Background
Methods
Study design
Populations
Population # | Study name | Patients (n) | Liver biopsy length (mm) | Blood tests | FS | Metavir F prevalence (%) | ||||
---|---|---|---|---|---|---|---|---|---|---|
0 | 1 | 2 | 3 | 4 | ||||||
1 | Metavar 4 | 205 | 23 ± 7 | x | - | 4.4 | 46.3 | 29.8 | 14.1 | 5.4 |
2 | Sniff 17 | 1056 | 21 ± 8 | x | - | 4.4 | 43.5 | 27.0 | 14.0 | 11.2 |
3 | Fibrostar | 458 | 25 ± 8 | x | x | 6.7 | 45.1 | 17.9 | 15.6 | 14.8 |
4 | Vindiag 7 | 349 | 25 ± 9 | x | x | 1.4 | 30.7 | 35.5 | 20.6 | 11.7 |
Diagnostic means
Fibrosis classifications
-
The histological fibrosis stage classification into 5 FM stages (Figure 1a), as determined on a liver specimen by a pathologist. This was the reference for accuracy.
-
The binary diagnosis of significant fibrosis (2 classes, Figure 1b) determined either on liver specimen or by the diagnostic cut-off in non-invasive tests. This is the usual diagnostic target of non-invasive tests and thus served as a comparator for the detailed classifications. Indeed, as it was expected that a more detailed classification would result in decreased accuracy, this binary accuracy allowed for the evaluation of the putative accuracy loss.
-
The fibrosis class classification used in non-invasive tests, for which there are two main types:
-
The classifications previously published for blood tests and Fibroscan. There are 6 classes for FibroMeter2G (Figure 1c) [4], 7 for FibroMeter3G (Figure 1d), 8 for Fibrotest (Figure 1e) [5] and 6 for Fibroscan [6]. The methodology for the development of FibroMeter2G classification has been published [4]: briefly, the percentiles of blood test values were segmented into different intervals according to an absolute majority probability (p ≥ 0.75) for one or several FM stages (their number had to be ≤ 3). We developed an improved fibrosis class classification for FibroMeter3G by using specific thresholds and changing slightly the fibrosis classes (Figure 1d). The optimization consisted in obtaining the best accuracy/precision ratio (number of Metavir fibrosis stages per fibrosis class of the non-invasive test).
-
The classifications derived from the cumulated cut-offs calculated for different binary diagnostic targets, usually significant fibrosis and cirrhosis. Physicians normally use these kinds of classifications for the interpretation of Fibroscan results. This process results in a classification including 3 classes: FM0/1, FM2/3, and FM4. The cut-off for severe fibrosis (FM≥ 3) may also be used, resulting in a classification with 4 classes: FM0/1, FM2, FM3, and FM4. We used the diagnostic cut-offs calculated for HCV in the meta-analysis of Stebbing et al[7], giving the following three classes: < 8.44 kPa: FM0/1, ≥ 8.44 kPa and < 16.14 kPa: FM2/3, ≥ 16.14 kPa: FM4.
Statistics
Results
Liver biopsy
Classification accuracy
Significant fibrosis (FM ≥ 2) | Fibrosis degree a
| p b
| |
---|---|---|---|
Local pathologists |
85.9
|
64.4
| < 10-3
|
Expert pathologist |
91.4
|
82.2
| < 10-3
|
Fibrotest (FT) |
74.2
|
34.3
| < 10-3
|
FibroMeter2G (FM2G) |
75.3
|
76.3
| 0.860 |
FibroMeter3G (FM3G) |
75.5
|
89.0
| < 10-3
|
Comparison b: | p | p | - |
All | < 10-3
| < 10-3
| - |
