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Received: 10 May 2016    Accepted: 10 August 2016

DOI: 10.1111/jvh.12617

ORIGINAL ARTICLE

Classification and regression tree analysis of acute-­on-­chronic

hepatitis B liver failure: Seeing the forest for the trees

K.-Q. Shi1,2  | Y.-Y. Zhou3 | H.-D. Yan4 | H. Li5 | F.-L. Wu1,2 | Y.-Y. Xie6 | 

M. Braddock7 | X.-Y. Lin6 | M.-H. Zheng1,2

1
Department of Hepatology, Liver Research
Center, The First Affiliated Hospital of Summary
Wenzhou Medical University, Wenzhou, At present, there is no ideal model for predicting the short-­term outcome of patients
China
2
with acute-­on-­chronic hepatitis B liver failure (ACHBLF). This study aimed to establish
Institute of Hepatology, Wenzhou Medical
University, Wenzhou, China and validate a prognostic model by using the classification and regression tree (CART)
3
Department of Cardiology, Jinhua analysis. A total of 1047 patients from two separate medical centres with suspected
Municipal Hospital, Jinhua, China
ACHBLF were screened in the study, which were recognized as derivation cohort and
4
Department of Infectious Diseases, Ningbo
No. 2 Hospital, Ningbo, China validation cohort, respectively. CART analysis was applied to predict the 3-­month
5
Department of Intensive Care Unit, Tianjin mortality of patients with ACHBLF. The accuracy of the CART model was tested using
Infectious Disease Hospital, Tianjin, China. the area under the receiver operating characteristic curve, which was compared with
6
Department of Clinical Laboratory, The
the model for end-­stage liver disease (MELD) score and a new logistic regression
First Affiliated Hospital of Wenzhou Medical
University, Wenzhou, China model. CART analysis identified four variables as prognostic factors of ACHBLF: total
7
Global Medicines bilirubin, age, serum sodium and INR, and three distinct risk groups: low risk (4.2%),
Development, AstraZeneca R&D,
Loughborough, UK
intermediate risk (30.2%-­53.2%) and high risk (81.4%-­96.9%). The new logistic regres-
sion model was constructed with four independent factors, including age, total biliru-
Correspondence
Ming-Hua Zheng, Department of
bin, serum sodium and prothrombin activity by multivariate logistic regression analysis.
Hepatology, Liver Research Center, The The performances of the CART model (0.896), similar to the logistic regression model
First Affiliated Hospital of Wenzhou
Medical University; Institute of Hepatology,
(0.914, P=.382), exceeded that of MELD score (0.667, P<.001). The results were con-
Wenzhou Medical University, Wenzhou, firmed in the validation cohort. We have developed and validated a novel CART model
China.
Email: zhengmh@wmu.edu.cn
superior to MELD for predicting three-­month mortality of patients with ACHBLF.
Xiang-Yang Lin, Department of Clinical Thus, the CART model could facilitate medical decision-­making and provide clinicians
Laboratory, the First Affiliated Hospital of
Wenzhou Medical University; Wenzhou, China.
with a validated practical bedside tool for ACHBLF risk stratification.
Email: linxy1968@126.com
KEYWORDS
Funding
acute-on-chronic hepatitis B liver failure, classification and regression tree, cohort study, model
This work was supported by grants from
National Natural Science Foundation of China for end-stage liver disease, prognostic prediction
(81500665), Natural Science Foundation of
Zhejiang Province (LY16H160047), Scientific
Research Foundation of Wenzhou (Y2013073
and 2016Y0031) and Project of New Century
551 Talent Nurturing in Wenzhou , and High
Level Creative Talents from Department of
Public Health in Zhejiang Province.

Abbreviations: ACHBLF, acute-on-chronic hepatitis B liver failure; ACLF, acute-on-chronic liver failure; APASL, Asian Pacific Association for the Study of the Liver; auROC, area under the re-
ceiver operating characteristic curve; CART, classification and regression tree; CI, confidence interval; HBV, hepatitis B virus; LRM, logistic regression model; MELD, model for end-stage liver
disease; OR, odds ratio; PTA, prothrombin activity; TBil, total bilirubin.

Co-first author: Ke-Qing Shi, Yao-Yao Zhou.

