Interobserver agreement and diagnostic accuracy of shearwave elastography for the staging of hepatitis C virus‐associated liver fibrosis

Our study aimed to evaluate the technical success rate, interobserver reproducibility, and accuracy of shearwave elastography (SWE) in the staging of hepatitis C virus (HCV)‐associated liver fibrosis.


| INTRODUCTION
Fibrosis and architectural distortion is a common endpoint of chronic liver disease (CLD) of various etiologies. Quantification of liver fibrosis is essential for therapeutic decision-making in these patients. According to current clinical practice guidelines, antiviral treatment is recommended when significant grade fibrosis is detected. After the diagnosis of cirrhosis has been established, regular screenings for complications and surveillance for hepatocellular carcinoma (HCC) must be initiated. 1 Traditionally, liver biopsy has been considered the "gold standard" reference method for the diagnosis of liver fibrosis. However, low patient compliance, prolonged procedure time, and the risk of complications are limiting its use in large populations. 2 Several noninvasive tests have been recently developed to overcome the limitations of liver biopsies.
The shearwave elastography (SWE) techniques are designed to measure liver stiffness (LS), which has been established as a surrogate marker of liver fibrosis. 3 In many institutions, transient elastography (TE) has become the standard method for noninvasive measurement of liver fibrosis. In recent guidelines on the treatment of HCV infection, noninvasive elastography techniques are recommended for the initial assessment of liver, with liver biopsy reserved for cases where there is uncertainty or potential additional etiologies. 4 Point shearwave elastography (pSWE) and two-dimensional shearwave elastography (2D-SWE) combine SWE with conventional B-mode sonograms.
Some studies have already demonstrated that reliability and diagnostic performance of SWE are identical and occasionally even superior to TE for the assessment of liver fibrosis. 5 The S-Shearwave elastography application has recently been made available on Samsung ultrasound (US) scanners. 6 In the present study, we have assessed interobserver reproducibility of S-Shearwave measurements in a group of healthy control subjects and patients with various grades of liver fibrosis.

| Study population
The present study has been approved by the institutional ethics committee of our university, and written informed consent was obtained from all subjects according to the Declaration of Helsinki. Between October 2016 and June 2017, we prospectively enrolled 59 adult subjects, which comprised two cohorts: a group of 10 healthy volunteers without known liver disease and a group of 49 CLD patients, who were referred for a regular follow-up from the outpatient clinic. The most common etiology in the patient cohort was chronic hepatitis C with 33 cases. Clinical and demographic data of the study subjects are summarized in Table 1.

| Liver US and SWE
The Samsung RS80A Prestige US scanner (Samsung Medison, Hongcheon, Korea) equipped with the CA1-7A convex probe was used for all examinations. All pSWE measurements were performed with the S-Shearwave v3.0 application, following the manufacturer's recommended protocol ( Figure 1). Briefly, subjects were fasting for at least 4 hours before the examination. The right lobe of the liver was visualized through an intercostal view. The operator positioned the pSWE measurement box near the centerline of the ultrasound beam, at least 1.5 cm from the liver capsule but not deeper than 6 cm from the skin surface. LS measurements were taken during a breath held at mid-inspiration. The median LS value was reported in m/s. 2D-SWE measurements were performed with the S-Shearwave Imaging application in a subset of the patients. Briefly, a color-coded elastogram of the liver parenchyma was obtained with a convex probe, and the average LS was recorded in circular ROIs, which were approximately 1 cm in diameter ( Figure 2). The ROI was positioned where the reliable measure index (RMI) was the highest based on a color-coded map ( Figure 3).

| Definition of technical success and reliable measurement
From each subject, at least 10 LS data were collected during pSWE. The RMI was automatically assigned by S-Shearwave to all measurements on a scale from 0.0 to 1.0, with 0.

| Interobserver comparison
In all subjects, pSWE was performed by two different observers on the same occasion. In 18 subjects, a 2D-SWE measurement of the LS was also performed by one of the examiners. The observers were blinded to each other's measurements and the patient's prior TE results.

