LIV-4: A novel model for predicting transplant-free survival in critically ill cirrhotics

Table 1 Training cohort: Patient characteristics and univariate analysis of factors associated with In-hospital mortality

Factor	Total (n = 436)		Discharged alive (n = 317)		In-hospital death (n = 119)		P value
	n	Summary	n	Summary	n	Summary
Age (yr)	436	57.0 ± 10.6	317	57.5 ± 10.3	119	55.5 ± 11.3	< 0.0811
Gender	436		317		119		< 0.623
Female		151 (34.6)		112 (35.3)		39 (32.8)
Male		285 (65.4)		205 (64.7)		80 (67.2)
Ethnicity	420		308		112		< 0.413
White/Caucasian		340 (81.0)		254 (82.5)		86 (76.8)
Black/African/Haitian		60 (14.3)		41 (13.3)		19 (17.0)
Other		20 (4.8)		13 (4.2)		7 (6.3)
Any previous ICU stay during same admission	436	13 (3.0)	317	6 (1.9)	119	7 (5.9)	< 0.0293
Comorbidities
Diabetes	436	129 (29.6)	317	100 (31.5)	119	29 (24.4)	< 0.143
COPD	436	61 (14.0)	317	49 (15.5)	119	12 (10.1)	< 0.153
Severe COPD	436	12 (2.8)	317	10 (3.2)	119	2 (1.7)	< 0.403
Solid tumor with metastasis	436	3 (0.69)	317	1 (0.32)	119	2 (1.7)	< 0.182
Immune suppression	436	21 (4.8)	317	16 (5.0)	119	5 (4.2)	< 0.713
Mechanical ventilation	436	170 (39.0)	317	111 (35.0)	119	59 (49.6)	< 0.0053
Dialysis > 2 times in 7 d	436	35 (8.0)	317	20 (6.3)	119	15 (12.6)	< 0.0313
Liver disease etiology
AIAT	436	9 (2.1)	317	8 (2.5)	119	1 (0.84)	< 0.273
AIH	436	17 (3.9)	317	11 (3.5)	119	6 (5.0)	< 0.453
ALD	436	197 (45.2)	317	138 (43.5)	119	59 (49.6)	< 0.263
Cryptogenic	436	25 (5.7)	317	21 (6.6)	119	4 (3.4)	< 0.193
HCV	436	147 (33.7)	317	102 (32.2)	119	45 (37.8)	< 0.273
HBV	436	9 (2.1)	317	5 (1.6)	119	4 (3.4)	< 0.243
NASH	436	96 (22.0)	317	75 (23.7)	119	21 (17.6)	< 0.183
PBC	436	6 (1.4)	317	5 (1.6)	119	1 (0.84)	< 0.994
PSC	436	2 (0.46)	317	2 (0.63)	119	0 (0.0)	< 0.994
24-hour urine output (cc)	400	1005.2 (454.8, 1589.8)	295	1090.0 (633.3, 1726.6)	105	563.8 (105.6, 1210.9)	< 0.0012
Variceal bleed	436	112 (25.7)	317	86 (27.1)	119	26 (21.8)	< 0.263
Vasopressors on day of admission	436		317		119		< 0.0012
0		208 (47.7)		170 (53.6)		38 (31.9)
1		175 (40.1)		126 (39.7)		49 (41.2)
≥ 2		53 (12.12)		21 (6.63)		32 (26.9)
Encephalopathy	436		317		119		< 0.432
None		106 (24.3)		81 (25.6)		25 (21.0)
Mild		123 (28.2)		88 (27.8)		35 (29.4)
Moderate/severe		207 (47.5)		148 (46.7)		59 (49.6)
Ascites	436		317		119		< 0.0852
None		114 (26.1)		86 (27.1)		28 (23.5)
Mild		129 (29.6)		100 (31.5)		29 (24.4)
Moderate/severe		193 (44.3)		131 (41.3)		62 (52.1)
Labs and vitals
Platelets (k/μL)	436	81.0 (56.5, 117.5)	317	83.0 (60.0, 117.0)	119	73.0 (49.0, 119.0)	< 0.212
Prothrombin time (sec)	436	16.8 (14.2, 20.7)	317	15.6 (13.7, 18.0)	119	21.4 (18.3, 27.8)	< 0.0012
