G 25.1 90.9 95.5 88.3 80.3 83.0

VCTE 13.8 87.7 92.9 83.5 88.1 80.0

p ^b 0.007 0.080 0.135 0.091 0.024 0.004

VCTE: vibration controlled transient elastography (by Fibroscan). Significant differences are shown in bold. Colour codes: accuracy (%) <60, 60-70, 70-80, 80-90, >90.

a Optimism bias. ^b Paired McNemar test

(25)

Tableau A6g. Comparison of correctly classified patient rate (%) in classification metric between FibroMeterfamilyand VCTE as a function of fibrosis classes of classification metric in the three combined populations #2 to #4 with VCTE (1746 patients, Table S9).

Fibrosis class

0/1 1/2 2 3 3/4 4 All

FibroMeter^V2G^a 92.7 71.9 88.0 84.5 73.6 47.8 79.1

CirrhoMeter^V2G 80.4 73.0 88.2 76.9 76.8 83.0 77.9

Multi-FibroMeter^V2G 89.4 72.1 87.1 84.1 89.2 73.3 83.0

FibroMeter^{V3G b} 91.5 59.1 85.1 87.0 71.6 - 75.7

CirrhoMeter^V3G 78.9 71.5 85.9 79.4 66.9 68.9 76.3

Multi-FibroMeter^V3G 86.7 71.6 85.2 84.8 93.3 72.7 82.7

VCTE ^c 84.7 77.4 87.6 75.9 76.7 64.5 80.0

FM^2G: FibroMeter^V2G, CM^2G: CirrhoMeter^V2G, MFM^2G: Multi-FibroMeter^V2G, VCTE: vibration controlled transient elastography (by Fibroscan).

Test with highest accuracy per class is depicted in bold characters. Colour codes: accuracy (%) <60, 60-70, 70-80, 80-90, >90

a Class 1 (64.2%) is not reported since absent in other tests

b Different classification for two classes: F2/3 (accuracy: 64.5%) and no F4

c Optimism bias in population #2

(26)

Table A7. Combined populations included for statistical comparisons of tests.

Population included

Tests available (n) Patients

(n)

Cause of population exclusion Optimism bias in comparison

with FibroMeter family

Test not available in all patients

#1 to #4 11: FibroMeter family, APRI, Fib4, Hepascore, Zeng (= list A)

3809 - None

#1 to #4 6: FibroMeter family 3809 None ^a None

#2 to #4 11: list A 2797 Population #1 ^b None

#1 to #3 12: list A + Fibrotest 2416^c - Fibrotest in population #4

#2 and #3 12: list A + Fibrotest 1461 Population #1 ^b Fibrotest in population #4

#2 to #4 12: list A + VCTE 1746 Population #1 ^b VCTE in population #1

#2 and #3 13: list A + Fibrotest + VCTE 1017^d - VCTE in population #1

Fibrotest in population #4 VCTE: vibration controlled transient elastography (by Fibroscan)

Bold characters depict patients used for statistical comparison of test performance

a Comparison limited to the FibroMeter family

b Exclusion of population #1 for comparison between the FibroMeter family and other tests

c Combined populations #1 to #3 correspond to the maximum number of patients with Fibrotest but this sample was not used due to optimism bias in the comparison between Fibrotest and FibroMeter family in population #1.

d This subgroup corresponds to the maximum number of patients with the maximum number of tests evaluated; this sample was only used in Figure A3.

(27)

Table A8. AUROCs for all classical diagnostic targets and Obuchowski indices for Metavir fibrosis (F) stages of 12 blood tests in the non-CHC validation population #3 (936 patients). Complementary data of Table S1.