J Viral Hepat 2016; 1–9 wileyonlinelibrary.com/journal/jvh © 2016 John Wiley & Sons Ltd  |  1
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2       SHI
1 |  INTRODUCTION
Hepatitis B virus (HBV) infection is recognized as a global health
problem and may lead to cirrhosis and hepatocellular carcinoma thus
increasing the burden of liver-­related morbidity and mortality. In
the light of the Asian Pacific Association for the Study of the Liver
(APASL), acute-­on-­chronic liver failure (ACLF) is now recognized as a
life-­threatening condition with acute hepatic deterioration of previ-
ously well-­compensated chronic liver disease and is associated with
short-­term mortality of 50%-­90% as a result of irreversible multisys-
tem organ failure.1,2 In China, acute-­on-­chronic hepatitis B liver failure
(ACHBLF) accounts for 85% of the hepatitis-­induced ACLF because
of the high prevalence of HBV infection.3,4 In general, nucleoside an-
alogue therapy and supportive treatment failed to show significant
improvement and the prognosis patients with the disease remains
poor. Liver transplantation is the definitive treatment for ACHBLF;
however, due to the shortage of donor livers, there is an urgent need
for a robust prognostic model for better diagnosis of ACHBLF and the
necessary risk stratification of patients which is required for referral to
transplantation.
Currently, the model of end-­stage liver disease (MELD) score is a
well-­accepted prognostic model and is applicable across a broad spec-
trum of liver disease including ACHBLF. MELD assists in the assess-
ment of residual liver function and prediction of short-­term mortality
and has been applied extensively for the allocation of donor livers
worldwide.5 However, MELD scores alone have failed to predict ac-
curate prognosis and their suitability as prognostic indicators remains
6
controversial.
To further increase the accuracy and accessibility of predic-
tion, we have established a user-­friendly prognostic model using the
F I G U R E   1   A flow diagram of study participants included in the study
et  al
classification and regression tree (CART) analysis. The CART analysis is a
nonparametric and nonlinear approach based on recursive partitioning
analysis. It is an innovative decision tree algorithm in which several ‘pre-
dictor’ variables are crucial to identify patients at different levels of risk
through the progressive binary splits. Due to its ease of implementation,
CART analysis has been utilized to develop prediction models in various
medical fields to enable better clinical decision-­making.7-9 To date, this
method had not been used in the risk assessment of ACHBLF patients.
In this study, we sought to develop a simple and accurate predic-
tion model for stratifying ACHBLF patients by utilizing CART analysis.
Furthermore, the accuracy of the novel model in predicting 3-­month
mortality would be tested in an independent cohort, which is com-
pared with MELD scores and a new logistic regression model (LRM).
The results of this study will further facilitate the risk assessment and
the individualized management of ACHBLF patients.
2 | METHODS
2.1 | Study design
Medical records from three separate medical centres with the
same medical record systems were retrieved from January 2007 to
December 2015 and designated as a derivation cohort and a vali-
dation cohort, respectively (derivation cohort: the First Affiliated
Hospital of Wenzhou Medical University; validation cohort: Ningbo
No. 2 Hospital and Tianjin Infectious Disease Hospital). A total of
1047 patients with suspected ACHBLF were enrolled in the study.
After exclusion of those who did not meet the inclusion criteria, 777
individuals (563 in the derivation cohort and 214 in the validation co-
hort) were finally included (Figure 1).
SHI et  al
The start date of the follow-­up was the date of diagnosis of
ACHBLF. All the patients were followed up for at least 3 months. The
patients who received liver transplantation within 3 months were con-
sidered as dead and more than 3 months as survival. Informed consent
was obtained from each included patient. The study was approved
by the Ethics Committee of the First Affiliated Hospital of Wenzhou
Medical University, Ningbo No. 2 Hospital and Tianjin Infectious
Disease Hospital, and performed according to Standards for the
Reporting of Diagnostic Accuracy Studies. The study was registered in
Chinese Clinical Trial Registry (ChiCTR-­OCH-­09000611).
2.2 | CART analysis
The CART analysis searched for the split on the variable that will parti-
tion the data into two homogenous groups—a group of mostly ‘1s’ (peo-
ple who died) and a group of mostly ‘0s’ (people who survival). Having
derived the best split for every variable, the CART algorithm parti-
tioned the data using the best overall split among the best splits and
assigned a predicted class to each subgroup. CART repeated this same