INR	436	1.5 (1.3, 1.9)	317	1.4 (1.2, 1.6)	119	2.0 (1.7, 2.6)	< 0.0012
Lactate (mmol/L)	341	2.3 (1.6, 3.4)	230	2.1 (1.4, 2.7)	111	3.0 (2.1, 5.4)	< 0.0012
MAP (mmHg)	436	65.0 (56.0, 106.0)	317	68.0 (60.0, 109.0)	119	58.0 (50.0, 68.0)	< 0.0012
ABG-pH	263	7.4 ± 0.10	170	7.4 ± 0.08	93	7.3 ± 0.12	< 0.0011
ABG-PaCO2 (mmHg)	263	31.0 (27.0, 38.0)	170	31.0 (26.0, 37.0)	93	33.0 (27.0, 40.0)	< 0.0982
ABG-PaO2 (mmHg)	263	104.0 (80.0, 139.0)	170	113.0 (85.0, 147.0)	93	94.0 (76.0, 132.0)	< 0.0192
ABG-FiO2 (%)	263	40.0 (27.0, 55.0)	170	40.0 (25.0, 50.0)	93	44.0 (30.0, 70.0)	< 0.0082
PaO2/FIO2 ratio	263	309.5 (195.0, 390.5)	170	337.5 (226.0, 426.7)	93	252.5 (143.0, 347.4)	< 0.0012
PAO2 (mmHg)	263	240.2 (151.0, 346.2)	171	231.5 (143.3, 324.0)	93	264.0 (168.4, 471.6)	< 0.0082
A-a gradient (mmHg)	263	119.8 (47.4, 233.9)	171	100.2 (38.6, 204.3)	93	166.7 (59.5, 319.6)	< 0.0012
Temperature (°C)	436	36.5 (36.2, 36.8)	317	36.5 (36.3, 36.8)	119	36.3 (35.4, 36.6)	< 0.0012
GCS	436	13.0 (8.0,14.0)	317	13.0(9.0,15.0)	119	11.0 (7.0, 14.0)	< 0.0012
Respiratory rate (rpm)	436	33.0 (26.0, 40.0)	317	33.0 (25.0, 39.0)	119	36.0 (27.0, 43.0)	< 0.0522
Heart rate (bpm)	436	92.8 ± 28.1	317	91.8 ± 25.7	119	95.5 ± 33.6	< 0.211
Hematocrit (%)	436	26.6 ± 5.9	317	27.1 ± 5.7	119	25.3 ± 6.2	< 0.0051
WBC (k/μL)	436	7.5 (5.0, 11.4)	317	6.6 (4.6, 9.8)	119	10.7 (6.6, 17.7)	< 0.0012
Potassium (mmol/L)	436	4.0 (3.6, 4.8)	317	3.9 (3.5, 4.6)	119	4.4 (3.8, 5.1)	< 0.0012
BUN (mg/dL)	436	35.0 (21.0, 55.5)	317	32.0 (20.0, 51.0)	119	46.0 (28.0, 66.0)	< 0.0012
Albumin (g/dL)	436	2.7 (2.2, 3.1)	317	2.7 (2.3, 3.1)	119	2.7 (2.2, 3.3)	< 0.572
Sodium (mmol/L)	436	136.6 ± 6.8	317	136.6 ± 6.6	119	136.4 ± 7.3	< 0.811
Creatinine (mg/dL)	436	1.6 (0.89, 2.8)	317	1.4 (0.80, 2.4)	119	2.2 (1.4, 3.5)	< 0.0012
Bilirubin (mg/dL)	435	4.2 (2.0, 10.4)	316	3.3 (1.7, 6.2)	119	11.7 (5.6, 25.9)	< 0.0012
Bicarbonate (mmol/L)	424	19.3 ± 5.4	310	19.9 ± 4.9	114	17.7 ± 6.3	< 0.0011
Glucose (mg/dL)	430	152.6 ± 90.3	314	153.9 ± 94.0	116	149.1 ± 79.8	< 0.631
Scores
MELD score	435	23.2 ± 9.8	316	20.3 ± 8.3	119	31.1 ± 8.9	< 0.0011
MELD-Na score	435	24.8 ± 9.2	316	22.1 ± 8.1	119	32.0 ± 8.1	< 0.0011
Child-Pugh score	435	10.8 ± 2.1	316	10.3 ± 2.1	119	11.9 ± 1.8	< 0.0011
SOFA score	263	10.2 ± 3.5	170	9.0 ± 2.9	93	12.4 ± 3.4	< 0.0011
CLIF-SOFA score	262	11.2 ± 3.5	169	9.9 ± 3.0	93	13.5 ± 3.2	< 0.0011
RFH score	259	0.05 (-0.77, 1.1)	167	-0.30 (-0.99, 0.59)	92	0.96 (0.08, 2.1)	< 0.0012
APS	435	65.6 ± 28.4	317	58.0 ± 22.1	118	86.2 ± 32.8	< 0.0011
APACHE III score	435	85.1 ± 28.3	317	77.7 ± 23.1	118	105.0 ± 31.5	< 0.0011

