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Keywords: Purpose: ANALI-scores are two prognostic magnetic resonance imaging (MRI)-based scores developed for patients
Magnetic resonance imaging with primary sclerosing cholangitis (PSC). Our study aims to assess the interreader agreement between expert
Prognosis radiologists of the two ANALI-scores and of the radiological parameters they utilize, and to test the prognostic
Radiology
performance of the scores in our population.
Sclerosing cholangitis
Method: Three radiologists evaluated MRIs of 98 PSC-patients from a prospectively collected cohort with median
follow-up of 6.7 years. Each parameter of ANALI-scores was assessed, and the scores were calculated. Interreader
agreement was assessed with intraclass correlation coefficient (ICC). After consensus reading was reached, the
prognostic value of ANALI-scores was assessed with Cox regression, and outcome-free survival rates were
evaluated with Kaplan-Meier estimates.
Results: The ANALI-score without gadolinium had poor to moderate (ICC = 0.56, 95 %CI: 0.42–0.68) and with
gadolinium poor (ICC = 0.30, 95 %CI: 0.16–0.44) agreement. Liver deformity (ICC = 0.28, 95 %CI: 0.13–0.44)
and parenchymal enhancement heterogeneity (ICC = 0.24, 95 %CI: 0.12–0.38) had poor agreement. Portal
hypertension had poor to moderate (ICC = 0.48, 95 %CI: 0.36–0.59) and dilatation of the intrahepatic ducts had
moderate (ICC = 0.64, 95 %CI: 0.54–0.73) agreement. Hazard ratios for liver-related death, transplantation or
cirrhosis decompensation of the ANALI-scores with and without gadolinium were 3.53 (95 %CI: 1.40–8.93) and
2.25 (95 %CI: 1.56–3.24), respectively. Outcome-free survival was better for patients with low ANALI-scores.
Conclusions: The ANALI-scores show poor to moderate agreement, which challenges their usefulness in clinical
practice. They are associated with clinical outcomes, confirming the value of imaging in prognosis of PSC, but
need further multicenter evaluation.
Abbreviations: ALP, Alkaline phosphatase; CI, Confidence interval; GBCA, Gadolinium-based contrast agent; HR, Hazard ratio; ICC, Intraclass correlation coef
ficient; INR, International normalized ratio; IHBD, Intrahepatic bile ducts; MRCP, Magnetic resonance cholangiopancreatography; MRI, Magnetic resonance imaging;
PH, Portal hypertension; PSC, Primary sclerosing cholangitis.
* Corresponding author at: Department of Radiology, Karolinska University Hospital, Hälsovägen 13, 14157, Huddinge, Sweden.
E-mail addresses: aristeidis.grigoriadis@ki.se (A. Grigoriadis), Ringe.Kristina@mh-hannover.de (K.I. Ringe), mats.n.andersson@sll.se (M. Andersson), nikolaos.
kartalis@ki.se (N. Kartalis), annika.bergquist@ki.se (A. Bergquist).
https://doi.org/10.1016/j.ejrad.2021.109884
Received 19 June 2021; Received in revised form 25 July 2021; Accepted 27 July 2021
Available online 31 July 2021
0720-048X/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
A. Grigoriadis et al. European Journal of Radiology 142 (2021) 109884
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A. Grigoriadis et al. European Journal of Radiology 142 (2021) 109884
Table 2 normalized ratio (INR) and alkaline phosphatase (ALP) [13–25]. For
Intraclass correlation coefficient (ICC) with 95% confidence intervals (CI) (in assessment of survival rates, patients were categorized in groups of low
parentheses) of intrahepatic bile duct dilatation, liver deformity, parenchymal and high scores, ≤ 2 and >2 for the score without gadolinium and ≤1
enhancement heterogeneity, presence of portal hypertension and ANALI scores and >1 for the score with gadolinium, respectively. Kaplan-Meier esti
with and without gadolinium. mates were calculated and the curves were compared with log-rank test,
Parameter ICC (95% CI) when applicable. P-value <0.05 was considered significant. STATA
IHBD† dilatation 0.64 (0.54–0.73) v15.1 statistical package was used for statistical analysis.