process on each predictor in the model, identifying the best split by
iteratively testing all possible splits and settling on the split that pro-
duced the greatest reduction in impurity. CART proceeded recursively
in this fashion until prespecified stopping criteria were reached and ex-
amples of stopping criteria included creating a prespecified number of
nodes, or reaching a point at which no further reduction in node impu-
rity is possible. Allowing the algorithm to proceed indefinitely enabled
the model to identify splits that were completely or nearly completely
homogenous. In the study, the CART analysis was applied to predict
the 3-­month mortality of patients with ACHBLF. As we have reported
in a previous study, the terminal subgroups were most homogeneous
with respect to the probability of mortality.10 Patients with ACHBLF at
low, intermediate and high mortality risk were identified according to
the mortality rates of subgroups. Mortality rates for these risk groups
and the odds ratios (ORs) and 95% confidence interval (CI) between
risk groups were also determined.
2.3 | Construction of the LRM
As we previously reported, we performed univariate logistic regression
analysis for determining the association of clinical characteristics and
laboratory parameters with prognosis in the derivation cohort.11,12
Then, those covariables with univariate significance (P<.05) were in-
cluded in a multivariate logistic regression analysis to identify inde-
pendent predictors for the prognosis of the patients with ACHBLF.
For this analysis, the conditional probabilities for stepwise entry and
removal of a factor were .05 and .10, respectively. Based on the re-
sults of multiple logistic regression analysis, LRM was developed.
Odds ratios (OR) and 95% confidence interval (CI) were calculated.
2.4 | CART model validation and comparison
The ability of the derived tree to stratify patients with ACHBLF into
different risks of mortality was tested in the independent validation
|
      3
cohort. The patients from the validation cohort were allocated to sub-
groups using the flow chart of the derived CART tree. The patients at
low, intermediate and high risk for 3-­month mortality were identified
and the OR and 95% CI between risk groups were determined. To
assess model calibration, the correlation between the model deriva-
tion and the validation data set was also calculated. To validate the
model further, we compared its performance with that of LRM and
MELD score using the area under the receiver operating characteristic
curve (auROC) in both cohorts. MELD score was calculated accord-
ing to the modified Malinchoc formula: R=9.57×ln(creatinine [mg/
dL])+3.78×ln(bilirubin [mg/dL])+11.2×ln(INR)+6.43.
2.5 | Statistical analysis
Continuous variables were expressed by mean ± standard deviation
(SD); the Mann-­Whitney U test and the chi-­square test were used to
compare continuous and categorical variables, respectively. CART anal-
ysis was performed using data mining software Clementine version 12.0
(SPSS Inc, Chicago, IL). Additional statistical analysis was performed in
SPSS 13.0 software (SPSS Inc, Chicago, IL, USA). ROC curve analysis
was computed using MedCalc 10.0 software (Mariakerke, Belgium).
3 | RESULTS
3.1 | Baseline characteristics of patients in the
derivation and validation cohorts
The baseline characteristics of the two cohorts of patients are listed
in Table 1. The condition of the patients in the training cohort was
confirmed in the external validation cohort. There were 23 patients
in training cohort (18 patients within 3 months) and 11 patients in
validation cohort (eight patients within 3 months) received liver trans-
plantation, respectively. Table 2 shows characteristics of the deriva-
tion and validation cohorts, stratified by mortality.
3.2 | CART analysis
Ten variables which were significant in univariate logistic regression
analysis were evaluated in the CART analysis. In the CART model,
TBil was identified as the variable of initial split with an optimal
cut-­off value of 11.51 mg/dL. Among patients with TBil higher than
11.51 mg/dL, age was selected as the variable of second split at a dis-
crimination level of 38.5 years (y). When age >38.5 years, the next
best predictor of ACHBLF was serum sodium with an optimal cut-­off
of 126.5 mmol/L. For the node with patients having a TBil level of
greater than 11.51 mg/dL, age >38.5 years and serum sodium level
of higher than 126.5 mmol/L, INR was selected as additional sig-
nificant variable, dichotomized at a level of 2.82. Any additional risk
nodes involving additional variables could not be generated to offer
incremental risk discrimination. Therefore, a total of five subgroups
of patients were produced by four predictive variables selected in
this CART analysis: subgroup 1 (TBil ≤ 11.51 mg/dl), subgroup 2 (TBil
>11.51 mg/dL and age ≤38.5 years), subgroup 3 (TBil >11.51 mg/
 |
4       SHI et  al