Values presented as Mean ± SD, Median (P25, P75) or n (column %). P values:

¹ANOVA.

²Kruskal-Wallis test.

³Pearson’s χ² test.

⁴Fisher’s Exact test. ICU: Intensive care unit; COPD: Chronic obstructive pulmonary disease; A1AT: Alpha 1 anti-trypsin deficiency; AIH: Autoimmune hepatitis; ALD: Alcoholic liver disease; HCV: Hepatitis C virus; HBV: Hepatitis B virus; NASH: Non-alcoholic steatohepatitis; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; INR: International normalized ratio; MAP: Mean arterial pressure; ABG: Arterial blood gas; PaCO₂: Partial arterial pressure of carbon dioxide; PaO₂: Oxygen; FiO₂: Inspired oxygen concentration; A-a gradient: Alveolar arterial partial pressure oxygen gradient; FiO₂/PaO₂: Oxygenation index; GCS: Glascow coma scale; rpm: Respirations per minute; bpm: Beats per minute; WBC: White blood cell count; BUN: Blood urea nitrogen; MELD: Model for end-stage liver disease; Na: Sodium; CPS: Child-Pugh score; SOFA: Sequential (or sepsis-related) organ failure assessment; CLIF-SOFA: Chronic liver failure-sequential organ failure assessment; RFH: Royal free hospital; APS: Acute physiology score; APACHE: Acute physiology and chronic health evaluation.

Table 2 Training cohort: Factors associated with in-hospital mortality: multivariate logistic regression with variable transformations

Factor	Estimate (95%CI)	OR (95%CI)	P value
Ln (Bilirubin)	0.61 (0.34, 0.89)	1.8 (1.4, 2.4)	< 0.001
1/PT	-47.2 (-67.3, -27.1)	0.09 (0.03, 0.26)1	< 0.001
WBC	0.07 (0.03, 0.11)	1.07 (1.03, 1.1)	< 0.001
MAP	-0.02 (-0.03, -0.01)	0.91 (0.86, 0.96)2	< 0.001

¹OR corresponds to 0.05 increment in 1/PT.

²OR corresponds to 5-unit increment in MAP. Ln: Natural logarithm; OR: Odds ratio; CI: Confidence interval; PT: Prothrombin time; WBC: White blood cell count; MAP: Mean arterial pressure.

Table 3 Training cohort: Predictive abilities of critical care and liver-specific scores compared to the LIV-4 score

Score compared to LIV-4	P value
MELD	0.009
MELD-Na	0.002
Child-Pugh Score	< 0.001
SOFA	0.061
CLIF-SOFA	0.091
RFH	0.04
APS	0.001
APACHE III	0.002

MELD: Model for end-stage liver disease; Na: Sodium; SOFA: Sequential (or Sepsis-Related) organ failure assessment; CLIF-SOFA: Chronic liver failure-sequential organ failure assessment; RFH: Royal free hospital; APS: Simplified acute physiology score; APACHE: Acute physiology and chronic health evaluation.