AUROC Obuchowski index

F≥1 F≥2 F≥3 F=4 Value Rank

FibroMeter^V2G 0.797 0.829 0.849 0.874 0.782 2

CirrhoMeter^V2G 0.748 0.792 0.855 0.892 0.759 7

Multi-FibroMeter^V2G 0.788 0.823 0.857 0.902 0.782 1

FibroMeter^V3G 0.774 0.814 0.827 0.838 0.762 6

CirrhoMeter^V3G 0.718 0.770 0.829 0.862 0.735 9

Multi-FibroMeter^V3G 0.765 0.807 0.835 0.870 0.763 5

APRI 0.733 0.729 0.710 0.676 0.687 11

Fib4 0.684 0.734 0.767 0.788 0.696 12

Fibrotest 0.731 0.764 0.763 0.809 0.729 10

Hepascore 0.789 0.819 0.849 0.900 0.779 4

Zeng score 0.738 0.789 0.829 0.876 0.746 8

FibroMeter^ALD2G 0.769 0.817 0.872 0.910 0.780 3

Best result per diagnostic target is indicated in bold.

Color codes: AUROC: <0.7, 0.7-0.8, 0.8-0.9, >0.9; Obuchowski index: <0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9

(28)

Table A9. AUROC for cirrhosis and Obuchowski indices of all tests in the CHB (n=152), HIV/CHC (n=444), NAFLD (n=224) and ALD (n=115) validation sub-populations #3 (936 patients). Complementary data of Table S2.

CHB HIV/CHC NAFLD ALD

AUROC

F=4

Obuchowski AUROC F=4

Obuchowski AUROC F=4

Obuchowski

FibroMeter^V2G 0.918 0.789 0.785 0.760 0.836 0.773 0.903 0.758

CirrhoMeter^V2G 0.940 0.768 0.832 0.737 0.857 0.750 0.900 0.772

Multi-FibroMeter^V2G 0.952 0.796 0.834 0.769 0.883 0.777 0.888 0.764

FibroMeter^V3G 0.909 0.781 0.758 0.749 0.793 0.749 0.819 0.715

CirrhoMeter^V3G 0.940 0.761 0.809 0.727 0.808 0.723 0.849 0.738

Multi-FibroMeter^V3G 0.946 0.791 0.800 0.756 0.822 0.744 0.837 0.723

APRI 0.810 0.727 0.678 0.712 0.679 0.680 0.527 0.532

Fib4 0.890 0.731 0.743 0.699 0.691 0.691 0.707 0.625

Fibrotest 0.887 0.767 0.793 0.733 0.697 0.670 - -

Hepascore 0.912 0.781 0.819 0.723 0.920 0.780 0.920 0.780

Zeng score 0.921 0.783 0.790 0.711 0.920 0.785 0.871 0.772

VCTE 0.906 0.746 - - 0.951 0.808 - -

FibroMeter^NAFLD - - - - 0.819 0.714 - -

NAFLD fibrosis score - - - - 0.775 0.673 - -

FibroMeterÂLD2G 0.915 0.758 0.830 0.728 0.949 0.803 0.929â 0.794â

VCTE: vibration controlled transient elastography (by Fibroscan). Color codes: AUROC: <0.7, 0.7-0.8, 0.8-0.9, >0.9; Obuchowski index: <0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9.

a Optimism bias

(29)

Table A10. Diagnostic performance of 11 blood tests in the miscellaneous validation population #4 (1220 patients). Complementary data of Table S3.

AUROC Obuchowski index

F≥1 F≥2 F≥3 F=4 Value Rank

FibroMeter^V2G 0.774 0.832 0.836 0.870 0.778 2

CirrhoMeter^V2G 0.736 0.805 0.838 0.904 0.762 4

Multi-FibroMeter^V2G 0.774 0.839 0.854 0.900 0.789 1

FibroMeter^V3G 0.746 0.822 0.825 0.847 0.761 5

CirrhoMeter^V3G 0.707 0.796 0.829 0.886 0.747 8

Multi-FibroMeter^V3G 0.755 0.827 0.839 0.881 0.774 3

APRI 0.705 0.734 0.756 0.775 0.699 11

Fib4 0.677 0.759 0.807 0.832 0.714 10

Hepascore 0.768 0.783 0.794 0.854 0.751 7

Zeng score 0.704 0.802 0.842 0.876 0.745 9

FibroMeter^ALD2G 0.746 0.800 0.835 0.891 0.761 6

Best result per diagnostic target is indicated in bold.