T A B L E   1   Baseline characteristics of the

Derivation cohort Validation cohort
derivation and validation cohorts
Variable (n=563) (n=214) P value

Clinical parameters
Age (years) 46.8±14.0 45.1±14.0 .661
BMI (kg/m2) 22.4±3.3 22.6±3.9 .028
Male gender (%) 443 (78.7%) 167 (78.0%) .844
Liver cirrhosis (%) 263 (46.7%) 108 (50.5%) .349
Hepatorenal syndrome (%) 37 (6.6%) 13 (6.1%) .801
Infection (%) 92 (16.3%) 36 (16.8%) .872
HBeAg (%) 303 (58.6%) 110 (51.4%) .546
Laboratory parameters
Haemoglobin (g/L) 112.4±19.8 127.6 ±22.1 .132
9
Platelet (10 /L) 101.5±56.5 100.1±48.9 .026
Total bilirubin (μmol/L) 18.4±9.4 16.9±8.1 .004
Albumin (g/L) 29.9±5.7 31.4±5.6 .564
ALT (U/L) 187.7±445.5 659.2±692.0 <.001
AST (U/L) 164.9±291.3 516.4±558.8 <.001
Alkaline phosphatase (U/L) 138.0±54.0 157.6±53.0 .649
γ-­GT(U/L) 90.7±71.4 136.1±134.7 <.001
Creatinine (μmol/L) 0.86±0.53 1.54±1.52 <.001
Serum sodium (mmol/L) 132.6±6.7 131.4±7.1 .016
AFP (μg/L) 183.0±322.0 226.8±583.8 <.001
PT (s) 30.6±10.2 30.1±9.7 .932
PTA (%) 27.9±9.1 22.5± 8.8 .852
INR 2.9±1.56 2.8±1.00 .247
log (HBV DNA) 5.47± 1.56 5.68±1.73 <.001
Scoring system
MELD score 25.6±7.0 29.3±7.8 .044

BMI, body mass index; ALT, alanine aminotranferase; AST, aspartate aminotranferase; γ-­GT, γ-­glutamyl
transferase; AFP, α-­fetoprotein; HBeAg, hepatitis B e antigen; PT, prothrombin time; PTA, prothrombin
time activity; INR, international normalized ratio; MELD, model for end-­stage liver disease.

dL, age >38.5 years, and serum sodium ≤126.5 mmol/L), subgroup 4
(TBil >11.51 mg/dL, age >38.5 years, serum sodium >126.5 mmol/L,
and INR ≤2.82) and subgroup 5 (TBil >11.51 mg/dL, age >38.5 years,
serum sodium >126.5 mmol/L and INR >2.82) (Figure 2).
The probabilities of 3-­month mortality in the five subgroups were
highly distinct. Patients were stratified into three risk levels: a low-­risk
group (subgroup 1) with mortality rate of 4.2%, an intermediate-­risk
group (subgroup 2 and subgroup 4) with the mortality rate ranging from
30.2% to 53.2% and a high-­risk group (subgroup 3 and subgroup 5) with
mortality rate ranging from 81.4% to 96.9%. Subjects in the intermediate-­
risk and high-­risk groups had 1.68-­fold (95% CI: 1.48-­1.91, P<.001) and
10.74-­fold (95% CI: 6.51-­17.71, P<.001) increased rates of mortality, re-
spectively, compared with those in the low-­risk group (Table 3).
3.3 | CART tree validation and comparison
The decision tree generated by CART analysis was validated for its
ability to risk-­stratify patients in the validation cohort of 214 subjects,
which was independent of the model building data set. Each patient
was allocated to subgroups according to flow chart of the derived
CART tree. The rates of mortality in each subgroup are shown in Fig.
S1, which were closely correlated with those in the model building
data set (r2=.966) (Figure 3). This CART tree was also able to strat-
ify patients in the validation cohort into high, intermediate and low
risk. Subjects in the intermediate-­risk and high-­risk groups had 1.31-­
fold (95% CI: 1.14-­1.51, P<.001) and 6.62-­fold (95% CI: 3.61-­12.13,
P<.001) increased rates of mortality, respectively, compared with
those in the low-­risk group, which were similar to those of the deriva-
tion cohort (Table 3).
3.4 | Construction of the LRM
To identify independent predictors of mortality, the univariate and
multivariate logistic regression analyses were performed in the train-
ing cohort (Table 4). In univariate logistic regression analysis, we
found that age, gender, TBil, γ-­GT, creatinine, serum sodium, PT, PTA,
SHI et  al |
      5

