Development of a deep learning model for guiding treatment decisions of acute variceal bleeding in patients with cirrhosis

Table 1 Baseline characteristics and outcomes of acute variceal bleeding patients in the training, internal validation and external validation cohort, mean ± SD/n (%)

Characteristics	Training cohort (n = 668)	Internal validation cohort (n = 167)	P value	External validation cohort (n = 392)
Demographic characteristics
Age (years)	52.5 ± 11.8	52.6 ± 10.2	0.927	53.1 ± 11.8
Sex			0.273
Male	473 (70.8)	126 (75.4)		278 (70.9)
Female	195 (29.2)	41 (24.6)		114 (29.1)
Etiology of cirrhosis			0.394
Chronic HBV infection	401 (60.0)	117 (70.1)		246 (62.8)
Chronic HCV infection	41 (6.1)	10 (6.0)		28 (7.1)
Alcohol	73 (10.9)	16 (9.6)		56 (14.3)
Others	92 (13.8)	14 (8.3)		35 (8.9)
Cryptogenic	61 (9.1)	10 (6.0)		27 (6.9)
Medical history
Previous variceal bleeding	240 (35.9)	65 (38.9)	0.407	163 (41.6)
Location of varices			0.299
Esophageal varices only	388 (58.0)	105 (62.9)		214 (54.6)
Esophageal and gastric varices	280 (42.0)	62 (37.1)		178 (45.4)
Hepatic encephalopathy	65 (9.7)	17 (10.2)	0.437	33 (8.4)
Ascites			0.502
Mild	237 (35.4)	76 (45.5)		142 (36.2)
Moderate	96 (14.4)	31 (18.6)		68 (17.4)
Massive	45 (6.7)	13 (7.8)		30 (7.7)
Heart rate at admission (beats/minute)	85.0 ± 15.6	85.7 ± 16.6	0.632	87.5 ± 15.5
Systolic blood pressure at admission (mmHg)	115.8 ± 17.5	116.5 ± 16.2	0.640	113.6 ± 19.8
Diastolic blood pressure at admission (mmHg), median IQR	71.0 (63-79)	71.0 (62.5-79.5)	0.746	64.0 (55.5-72.5)
Laboratory examination
White blood cell (× 109 cell/L), median IQR	7.3 (5.4-10.0)	7.6 (6.2-9.0)	0.052	7.6 (5.3-9.7)
Red blood cell (× 109 cell/L)	2.7 ± 0.8	2.8 ± 0.7	0.483	2.3 ± 0.6
Hemoglobin (g/L)	77.3 ± 22.3	78.5 ± 23.4	0.521	70.8 ± 24.8
Platelet count (× 109/L), median IQR	84.0 (61.0-117.0)	85.0 (62.5-128.0)	0.867	94.5 (69.0-129.0)
NEC (× 109/L), median IQR	5.7 (4.3-8.0)	5.7 (4.3-8.2)	0.674	6.3 (3.8-12.5)
AST (U/L), median IQR	94.0 (83.7-118.2)	104.0 (93.0-125.5)	0.561	113.0 (103.5-133.0)
ALT (U/L), median IQR	54.0 (46.0-67.0)	53.0 (46.0-62.5)	0.681	56.0 (49.0-70.0)
TBIL (μmol/L)	38.0 ± 63.2	34.4 ± 38.0	0.577	33.0 ± 33.2
Albumin (g/L)	28.5 ± 5.4	29.0 ± 5.0	0.267	31.7 ± 8.8
INR	1.4 ± 2.7	1.3 ± 0.3	0.606	1.6 ± 1.5
APTT (second)	38.4 ± 16.3	36.6 ± 9.8	0.176	37.2 ± 13.4
TT (second)	19.9 ± 3.6	19.4 ± 3.2	0.124	19.8 ± 5.8
PT (second), median IQR	14.2 (12.9-15.8)	13.9 (12.9-15.6)	0.269	15.4 (13.9-17.9)
Creatinine (μmol/L), median IQR	92.0 (81.0-107.0)	90.0 (80.0-102.5)	0.814	86.0 (75.0-105.0)
Risk stratification index
MELD score (points)	11.3 ± 3.2	12.1 ± 5.0	0.049	12.2 ± 3.7
Child-Pugh score (points), median IQR	8.0 (7.0-9.0)	8.0 (7.0-9.1)	0.797	7.0 (5.5-8.5)
Child-Pugh class			0.395
A (5-6)	142 (21.3)	29 (17.4)		125 (31.9)
B (7-9)	407 (60.9)	111 (66.5)		180 (45.9)
C (10-13)	119 (17.8)	27 (16.2)		87 (22.2)
Early TIPS criteria			0.745
Low risk	534 (79.9)	136 (81.4)		280 (71.4)
High risk	134 (20.1)	31 (18.6)		112 (28.6)
Treatment procedure
Initial pharmacological therapy			0.275
Octreotide	177 (26.5)	47 (28.1)		90 (22.9)
Somatostatin	403 (60.3)	91 (54.5)		255 (65.1)
Terlipressin	88 (13.2)	29 (17.4)		47 (12.0)
Outcome measurements
6-week treatment failure to control bleeding	78 (11.8)	22 (13.2)	0.113	55 (14.0)
ICU requirement	155 (23.2)	38 (22.8)	0.785	81 (20.7)
1-year mortality	126 (18.8)	30 (18.0)	0.261	67 (17.1)
Treatment-related adverse events
Hepatic encephalopathy	86 (12.9)	26 (15.6)	0.093	74 (18.9)
New or worsening ascites	18 (2.7)	3 (1.8)	0.194	10 (2.6)