Liver deformity 0.28 (0.13–0.44)
Parenchymal enhancement heterogeneity 0.24 (0.12–0.38) 3. Results
Portal hypertension 0.48 (0.36–0.59)
ANALI score with gadolinium 0.30 (0.16–0.44)
ANALI score without gadolinium 0.56 (0.42–0.68) 3.1. Clinical characteristics
†
IHBD, intrahepatic bile ducts.
The study population consisted of 98 patients with large duct PSC, 63
(64%) males and the median age at inclusion was 40 years (range
related death, liver transplantation, and cirrhosis decompensation, 20–79) and median duration of PSC till MRI was 7.1 years (range
whichever came first. Univariate Cox proportional hazards regression 0.5–25). During median follow-up of 6.7 years, 19 patients (19%)
analysis was performed to evaluate association between outcomes and developed outcomes. Twelve (12%) patients underwent liver trans
the ANALI scores, MELD score and laboratory parameters. Multivariate plantation (ten patients due to liver decompensation and two due to
analysis with adjustment for age and sex was also performed. Some of high-grade dysplasia), six (6%) patients developed liver decompensa
the variables included in the analyses were tested previously and have tion, and one patient died of end-stage liver disease. Three additional
shown prognostic value. These include bilirubin, albumin, international patients developed hepatobiliary cancer and were still alive at the end of
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A. Grigoriadis et al. European Journal of Radiology 142 (2021) 109884
study period (one cholangiocarcinoma, one gallbladder cancer and one gadolinium. The distribution of the scores in the study population after
hepatocellular carcinoma), but these events were not included as out consensus reading is shown in Supplementary Figs. 1 and 2. Median
comes in survival analysis according to the study definition. MELD score was 6 (range 6–17).
Interreader agreement for each variable individually and for the two Only one patient with ANALI score without gadolinium between
ANALI scores with and without gadolinium are shown in Table 2. The 0 and 2 and no patient with ANALI score with gadolinium 0 developed
ANALI score without gadolinium had poor to moderate interreader outcomes. In the univariate Cox regression analysis, the two ANALI
agreement (ICC = 0.56, 95% CI: 0.42–0.68), whereas the score with scores, MELD score and all laboratory tests were significantly associated
gadolinium had poor agreement (ICC = 0.30, 95% CI: 0.16–0.44) with outcomes and remained significant even after adjusting for sex and
(Figs. 1 and 2). The parameters of the two scores exhibited agreement age (Table 3). The ANALI score without gadolinium demonstrated a
varying from poor to moderate, with parenchymal enhancement het hazard ratio (HR) of 2.25 (95% CI, 1.56–3.24), and the score with
erogeneity having the lowest agreement (ICC = 0.24, poor, 95% CI: gadolinium had a HR of 3.53 (95% CI, 1.40–8.93) in the univariate
0.12–0.38) and dilatation of the intrahepatic ducts the highest (ICC = analysis. The only laboratory parameter with HR higher than the two
0.64, moderate, 95% CI: 0.54–0.73). Liver deformity, which is used in scores was INR with a HR of 6.16 (95% CI, 1.91– 19.89). MELD score had
both scores, had poor agreement (ICC = 0.28, 95% CI: 0.13–0.44), and a HR of 1.54 (95% CI, 1.34– 1.76). Outcome-free survival was signifi
evaluation of portal hypertension had poor to moderate agreement (ICC cantly better for patients with low ANALI scores as shown in the Kaplan-
= 0.48, 95% CI: 0.36–0.59). After consensus reading, the median value Meier estimates in Fig. 3 and in Supplementary Figs. 3 and 4. P-value for
was 2 for the ANALI score without gadolinium and 1 for the score with log-rank test for the score with gadolinium was P = 0.017. Log-rank test
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A. Grigoriadis et al. European Journal of Radiology 142 (2021) 109884
Table 3
Risk estimates for clinical outcomes (liver-related death, liver transplantation or cirrhosis decompensation) of ANALI scores, MELD
score and laboratory parameters.