T A B L E   2   Baseline characteristics of the derivation and validation cohorts, stratified by mortality

Derivation cohort (n=563) Validation cohort (n=214)

Variables Survival (n=327) Death (n=236) P value Survival (n=138) Death (n=76) P value

Clinical parameters
Age (years) 42.5±13.6 52.7±12.4 .106 40.0±12.6 54.4±11.7 .527
2
BMI (kg/m ) 22.5±3.2 22.3±3.4 .917 22.3±4.1 23.1±3.6 .592
Male gender (%) 268 (82.0%) 175 (74.2%) .026 108 (78.3%) 59 (77.6%) .915
Liver cirrhosis (%) 146 (44.6%) 117 (49.6%) .248 68 (49.3%) 40 (52.3%) .638
Hepatorenal syndrome 17 (5.2%) 20 (8.5%) .122 14 (10.1%) 9 (11.8%) .701
(%)
Infection (%) 48 (14.7%) 44 (18.6%) .209 17 (12.3%) 19 (25.0%) .018
HBeAg (%) 168 (51.4%) 135 (57.2%) .171 65 (47.1%) 45 (59.2%) .090
Laboratory parameters
Haemoglobin (g/L) 112.8±18.8 111.7± 21.1 .016 129.6±21.4 123.9±23.0 .634
Platelet (109/L) 103.7±52.5 98.4±61.6 .166 103.8±48.6 93.4±49.0 .271
Total bilirubin (μmol/L) 13.9±5.9 24.7±9.7 .088 13.7±5.6 22.6±8.9 <.001
Albumin (g/L) 30.2±6.0 29.4±5.3 <.001 31.8±6.0 30.8±4.7 .051
ALT (U/L) 209.2±515.0 157.9±324.3 .003 694.5±704.6 595.0±668.3 .293
AST (U/L) 156.0±303.0 177.1±274.5 .773 523.4±592.6 503.8±495.0 .127
Alkaline phosphatase 135.9±53.2 140.5±55.0 .188 148.3±48.7 174.9±56.6 .375
(U/L)
γ-­GT(U/L) 99.8±80.4 80.0±57.7 .025 134.4±119.0 139.3±160.2 .665
Creatinine (μmol/L) 0.82±0.56 0.93±0.49 .102 1.52±1.35 1.58±1.81 .665
Serum sodium 135.1±4.8 129.2±7.4 <.001 133.0±6.0 128.4±8.0 <.001
(mmol/L)
AFP (μg/L) 213.6±353.4 140.7±267.5 .031 278.4±561.0 245.0±628.0 .550
PT (s) 29.2±9.8 32.6±10.5 .040 26.6±5.5 36.5±12.2 <.001
PTA (%) 29.5±8.7 25.8±9.1 .151 25.9±8.2 16.2±5.8 <.001
INR 2.70±1.70 3.12±1.31 .157 2.43±0.70 3.47±1.14 <.001
log (HBV DNA) 5.52±1.55 5.41±1.58 .088 5.62±1.71 5.79±1.77 .676
Scoring system
MELD score 23.5±6.3 28.6±6.8 0.017 27.6±7.2 32.2± 8.0 .569

BMI, body mass index; ALT, alanine aminotranferase; AST, aspartate aminotranferase; γ-­GT, γ-­glutamyl transferase; AFP, α-­fetoprotein; PT, prothrombin
time; PTA, prothrombin time activity; INR, international normalized ratio; MELD, model for end-­stage liver disease.