Local pathologist vs. expert | 0.184 | < 10-3
| - |
Local pathologist vs. FT | 0.003 | < 10-3
| - |
Local pathologist vs. FM2G
| 0.005 | 0.007 | - |
Local pathologist vs. FM3G
| 0.004 | < 10-3
| - |
Expert pathologist vs. FT | < 10-3
| < 10-3
| - |
Expert pathologist vs. FM2G
| < 10-3
| 0.092 | - |
Expert pathologist vs. FM3G
| < 10-3
| 0.126 | - |
FT vs. FM2G
| 0.839 | < 10-3
| - |
FT vs. FM3G
| 0.878 | < 10-3
| - |
FM2G vs. FM3G
| 1 | < 10-3
| - |
Discrepancy
Discrepancy score | Significant discrepancies (%) | |||||||
---|---|---|---|---|---|---|---|---|
Population # | 1a
| 2 | 3 | 4 | 1a
| 2 | 3 | 4 |
Local pathologist | 0.40 ± 0.58 | - | - | - | 4.9 | - | - | - |
Expert pathologist | 0.17 ± 0.38 | - | - | - | 0.0 | - | - | - |
Fibrotest | 0.86 ± 0.77 | 0.84 ± 0.80 | 0.86 ± 0.93 | 0.92 ± 0.82 | 17.2 | 18.2 | 21.3 | 22.2 |
FibroMeter2G
| 0.30 ± 0.58 | 0.30 ± 0.55 | 0.36 ± 0.62 | 0.38 ± 0.61 | 5.6 | 4.6 | 5.7 | 6.0 |
FibroMeter3G
| 0.11 ± 0.33 | 0.14 ± 0.37 | 0.23 ± 0.44 | 0.17 ± 0.40 | 0.5 | 0.7 | 0.9 | 0.9 |
Fibroscan | - | - | 0.50 ± 0.79 | 0.64 ± 0.74 | - | - | 12.9 | 12.3 |
p b
| < 10-3
| < 10-3
| < 10-3
| < 10-3
| < 10-3
| < 10-3
| < 10-3
| < 10-3
|
Blood tests
Classification accuracy
Discrepancy
Elastometry
Classification accuracy
Population #3 | Population #4 | |||||
---|---|---|---|---|---|---|
Significant fibrosis (FM ≥ 2) | Fibrosis class classification | p a
| Significant fibrosis (FM ≥ 2) | Fibrosis class classification | pa
| |
Fibrotest (FT) |
71.3
|
42.5
| < 10-3
|
75.2
|
33.5
| < 10-3
|
FibroMeter2G (FM2G) |
75.2
|
68.7
| 0.001 |
77.7
|
68.2
| < 10-3
|
FibroMeter3G (FM3G) |
74.0
|
77.1
| 0.255 |
76.8
|
83.4
| 0.011 |
Fibroscan (FS) |
73.7
|
64.9
| < 10-3
|
75.2
|
50.7 (52.8)
b
| < 10-3 (< 10-3) |
Comparison a: | p | p | - | p | p | - |
All | 0.644 | < 10-3
| - | < 10-3
| < 10-3
| - |
FT vs. FM2G
| 0.101 | < 10-3
| - | 0.314 | < 10-3
| - |
FT vs. FM3G
| 0.064 | < 10-3
| - | 0.504 | < 10-3
| - |
FT vs. FS | 0.344 | < 10-3
| - | 1 | < 10-3 (< 10-3) | - |
FM2G vs. FM3G
| 1 | < 10-3
| - | 0.549 | < 10-3
| - |
FM2G vs. FS | 0.549 | 0.121 | - | 0.497 | < 10-3 (< 10-3) | - |
FM3G vs. FS | 1 | < 10-3
| - | 0.699 | < 10-3
| - |
Discrepancy
Reflection of histological stages by classifications
Discussion
Liver biopsy
Non-invasive tests
Liver biopsy | FibroMeter | Fibrotest | Fibroscan | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
2G | 3G | |||||||||||||||
Population # | 1 | 1 | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 | 3 | 4 |
Pathologist | Local a
| Expert | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
Metavir FM staging | 52.2/64.4 | 82.2 | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
Binary diagnosis b
| 77.1/85.9 | 91.4 | 75.3 | 78.1* | 75.2 | 77.7 | 75.5 | 77.9* | 74.0 | 76.8 | 74.2 | 74.5* | 71.3 | 75.2 | 73.7 | 75.2 |
Fibrosis class classification c
| - | - | 76.3 | 74.9* | 68.7 | 68.2 | 89.0 | 86.9* | 77.1 | 83.4 | 34.3 | 37.9* | 42.5 | 33.5 | 64.9 | 50.7 |
Discrepancy score d
| 0.55/0.40 | 0.17 | 0.30 | 0.30 | 0.36 | 0.38 | 0.11 | 0.14 | 0.23 | 0.17 | 0.86 | 0.84 | 0.86 | 0.92 | 0.50 | 0.64 |
Significant discrepancy (%) e
| 7.3/4.9 | 0.0 | 5.6 | 4.6 | 5.7 | 6.0 | 0.5 | 0.7 | 0.9 | 0.9 | 17.2 | 18.2 | 21.3 | 22.2 | 12.9 | 12.3 |