Color codes: AUROC: <0.7, 0.7-0.8, 0.8-0.9, >0.9; Obuchowski index: <0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9

(30)

Table A11. Diagnostic performance of 11 blood tests^a in the combined populations #2 to #4 (2797 patients). Complementary data of Table S5.

AUROC Obuchowski index Classification

F≥1 F≥2 F≥3 F=4 Value Rank Value (%) Rank

FibroMeter^V2G 0.790 0.824 0.836 0.868 0.780 2 80.2 3

CirrhoMeter^V2G 0.741 0.795 0.836 0.890 0.757 7 79.8 4

Multi-FibroMeter^V2G 0.778 0.824°* 0.849 0.897°* 0.783° 1 84.0* 1

FibroMeter^V3G 0.767 0.811 0.821 0.842 0.763 5 76.8 6

CirrhoMeter^V3G 0.716 0.781 0.820 0.869 0.741 8 78.4 5

Multi-FibroMeter^V3G 0.760 0.812°* 0.832 0.874* 0.768°* 3 83.7* 2

APRI 0.720 0.735 0.743 0.750 0.701 11 - -

Fib4 0.689 0.751 0.786 0.811 0.710 10 - -

Hepascore 0.774 0.792 0.811 0.867 0.761 6 - -

Zeng score 0.717 0.787 0.825 0.862 0.741 8 - -

FibroMeter^ALD2G 0.751 0.800 0.840 0.888 0.764 4 - -

The best result per diagnostic target is indicated in bold. ° depicts a reached ancillary objective criterion (with some exceptions, details in Table A16). * depicts a reached primary objective criterion. Details on p values of pair comparisons are reported in Table 6 for classification and in the Additional materials for scoring (Table A4).Color codes: see Table A8.

a Some blood tests are depicted for ancillary information beyond the ancillary objective (APRI, Fib4, FibroMeter^ALD2G). Fibrotest results are reported in Table A14.

(31)

Table A12. Correlations (Spearman coefficient: rs) of fibrosis tests with Metavir fibrosis (F) stages and area of porto-septal fibrosis in the CHC validation population #2 (641 patients for F, 510 for area) and in validation population #2 to #4 (2797 patients except for Fibrotest: 1461 patients, or Fibroscan: 1746 patients). Complementary data of Table S7.

Population #2 #2 to #4

Metavir F Area of porto-septal fibrosis Both Metavir F

rs Rank rs Rank Overall rank Score (rs) Classification (rs)

FibroMeter^V2G 0.619 2 0.534 3 2 0.638 0.626

CirrhoMeter^V2G 0.579 6 0.499 6 6 0.606 0.591

Multi-FibroMeter^V2G 0.635 1 0.543 2 1 0.650 0.626

FibroMeter^V3G 0.593 5 0.512 5 5 0.606 0.595

CirrhoMeter^V3G 0.549 10 0.480 7 8 0.574 0.558

Multi-FibroMeter^V3G 0.612 3 0.521 4 4 0.619 0.581

APRI 0.507 13 0.452 10 12 0.460 -

Fib4 0.518 12 0.441 12 13 0.505 -

Fibrotest 0.549 9 0.439 13 10 0.530 0.511

Hepascore 0.554 8 0.458 9 8 0.592 -

Zeng score 0.522 11 0.451 11 10 0.580 -

FibroMeter^ALD2G 0.559 7 0.461 8 7 0.614 0.590

VCTE 0.600 4 0.550 1 2 0.582 0.578

Metavir F - - 0.710 - - - -

VCTE: vibration controlled transient elastography (by Fibroscan), rs: Spearman coefficient

The best result per column among tests is indicated in bold. Color codes: correlation with Metavir F: <0.4, 0.4-0.5, 0.5-0.6, >0.6; correlation with area of portal fibrosis: <0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, >0.6

Rank: ex-aequo were ranked with other decimals. Overall rank was determined according to the sum of the 2 composite ranks.