AFP and INR were significantly associated with 3-­month mortality (all
P<.05). The above variables with univariate significance were then
entered into the multivariate logistic regression analyses. By taking
into consideration the relative points one by one, age (OR=1.057,
95% CI: 1.029-­1.085, P<.001), TBil (OR=1.201, 95% CI: 1.134-­1.272,
P<.001), serum sodium (OR=0.919, 95% CI: 0.863-­0.978, P=.008) and
PTA (OR=0.958, 95% CI: 0.939-­0.978, P<.001) were found to be in-
dependent predictors.
(95% CI: 0.878-­0.928). In the same data set, LRM had a similar ac-
curacy, with auROC of 0.894 (95% CI: 0.865-­0.918, P=.382); MELD
score had an auROC of 0.738 (95% CI: 0.699-­0.774), which was signif-
icantly lower than that of the CART tree (P<.001) (Figure 3A, Table 5).
In the validation cohort, CART tree and LRM also showed an excel-
lent predictive accuracy, with auROC of 0.896 (95% CI: 0.847-­0.934)
and 0.914 (95% CI: 0.868-­0.948, P=.4237), which was significantly
higher than that of MELD score (0.667, 95% CI: 0.599-­0.729, P<.001)
(Figure 3B, Table 5).

3.5 | Comparison between the CART tree and

other models
The predictive power for 3-­month mortality of ACHBLF between
CART tree, LRM and MELD score was compared (Figure 3). The per-
formance of the CART analysis was high, with an auROC of 0.905
4 | DISCUSSION
Owing to the evolution and the unpredictable outcome of rapidly pro-
gressive liver failure, accurate prediction for short-­term prognosis of
 |
6       SHI et  al

F I G U R E   2   Predictors of ACHBLF
and risk stratification for the derivation
cohort. Terminal subgroups of patients
discriminated by the analysis were
numbered from one to five. TBil, total
bilirubin; INR, international normalized
ratio

T A B L E   3   Mortality between risk groups

Derivation cohort Validation cohort

No. of No. of
Risk group subjects (%) Mortality (%) OR (95% CI) P value subjects (%) Mortality (%) OR (95% CI) P value

Low risk 211 (37.5) 9 (4.2) Reference 77 (36.0) 3 (3.9) Reference

Intermediate risk 195 (34.6) 84 (43.1) 1.68 (1.48-­1.91) <.001 75 (35.0) 20 (26.7) 1.31 (1.14-­1.51) <.001
High risk 157 (27.9) 143 (91.1) 10.74 (6.51-­17.71) <.001 62 (29.0) 53 (85.5) 6.62 (3.61-­12.13) <.001
Total 563 (100) 236 (41.9) 1.65 (1.53-­1.78) <.001 214 (100) 76 (35.5) 1.49 (1.34-­1.66) <.001

CI, confidence interval; OR, odds ratio.

ACHBLF patients is very important to select appropriate management
strategies for these patients. In recent years, several prognostic mod-
els have been developed for risk stratification of chronic liver disease.
The MELD scoring system was initially constructed by the Mayo Clinic
team to predict the prognosis of portal hypertension patients follow-
ing transjugular intrahepatic portosystemic shunt.13 Compared with
the Child-­Pugh score, it was more efficient and objective in predictive
survival in patients with chronic hepatitis and subsequently validated
to facilitate allocation of donor livers worldwide.14 However, MELD
scores may still not be an ideal acute-­stage indicator for ACHBLF
6
patients.
In the current study, we established a new LRM that integrates
age, TBil, serum sodium and PTA as independent prognostic factors
for 3-­month mortality. The forecast accuracy of this regression equa-
tion established in this study was 89.4% and 91.4% in the derivation
cohort and validation cohort, respectively. Notably, we further found
that this prognostic model was of a greater prognostic value than that
of the MELD scoring model. In addition to LRM, we also established
and validated a CART approach to predict the short-­term prognosis
of ACHBLF patients. The CART method identified four potential vari-
ables which are TBil, age, serum sodium and INR, as significant pre-
dictors of overall survival for ACHBLF patients. In a simple two-­ to
four-­step process, these variables permit identification of individuals
with low, intermediate or high risk for mortality.
It is well accepted that the hallmark of liver manifestation of ACLF
is hyperbilirubinaemia and coagulopathy.15 In the present study, TBil
SHI et  al |
      7