HBV: Hepatitis B virus; HCV: Hepatitis C virus; IQR: Interquartile range; NEC: Neutrophil count; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; TBIL: Total bilirubin; INR: International normalized ratio; APTT: Activated partial thromboplastin time; TT: Thrombin time; PT: Prothrombin time; MELD: Model for end-stage liver disease; TIPS: Transjugular intrahepatic portosystemic shunt; ICU: Intensive care unit.

Table 2 Baseline characteristics and outcomes of acute variceal bleeding patients treated with endoscopic variceal ligation plus pharmacotherapy or preemptive transjugular intrahepatic portosystemic shunt, mean ± SD/n (%)

Characteristics	High-risk for EVL + PT failure			Low-risk for EVL + PT failure
	EVL + PT (n = 220)	p-TIPS (n = 704)	P value	EVL + PT (n = 1007)	p-TIPS (n = 1159)	P value
Demographic characteristics
Age (years)	52.4 ± 10.9	52.6 ± 11.7	0.167	53.3 ± 11.8	51.5 ± 12.5	0.042
Sex			0.011			0.020
Male	162 (73.6)	457 (64.9)		715 (71.0)	729 (62.9)
Female	58 (26.4)	247 (35.1)		292 (29.0)	430 (37.1)
Etiology of cirrhosis			0.072			0.005
Chronic HBV infection	154 (70.0)	476 (67.6)		610 (60.6)	761 (65.7)
Chronic HCV infection	6 (2.7)	35 (5.0)		73 (7.2)	100 (8.6)
Alcohol	23 (10.5)	63 (8.9)		122 (12.1)	92 (7.9)
Others	18 (8.1)	92 (13.1)		123 (12.2)	133 (11.5)
Cryptogenic	19 (8.6)	38 (5.4)		79 (7.8)	73 (6.3)
Medical history
Previous variceal bleeding	93 (42.3)	319 (45.3)	0.537	375 (37.2)	447 (38.6)	0.618
Location of varices			0.692			0.544
Esophageal varices only	131 (59.5)	432 (61.4)		576 (57.2)	679 (58.6)
Esophageal and gastric varices	89 (40.5)	272 (38.6)		431 (42.8)	480 (41.4)
Hepatic encephalopathy	32 (14.5)	116 (16.4)	0.236	83 (8.2)	105 (9.1)	0.280
Ascites			0.021			0.066
Mild	89 (40.5)	263 (37.3)		366 (36.3)	395 (34.1)
Moderate	42 (19.1)	144 (20.4)		153 (15.2)	220 (19.0)
Massive	9 (4.1)	72 (10.2)		79 (7.8)	104 (9.0)
Heart rate at admission (beats/minute)	84.4 ± 14.4	83.1 ± 15.3	0.384	87.8 ± 16.4	86.8 ± 15.7	0.033
Systolic blood pressure at admission (mmHg)	112.0 ± 12.9	113.8 ± 17.9	0.067	117.4 ± 14.5	115.8 ± 16.0	0.003
Diastolic blood pressure at admission (mmHg)	67.5 ± 10.8	70.6 ± 12.4	0.002	69.5 ± 9.9	68.1 ± 11.5	0.042
Laboratory examination
White blood cell (× 109 cell/L)	8.4 ± 5.9	8.0 ± 3.9	0.246	6.0 ± 3.9	6.3 ± 4.4	0.095
Red blood cell (× 109 cell/L)	2.5 ± 0.7	2.4 ± 0.6	0.387	2.8 ± 0.7	3.5 ± 7.3	0.003
Hemoglobin (g/L)	75.2 ± 22.8	72.6 ± 22.6	0.038	77.7 ± 22.3	82.5 ± 24.9	< 0.001
Platelet count (× 109/L)	87.0 ± 57.8	86.4 ± 54.3	0.888	95.0 ± 89.0	97.6 ± 86.6	0.492
NEC (× 109/L)	7.6 ± 8.8	6.8 ± 5.7	0.115	5.1 ± 8.4	4.7 ± 5.9	0.196