(32)

Table A13. Dynamic sensitivity and reproducibility of fibrosis measurements (liver lesions or score tests): Progression and agreement (ric) between baseline (W0) and final (W96) measurements. Population of 101 patients. Complementary data of Table S8.

Progression Reproducibility

Mean ± SD ^a p ^b ric c

Metavir F 0.1290.783 0.102 0.837

Area of fibrosis (%) 0.2933.016 0.026 0.629

FibroMeter^V2G 0.0320.134 0.020 0.905

CirrhoMeter^V2G 0.0560.185 0.003 0.898

Multi-FibroMeter^V2G 0.0360.112 0.002 0.905

FibroMeter^V3G 0.0300.107 0.006 0.927

CirrhoMeter^V3G 0.0800.148 <0.001 0.922

Multi-FibroMeter^V3G 0.0540.098 <0.001 0.928

APRI 0.3991.049 <0.001 0.667

Fib4 0.9182.010 <0.001 0.616

Fibrotest 0.0160.171 0.338 0.790

Hepascore -0.0020.271 0.941 0.632

Zeng score 0.0040.166 0.827 0.765

FibroMeter^ALD2G 0.0280.289 0.331 0.714

Significant differences are shown in bold. Color codes: ric: <0.7, 0.7-0.8, 0.8-0.9, >0.9.

a Score progression: value W96 - value W0

b Paired Student t test

c Intra-class correlation coefficient

(33)

Table A14. Diagnostic performance of FibroMeter family and Fibrotest in the combined populations #2 and #3 (1461 patients).

AUROC Obuchowski index Classification

F≥1 F≥2 F≥3 F=4 Value Rank Value (%) Rank

FibroMeter^V2G 0.810 0.815 0.829 0.849 0.787 1 80.5 3

Multi-FibroMeter^V2G 0.791 0.813° 0.840 0.881° 0.787° 1 83.8° 2

FibroMeter^V3G 0.793 0.802 0.816 0.828 0.772 3 77.8 4

Multi-FibroMeter^V3G 0.774 0.802° 0.823 0.857° 0.772° 3 84.4° 1

Fibrotest 0.756 0.766 0.782 0.817 0.742 5 39.9 ^a 5

The best result per diagnostic target is indicated in bold. ° depicts a reached ancillary objective criterion (details in Table A16). Details on p values of pair comparisons are reported in the Additionalmaterials (Table A5). Color codes: see Table A8.

a The original method of the classification metric was different from that of other tests; p<0.001 vs each other test.

(34)

Table A15. Blood tests: constitutive biomarkers and availability in populations.

Biomarkers Population (with etiology)