F I G U R E   3   ROC analysis of the

predictive accuracy of CART model, LRM
and MELD score to predict 3-­mo mortality
of acute-­on-­chronic hepatitis B liver failure
in derivation cohort (A) and validation
cohort (B). CART, classification and
regression tree; LRM, logistic regression
model; MELD, model of end-­stage liver
disease

F I G U R E   4   Consensus analysis for

derivation cohort and validation cohort:
subgroup-­stratified comparison of the
ACHBLF rate. The rate of ACHBLF in
each subgroup was plotted. The x-­axis
represents the model building, and the y-­
axis represents the validation data sets

level and INR were positively associated with the risk of mortality.
The results of our investigation are concordant with previous studies
which reported that TBil level and high INR are independent prog-
nostic factors for ACLF. Several studies have suggested age being
positively associated with mortality of patients with liver failure,
which is consistent with our finding that older patients had a worse
2,11
prognosis. Some lines of evidence suggest that patients awaiting
liver transplantation with low serum sodium levels were more likely
to have a poor prognosis.16,17 Generally, hyponatraemia is a prognos-
tic marker of patients with liver failure. Accordingly, comprehensive
serum sodium and a MELD score, named as MELD to serum sodium
ratio (MESO), were interpreted to provide a more accurate predictive
approach, which was superior to the MELD score in predicting patient
short-­and long-­term mortality.18,19
Compared with traditional multivariate modelling methods, there
are several strengths in terms of the CART analysis. First, CART anal-
ysis can handle highly skewed data and uncover complex interactions
among variables instead of much input or categorization of the data.
It yields a easily viewed decision tree composed of progressive binary
splits, which is easy to interpret and may be applied at the bedside even
when computer access or a pocket digital assistant is not available.20
Secondly, the accuracy of this model is superior to MELD or comparable
to that of the more complicated model derived from logistic regression.
Recently, some score systems based on organ function, including CLIF
Consortium ACLF (CLIF-­C ACLF)21 score, Chronic Liver Failure-­SOFA
score (CLIF-­SOFAs),22 sequential organ failure assessment (SOFA)23
and acute physiology and chronic health evaluation (APACHE II)24 were
developed for predicting the mortality of ACLF or ACHBLF. These mod-
els could improve the prediction accuracy of the MELD score; how-
ever, they are so complex that hampers their clinical use. Thus, CART
model seems to be a simple robust tool with good discriminative ability.
Thirdly, this model could aid risk stratification and management of pa-
tients hospitalized with ACHBLF. Higher level monitoring and earlier,
more intensive treatment program including transplantation may give
priority to patients at higher risk, while patients estimated to be at
lower risk may be reassured other than over-­treatment.
However, the current analysis has some limitations. First, the
CART analysis is exploratory and not based on the probabilistic
 |
8       SHI et  al

T A B L E   4   Univariate and multivariate Cox proportional hazards regression analysis of the associations between mortality and variables in
the derivation cohort

Univariate analysis Multivariate analysis

Variables B HR 95% CI P value B HR 95% CI P value

Clinical parameters
Age (years) 0.057 1.059 1.044-­1.073 <.001 0.055 1.057 1.029-­1.085 <.001
Gender* −0.460 0.632 0.421-­0.947 .026
BMI (kg/m2) −0.016 0.984 0.914-­1.058 .661
HBeAg (%)* 0.235 1.265 0.903-­1.772 .171
Infection (%)* 0.287 1.332 0.851-­2.086 .210
HRS (%)* 0.524 1.688 0.864-­3.298 .125
LC (%)* 0.198 1.219 0.871-­1.705 .248
Laboratory parameters
Haemoglobin (g/L) −0.003 0.997 0.989-­1.006 .510
9
Platelet (10 /L) −0.002 0.998 0.995-­1.001 .278
Total bilirubin (μmol/L) 0.170 1.185 1.151-­1.220 <.001 0.183 1.201 1.134-­1.272 <.001
Albumin (g/L) −0.026 0.974 0.946-­1.003 .081
ALT (U/L) 0.000 1.000 0.999-­1.000 .187
AST (U/L) 0.000 1.000 1.000-­1.001 .398
Alkaline phosphatase (U/L) 0.002 1.002 0.997-­1.006 .476
γ-­GT (U/L) −0.004 0.996 0.992-­0.999 .026
Creatinine (μmol/L) 0.400 1.492 1.051-­2.118 .025
Serum sodium (mmol/L) −0.152 0.859 0.833-­0.887 <.001 −0.085 0.919 0.863-­0.978 .008
AFP (μg/L) −0.001 0.999 0.999-­1.000 .010
PT (s) 0.033 1.033 1.016-­1.050 <.001
PTA (%) −0.045 0.956 0.944-­0.968 <.001 −0.043 0.958 0.939-­0.978 <.001
INR 0.214 1.239 1.071-­1.433 .004
log (HBV DNA) −0.045 0.956 0.859-­1.065 .412