Parameter HR† (CI 95%) P-value HRadj‡ (CI 95%) P-value
was not performed for the score without gadolinium due to the low definition of IHBD dilatation in the ANALI scores has stringent cut-offs
number of outcomes in the low-score group (n = 1). (≤3 mm, 4 mm and ≥5 mm) which may, at least partly, explain the
poor to moderate agreement found for this parameter. Small differences
4. Discussion in the acquired measurements of ductal diameter may lead to change in
category and, thus, disagreement between readers. IHBD dilatation had
Our study shows that both ANALI scores with and without gadolin the highest agreement and seems to be the most promising. It can be
ium have poor to moderate interreader agreement. Despite disagree hypothesized that a wider range and/or fewer categories may improve
ment between readers, these scores were able to predict clinical agreement. The relatively poor agreement of the individual parameters
outcomes in consensus reader setting. included in the ANALI scores explains the poor agreement of the score
From the four parameters used in the scores, two (liver deformity and with gadolinium and the poor to moderate agreement of the score
parenchymal enhancement heterogeneity) have poor agreement, one without gadolinium. This is more pronounced for the score with gado
(portal hypertension) has poor to moderate agreement and one (IHBD linium, which utilizes two parameters that both show poor agreement,
dilatation) has moderate agreement. Evaluation of liver deformity is namely liver deformity and parenchymal enhancement heterogeneity.
quite subjective since, apart from the more objective calculation of the Poor agreement between readers in the evaluation of MRI of patients
caudate to right lobe ratio, it relies mainly on qualitative findings, such with PSC is well known. The results of our study are in line with two
as nodularity of surface and atrophy. This may explain the poor agree previously performed studies evaluating interreader agreement of MRI/
ment. Similarly, a clear definition is lacking for the parameter paren MRCP examinations in patients with PSC, although these studies did not
chymal enhancement heterogeneity, and its evaluation depends on specifically evaluate the parameters assessed here [8,9]. Altogether, it
reader perception. Portosystemic shunts are easy to assess on imaging can be concluded that evaluation of the MRI/MRCP of patients with PSC
when they are large, but can be hard to identify when only small varices is challenging. Before an imaging parameter can be considered a
are present, especially if no contrast agent is administered. The biomarker suitable for a prognostic model for patients with PSC in
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A. Grigoriadis et al. European Journal of Radiology 142 (2021) 109884
clinical practice, a good interreader agreement has to be established. CRediT authorship contribution statement
Despite the shortcomings of disagreement between readers, these
scores seem useful if consensus between readers can be achieved. We Aristeidis Grigoriadis: Conceptualization, Data curation, Formal
demonstrated that both ANALI scores are significantly associated with analysis, Investigation, Methodology, Project administration, Software,
outcomes. The risk of developing outcome increased by 2.3 times for Supervision, Validation, Visualization, Writing - original draft. Kristina
each incremental increase of the score without gadolinium, and by 3.5 I. Ringe: Conceptualization, Data curation, Formal analysis, Method
times for each incremental increase of the score with gadolinium. Both ology, Supervision, Validation. Mats Andersson: Conceptualization,
scores had a higher HR compared to the MELD score (HR, 1.5). These Data curation, Methodology, Project administration, Validation. Niko
results are similar to those found in the study by Lemoinne et al. [7], laos Kartalis: Conceptualization, Data curation, Formal analysis,
where the HRs of the score with and without gadolinium were 2.9 and Investigation, Methodology, Project administration, Supervision, Vali
2.5, respectively. In our study, contrast agent was administered to all dation. Annika Bergquist: Conceptualization, Data curation, Formal
patients, unlike in the study by Lemoinne et al. [7] where there was a analysis, Investigation, Methodology, Project administration, Supervi
selection who were administered contrast agent (mostly patients with sion, Validation, Visualization, Resources.
more severe disease). This may, at least partly, explain the higher HR of
3.5 for the ANALI score with gadolinium found in our study. Interest Appendix A. Supplementary material
ingly, INR demonstrated the highest HR point estimate (HR, 6.16)
among all variables evaluated. However, confidence intervals of INR HR Supplementary data to this article can be found online at https://doi.
were quite wide (95 %CI, 1.91–19.89), indicating low precision, which org/10.1016/j.ejrad.2021.109884.
may explain this result.
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