Age Sex Wt AST ALT Plt Bil GGT A2M HA Hpt Apo Ur PI Glu Fer Alb #1 CHC

#2 CHC

#3a CHB

#3b HIV

#3c NAFLD

#3d ALD

#4 Mixed All

FibroMeter^V2G x x - x - x - - x x - - x x - - -  ^a x x x x x x x

CirrhoMeter^V2G x x - x - x - - x x - - x x - - - ^a x x x x x x x

MFM^V2G x x - x x x - - x x - - x x - - - ^a x x x x x x x

FibroMeter^V3G x x - x - x - x x - - - x x - - - ^a x x x x x x x

CirrhoMeter^V3G x x - x - x - x x - - - x x - - - ^a x x x x x x x

MFM^V3G x x - x x x - x x - - - x x - - - ^a x x x x x x x

APRI - - - x - x - - - - - - - - - - -  x x x x x x x

Fib4 x - - x x x - - - - - - - - - - - x x x  x x x x

Fibrotest x x - - - - x x x x x - - -  x x x x - - -

Hepascore x x - - - - x x x x - - - - - -  x x x x x x x

Zeng score x - - - - - - x x x - - - - - - - x x  x x x x x

FibroMeter^NAFLD x - x x x x - - - - - - - x x - - - - -  - - -

NAFLD fibrosis score x - x x x x - - - - - - - - x - x - - - -  - - -

FibroMeter^ALD2G - - - - - - - - x x - - - x - - - x x x x x ^a x x

Tests included (n) 12 8 2 10 5 10 2 6 10 6 1 1 6 7 2 1 1 12 12 12 12 14 11 11 11

MFM: multi-FibroMeter, Wt: weight (or body mass index in NAFLD fibrosis score), Plt: platelets, Bil: bilirubin, GGT: gamma-glutamyl transpeptidase, A2M: alpha2-macroglogulin, HA: hyaluronic acid, Hpt: haptoglobin, Apo: apoA1, Ur: urea, PI: prothrombin index (%), Glu:

glucose, Fer: ferritin, Alb: albumin

x: available, : available in the CLD etiology used for test development in the pivotal study

a Population used for test construction in the present study implying an optimism bias

(35)

Table A16. Summary of all judgement criteria for the Multi-FibroMeter objectives as a function of compared tests in the combined populations of maximum size^a.

Judgment criteria Test compared Criteria fulfilled by Multi-FibroMeter

V2G V3G

Primary objective:

AUROC cirrhosis >

FibroMeter

Yes Yes

Obuchowski index > Yes ^b Yes

AUROC significant F ≥ Yes Yes

Classification metric > Yes Yes

AUROC cirrhosis ≥ CirrhoMeter Yes Yes^b

Ancillary objectives:

AUROC cirrhosis >

Fibrotest

Yes Yes

Obuchowski index > Yes Yes

AUROC significant fibrosis > Yes Yes

AUROC cirrhosis >

Hepascore

Yes No^c

Obuchowski index > Yes No^c

AUROC cirrhosis >

Zeng score

Yes No^c

Obuchowski index > Yes Yes

AUROC cirrhosis 

VCTE

Yes No^d

Obuchowski index > Yes No^c

AUROC significant fibrosis > Yes No^c

VCTE: vibration controlled transient elastography (by Fibroscan). Green, blue, yellow and grey backgrounds indicate respectively that the

criterion was reached, overreached, partially reached (superior value without significant difference) or not reached (inferior value with significant

(36)

difference). Significant differences are shown in bold. Red characters depict a statistical gain for Multi-FibroMeter for the test compared in comparison with FibroMeter or CirrhoMeter. Details on p values of pair comparisons are reported in the Additional material for scoring.

a Combined populations: #1 to #4 for main objective (3809 patients) and #2 to #4 for ancillary objective (2797 patients except for Fibrotest: 1461 or VCTE: 1746) to avoid optimism bias in comparisons.

Yes and no refer to criterion reached or not with the following precisions:

b Borderline significance

c Non-significant superior value of Multi-FibroMeter

d Significant inferior value of Multi-FibroMeter

(37)

Week 0

Week96

Figure A1. Comparison of reproducibility between baseline (week 0) and final (week 96) measurements of two examples of blood test scores among scores with comparable scale listed in Table A13. One had the highest reproducibility (Multi-FibroMeter^V3G) and the other one had the lowest reproducibility (Hepascore).

(38)

0,74 0,76 0,78 0,8 0,82 0,84 0,86 0,88 0,9 0,92

0,68 0,7 0,72 0,74 0,76 0,78 0,8 0,82

Obuchowskiindex CirrhosisAUROC

Figure A2. Comparison of AUROCs for cirrhosis and Obuchowski indices between 13 tests in population #2 (641 patients). Tests are ranked according to increasing Obuchowski index. This graph shows that AUROCs for cirrhosis and Obuchowski indices are globally proportional with one noteworthy exception: VCTE (Fibroscan); Multi-FibroMeter^V2G had the best compromise between the AUROC and the Obuchowski index.

(39)

Figure A3. Correct classification rate as a function of Metavir F of tests with available classification metrics in combined populations #2 and #3 (1017 patients). Optimism bias concerns only VCTE in population #2.