HR, Hazard ratio; CI, confidence interval; BMI, body mass index; HBeAg, hepatitis B e antigen; HRS, hepatorenal syndrome; LC, liver cirrhosis; ALT, alanine
aminotranferase; AST, aspartate aminotranferase; γ-­GT, γ-­glutamyl transferase; PT, prothrombin time; PTA, prothrombin time activity; INR, international
normalized ratio.
*Dichotomous values.

T A B L E   5   The predictive value of mortality of the CART score and other models in the derivation and validation cohorts

Models auROC 95% CI P value Youden index Sensitivity (%) Specificity (%) +LR −LR +PV −PV

Derivation cohort
CART 0.905 0.878-­0.928 0.6529 85.17 80.12 4.28 0.19 75.6 88.2
LRM 0.894 0.865-­0.918 .3823 0.6569 82.2 83.49 4.98 0.21 78.2 86.7
MELD 0.738 0.699-­0.774 <.001 0.4098 64.83 76.15 2.72 0.46 66.2 75.0
Validation cohort
CART 0.896 0.847-­0.934 0.6322 69.74 93.48 10.69 0.32 85.5 84.9
LRM 0.914 0.868-­0.948 .4237 0.684 73.68 93.48 11.3 0.28 86.2 86.6
MELD 0.667 0.599-­0.729 <.001 0.3103 22.37 93.48 3.43 0.83 65.4 68.6

auROC, area under the receiver operating characteristic curve; CI, confidence interval; +LR, positive likelihood ratio; −LR, negative likelihood ratio; +PV,
positive predictive value; −PV, negative predictive value. P value, compared with auROC of CART.

method, which may lead to overestimating the importance of in- subgroup analysis is needed in a further study. Second, our study was
cluded risk factors or missing other potential confounders that retrospective in nature, which might be subject to potential bias and
may influence each patient’s actual risk.25 A larger population and affect the validity of overall findings. Third, the CART analysis was
SHI et  al
built on a single centre and tested on other two centres with data of
homogeneous subgroups of individuals. The transportability of our
model to similar patients in another centre is as yet untested. Fourth,
the current CART model was developed by the baseline clinical char-
acteristics. Because of the dynamic nature of ACHBLF, a dynamic
prediction could represent disease progression and outcome. Thus,
multicentre, prospective studies of larger populations are needed to
further verify the applicability of this model, and to develop a chang-
ing CART model.
In summary, this CART model provides clinicians with a validated
practical bedside tool for ACHBLF risk stratification, although further
studies in this area are required. This innovative approach aims to
enhance, not replace, physician assessment by identifying important
predictors and highlighting complementary results. Therefore, a com-
bination of classical prognostic models such as MELD and this CART
method could help to streamline patients with ACHBLF for either liver
transplantation or medical therapy.
AUT HOR CONTRI B UTI O N S
Ke-­Qing Shi participated in study design, data collection and analysis,
interpreted data and drafted the manuscript. Yao-­Yao Zhou analysed
the data and helped to draft the manuscript. Hua-­Dong Yan and Hai
Li collected and analysed the data, interpreted the data and prepared
figures. Fa-­Ling Wu performed data collection and analysis. Yao-­Yao
Xie collected the data. Martin Braddock helped to draft the manu-
script. Xiang-­Yang Lin involved in study design and supervision. Ming-­
Hua Zheng participated in study design, study supervision, obtained
funding and helped to draft the manuscript. All authors saw and ap-
proved the final version of the manuscript.
CO NFLI CT OF I NTE RE S T
The authors disclose no conflict.
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