AST (U/L)	124.9 ± 233.5	106.1 ± 167.5	0.189	76.1 ± 493.4	50.3 ± 99.0	0.082
ALT (U/L)	62.0 ± 101.9	55.6 ± 40.8	0.176	49.6 ± 214.2	34.9 ± 40.8	0.022
TBIL (μmol/L)	104.1 ± 120.8	60.2 ± 49.5	< 0.001	23.7 ± 23.8	27.3 ± 25.4	< 0.001
Albumin (g/L)	25.2 ± 4.6	25.6 ± 6.9	0.421	29.2 ± 5.3	32.9 ± 8.7	< 0.001
INR	1.6 ± 0.5	2.1 ± 1.8	< 0.001	1.4 ± 2.9	1.4 ± 1.4	0.898
APTT (second)	49.2 ± 19.1	46.2 ± 19.7	0.047	36.0 ± 14.6	35.3 ± 10.9	0.203
TT (second)	21.4 ± 3.8	22.1 ± 7.0	0.156	19.5 ± 3.5	19.3 ± 5.4	0.315
PT (second)	18.5 ± 6.7	23.9 ± 20.3	0.001	14.2 ± 3.5	15.6 ± 3.4	< 0.001
Creatinine (μmol/L)	100 ± 82.9	86.8 ± 58.4	0.009	82.5 ± 70.1	73.6 ± 44.1	< 0.001
Risk stratification index
MELD score (points)	13.5 ± 4.0	15.9 ± 6.5	0.002	11.2 ± 3.6	12.5 ± 3.8	0.034
Child-Pugh score (points), median IQR	7.9 (5.1-10.7)	8.2 (6.1-10.3)	0.068	7.4 (5.5-9.3)	7.2 (5.6-8.8)	< 0.001
Child-Pugh class			0.167			< 0.001
A (5-6)	42 (19.2)	101 (14.4)		254 (25.2)	336 (29.0)
B (7-9)	131 (59.5)	424 (60.3)		567 (56.3)	719 (62.1)
C (10-13)	47 (21.4)	179 (25.4)		186 (18.5)	104 (8.9)
Early TIPS criteria			< 0.001			< 0.001
Low risk	161 (73.2)	390 (55.4)		789 (78.4)	707 (61.0)
High risk	59 (26.8)	314 (44.6)		218 (21.6)	452 (39.0)
Treatment procedure
Initial pharmacological therapy			0.087			< 0.001
Octreotide	283 (28.1)	314 (27.1)		31 (14.1)	140 (19.9)
Somatostatin	597 (59.3)	730 (63.0)		152 (69.1)	513 (72.9)
Terlipressin	127 (12.6)	115 (9.9)		37 (16.8)	51 (7.2)
p-TIPS stent diameter
< 8 mm		137 (19.5)			61 (5.3)
8 mm		554 (78.2)			1025 (88.4)
10 mm		16 (2.3)			73 (6.3)
Outcome measurements
6-week treatment failure to control bleeding	87 (39.6)	27 (3.8)	< 0.001	68 (6.8)	22 (1.9)	0.013
ICU requirement	102 (46.4)	144 (20.5)	0.005	172 (17.1)	151 (13.0)	0.049
1-year mortality	82 (37.3)	103 (14.6)	< 0.001	141 (14.0)	121 (10.4)	0.036
Treatment-related adverse events
Hepatic encephalopathy	36 (16.4)	285 (30.5)	< 0.001	150 (14.9)	314 (27.1)	< 0.001
New or worsening ascites	12 (5.5)	10 (1.4)	< 0.001	19 (1.9)	10 (0.9)	< 0.001

EVL: Endoscopic variceal ligation; PT: Pharmacotherapy; p-TIPS: Preemptive transjugular intrahepatic portosystemic shunt; HBV: Hepatitis B virus; HCV: Hepatitis C virus; IQR: Interquartile range; NEC: Neutrophil count; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; TBIL: Total bilirubin; INR: International normalized ratio; APTT: Activated partial thromboplastin time; TT: Thrombin time; PT: Prothrombin time; MELD: Model for end-stage liver disease; TIPS: Transjugular intrahepatic portosystemic shunt; ICU: Intensive care unit.