| Statistical analysis
The statistical analysis was completed with the R x64 v3.4.1 statistical package (www.r-project.org). The limit of statistical significance was set at P < .05. The intraclass correlation coefficient (ICC) was calculated for LS values, and the Cohen's kappa statistic was calculated for agreement on the stages of liver fibrosis (METAVIR F0-F4), where prior TE results were used as a reference. Good interobserver agreement was assumed in these tests when coefficient values were ≥0.75.
Diagnostic performance and cut-off LS values of significant liver fibrosis were calculated from measurements from both observers using receiver operating characteristic (ROC) curve analysis. 7 3 | RESULTS

| Comparison of the control and patient groups
The multivariate analysis of variance test was used to compare demographic and physiologic variables between the control and patient groups.
There was no significant difference in average weight (78 kg, 95% confi-

| Technical success rate and reliability of S-Shearwave measurements
The overall technical success rate with pSWE was 95% (112/118), considering all cases evaluated by the two examiners. In 4 patients F I G U R E 2 Example on a 2D-SWE measurement with the S-Shearwave imaging application. A color-coded map of liver elasticity is obtained, and the average stiffness value is measured in the circular region of interest selected by the operator. 2D-SWE, two-dimensional shearwave elastography F I G U R E 3 A color-coded map of the RMI is used for the ROI selection during 2D-SWE. The measurement ROI (as shown in Figure 2) is preferably placed by the operator at an area where the signal-to-noise ratio is the highest (red color) according to the RMI map. 2D-SWE, two-dimensional shearwave elastography; RMI, reliable measure index; ROI, region of interest (6.7%, 4/59), either one (2/59) or both examiners (2/59) failed to collect at least five valid data points; these were excluded from further analysis (  (Figure 4).    Table 2). The post hoc power calculation indicated that F0-F1 vs F2 classification had greater than 20% type II error rate, otherwise the size of the cohort was sufficient to achieve a minimum of 80% power in all of the ROC classifications.

| DISCUSSION
Morphological imaging techniques, such as B-mode US and computed tomography, have low sensitivity for diagnosing liver fibrosis. These modalities can only diagnose the cirrhotic stage when overt signs of architectural distortion and portal hypertension are present. 9 Other methods such as magnetic resonance elastography are only applicable to preselected patient groups. 10 According to recent guidelines, noninvasive markers including elastography are recommended for the initial assessment of liver fibrosis in both HBV-and HCV-associated liver diseases, while a liver biopsy is only preferred in selected cases, where there is uncertainty or potential additional etiologies. 4,11 SWE, including pSWE and 2D-SWE, are relatively new techniques, which can be performed on any patient during a routine liver US examination. 12 In our opinion, SWE arguably has the potential to become a universally accepted method for the assessment and follow-up of liver fibrosis.
Therefore, SWE can be easily integrated into HCC surveillance protocols. Notably, in two cases, a tumor was also found during the elastography scan, while in an additional case the LS measurement was successful even in the presence of a significant amount of ascites.
Although the operating principle is similar for all SWE systems, the diagnostic accuracy and cut-off values may be different based on the manufacturer. 13 Considering the potentially large number of operators, validation of these applications is essential to maintain diagnostic performance. There was no technically failed measurements in the control group, which highlights the straightforward operation of S-Shearwave.
In agreement with current guidelines, we acquired at least 10 data points in each subject. 3 Each of the data points was tagged with a signalto-noise indicator RMI. This is calculated from the wave equation residuals and shear wave magnitude by the S-Shearwave application. 14 The decreased signal-to-noise ratio results in low RMI reading. In our experience, RMI has been useful to identify a subset of cases where pSWE is technically challenging, and additional data points need to be collected for reliable measurement. The cause of technical failure in two cases was that elderly patients did not tolerate breath holds. Previous studies have found similar technical success rate with other pSWE scanners. 15,16 A prior study reported one failed (3%) and two unreliable measurements (6%) in 33 subjects examined with S-Shearwave. 6 The authors also  18,19 One previous publication has also reported an excellent interobserver agreement (ICC > 0.9) in a smaller patient group with the S-Shearwave application. 6 The intermethod agreement between pSWE and 2D-SWE (ICC = 0.91) was also excellent, although the relatively low number of subjects limits the power of the analysis.
TE is accepted as a surrogate of liver biopsy for the diagnosis of liver fibrosis according to the international guidelines on the diagnosis and treatment of chronic hepatitis. 1-3 Therefore it is quite reassuring that S-Shearwave elastography showed a high degree of correlation Our study has several limitations. Firstly, fibrosis grade in the patient group was estimated by TE, and liver biopsy was not available for comparison with pSWE. Our study design is still sound, as TE is a wellestablished surrogate of liver biopsy for grading fibrosis according to current clinical protocols. Patients could also be spared from unnecessary risk of complication from a liver biopsy. Secondly, the number of subjects was relatively small compared to larger multicenter studies.
Also, high grades of fibrosis (F3 and F4) were overrepresented among the patients. Therefore, investigation of larger cohorts of patients with a more uniform clinical background is necessary to formulate comprehensive diagnostic recommendations for S-Shearwave.
In conclusion, S-Shearwave elastography utilizes a user-friendly quality index the RMI for the selection of reliable LS measurements.
Both interobserver agreement intermethod reproducibility was excellent with S-Shearwave, and the method showed very good overall performance in the staging of liver fibrosis.