Table 4 Validation cohort characteristics

Factor	Training cohort (n = 436)		Validation cohort A (n = 336)		P value
	n	Statistics	n	Statistics
Gender	436		336		< 0.0302
Female		151 (34.6)		142 (42.3)
Male		285 (65.4)		194 (57.7)
Serum bilirubin	435	4.2 (2.0, 10.4)	336	5.0 (2.0, 13.5)	< 0.261
PT	436	16.8 (14.2, 20.7)	336	18.0 (14.8, 23.5)	< 0.0031
WBC	436	7.5 (5.0, 11.4)	336	8.3 (5.0, 14.0)	< 0.0401
MAP	436	65.0 (56.0, 106.0)	336	64.0 (56.0, 75.0)	< 0.261
Non-liver specific scores
APACHE III	435	83.0 (65.0, 102.0)	333	88.0 (70.0, 109.0)	< 0.0061
SOFA	263	10.0 (8.0, 12.0)	186	11.0 (8.0, 14.0)	< 0.0031
Liver specific scores
MELD	435	22.0 (16.0, 30.0)	336	25.0 (17.0, 33.0)	< 0.0041
MELD-Na	435	24.0 (18.0, 31.0)	336	27.0 (20.0, 34.0)	< 0.0061
CLIF-SOFA	262	11.0 (9.0, 13.0)	336	11.0 (9.0, 13.0)	< 0.531
RFH	259	0.05 (-0.77, 1.1)	184	0.83 (-0.18, 2.1)	< 0.0011
LIV-4	435	16.8 (5.7, 43.6)	336	23.0 (7.1, 57.7)	< 0.0071
Admission outcomes
ICU LOS (d)	436	2.6 (1.4, 5.2)	336	3.7 (2.0, 7.6)	< 0.0011
Hospital LOS (d)	436	8.7 (4.7, 16.8)	336	11.7 (5.7, 22.0)	< 0.0021
Hospital discharge status	436		336		< 0.172
Discharged alive		317 (72.7)		229 (68.2)
In-hospital death		119 (27.3)		107 (31.8)

¹Kruskal-Wallis test.

²Pearson’s χ² test. PT: Prothrombin time; WBC: White blood cell count; MAP: Mean Arterial Pressure; APACHE: Acute physiology and chronic health evaluation; SOFA: Sequential (or Sepsis-related) organ failure assessment; MELD: Model for end-stage liver disease; Na: Sodium; CLIF-SOFA: Chronic liver failure-sequential organ failure assessment; RFH: Royal Free Hospital; LOS: Length of stay.

Table 5 Validation cohort: Comparison of the various scores and LIV-4

Score comparison	Validation cohort P value
MELD vs LIV-4	< 0.75
MELD-Na vs LIV-4	< 0.47
SOFA vs LIV-4	< 0.94
CLIF-SOFA vs LIV-4	< 0.27
RFH vs LIV-4	< 0.001
APACHE III vs LIV-4	< 0.074

Areas under the ROC curves were compared using De-Long’s method. MELD: Model for end-stage liver disease; Na: Sodium; SOFA: Sequential (or Sepsis-related) organ failure assessment; CLIF-SOFA: Chronic liver failure-sequential organ failure assessment; RFH: Royal Free Hospital; APACHE: Acute physiology and chronic health evaluation; ROC: Receiver operator characteristics.

Table 6 Validity measures for LIV-4

Cohort	Measure	LIV-4 ≥ 26.5	LIV-4 ≥ 45.8
Validation Cohort	Sensitivity	81.3 (73.9, 88.7)	61.7 (52.5, 70.9)
	Specificity	71.2 (65.3, 77.0)	83.4 (78.6, 88.2)
	PPV	56.9 (49.0, 64.7)	63.5 (54.2, 72.7)
	NPV	89.1 (84.6, 93.6)	82.3 (77.4, 87.2)

Values presented as estimate (95%CI). PPV: Positive predictive value; NPV: Negative predictive value; CI: Confidence Interval.