Table 3 Univariate and multivariate regression analysis for composite outcomes in acute variceal bleeding patients treated with endoscopic variceal ligation plus pharmacotherapy or preemptive transjugular intrahepatic portosystemic shunt, mean ± SD/n (%)

Variables	High-risk patients for EVL + PT failure				Low-risk patients for EVL + PT failure
	Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
1-year mortality
Age (years, ≥ 60 vs < 60)	1.125 (0.924-1.371)	0.241			1.312 (1.009-1.706)	0.043	1.189 (0.841-1.680)	0.328
Sex (male vs female)	1.095 (0.909-1.320)	0.337			0.981 (0.765-1.257)	0.879
Etiology of cirrhosis	1.123 (0.892-1.414)	0.325			0.792 (0.587-1.068)	0.127
Location of varices	0.997 (0.808-1.229)	0.974			0.802 (0.609-1.055)	0.115
Hepatic encephalopathy (yes vs no)	1.464 (1.204-1.781)	< 0.001	1.132 (0.875-1.465)	0.345	1.369 (1.066-1.757)	0.014	1.027 (0.738-1.429)	0.876
Ascites (yes vs no)	1.784 (1.421-2.241)	< 0.001	1.409 (1.134-1.957)	< 0.001	2.282 (1.648-3.160)	< 0.001	2.088 (1.538-2.834)	< 0.001
Systolic blood pressure at admission (≥ 120 mmHg vs < 120 mmHg)	1.019 (0.847-1.227)	0.84			1.054 (0.829-1.340)	0.668
Diastolic blood pressure at admission (≥ 90 mmHg vs < 90 mmHg)	1.353 (0.779-2.348)	0.283			0.777 (0.458-1.316)	0.348
MELD score (> 13 vs ≤ 13)	4.968 (3.543-6.967)	< 0.001	1.320 (1.046-1.665)	0.006	5.284 (3.331-8.381)	< 0.001	2.208 (1.155-3.504)	< 0.001
Child-Pugh class (C vs A + B)	4.137 (1.977-7.926)	< 0.001	3.309 (2.535-4.554)	< 0.001	-	0.996
Different treatment strategies (EVL + PT vs p-TIPS)	2.377 (1.855-2.842)	< 0.001	1.671 (1.096-2.259)	0.029	0.954 (0.671-1.355)	0.791
6-week treatment failure
Age (years, ≥ 60 vs < 60)	1.251 (1.170-1.363)	0.009	1.090 (0.898-1.322)	0.376	1.225 (1.075-1.526)	0.028	1.128 (0.870-1.389)	0.437
Sex (male vs female)	1.087 (0.917-1.272)	0.346			0.997 (0.792-1.238)	0.947
Etiology of cirrhosis	1.134 (0.917-1.392)	0.248			0.821 (0.631-1.068)	0.144
Location of varices	1.025 (0.839-1.240)	0.839			0.852 (0.665-1.094)	0.205
Hepatic encephalopathy (yes vs no)	1.430 (1.211-1.704)	< 0.001	1.251 (1.010-1.548)	0.040	1.378 (1.094-1.725)	0.007	1.180 (0.984-1.548)	0.230
Ascites (yes vs no)	1.750 (1.415-2.187)	< 0.001	1.256 (1.093-1.667)	< 0.001	2.001 (1.515-2.666)	< 0.001	1.875 (1.375-2.571)	< 0.001
Systolic blood pressure at admission (≥ 120 mmHg vs < 120 mmHg)	1.051 (0.875-1.260)	0.591			1.079 (0.855-1.339)	0.563
Diastolic blood pressure at admission (≥ 90 mmHg vs < 90 mmHg)	1.303 (0.846-2.115)	0.288			0.826 (0.540-1.280)	0.353
MELD score (> 13 vs ≤ 13)	5.020 (3.750-6.667)	< 0.001	1.516 (1.167-1.923)	0.002	4.520 (3.697-6.750)	< 0.001	3.427 (2.167-4.154)	< 0.001
Child-Pugh class (C vs A + B)	6.125 (2.567-9.450)	< 0.001	4.231 (2.540-6.221)	< 0.001		0.995
Different treatment strategies (EVL + PT vs p-TIPS)	2.350 (1.903-2.999)	< 0.001	1.705 (1.300-2.250)	< 0.001	1.955 (1.700-2.300)	0.018	1.051 (0.746-1.320)	0.082

EVL: Endoscopic variceal ligation; PT: Pharmacotherapy; HR: Hazard ratio; CI: Confidence interval; MELD: Model for end-stage liver disease; p-TIPS: Preemptive transjugular intrahepatic portosystemic shunt.