Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. HCC Surveillance
2.3. Calculation of HCC Risk Scores from Prediction Models
2.4. Statistical Analysis
3. Results
3.1. Baseline Characteristics and HCC Development
3.2. Independent Predictive Factors of HCC Development in Cirrhotic Patients with CHB
3.3. Predictive Performance and HCC
3.4. Risk Stratification in Cirrhotic Patients with CHB
3.5. On-Treatment LS Value in Cirrhotic Patients with CHB
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variables | Total (n = 1339) |
---|---|
Age (year) | 54 (47, 59) |
<40 | 87 (6.5) |
40–50 | 343 (25.6) |
50–60 | 578 (43.2) |
60–70 | 265 (19.8) |
≥70 | 51 (3.8) |
Male sex | 717 (53.5) |
Diabetes mellitus | 190 (14.2) |
HBeAg positivity | 514 (38.4) |
TDF use (vs. ETV) | 684 (51.1) |
Platelet count (×103/μL) | 134 (99, 172) |
Total bilirubin (mg/dL) | 0.9 (0.7, 1.3) |
Serum albumin (g/dL) | 4.2 (3.8, 4.4) |
Prothrombin time (INR) | 1.04 (0.98, 1.13) |
Aspartate aminotransferase (IU/L) | 39 (28, 59) |
Alanine aminotransferase (IU/L) | 37 (25, 59) |
Alpha-fetoprotein (ng/mL) (n = 910) | 4.48 (2.74, 8.57) |
Liver stiffness value † (kPa) | 11.2 (7.4, 17.3) |
1 year after AVT (kPa) (n = 808) | 8.9 (2.7, 13.4) |
Follow-up and treatment duration (month) | 56.8 (35.6, 75.3) |
PAGE-B | 15 (12, 18) |
Modified PAGE-B | 12 (10, 14) |
Modified REACH-B | 9 (8, 11) |
CAMD | 15 (13, 16) |
aMAP | 67.3 (63.0, 71.3) |
HCC-RESCUE | 84 (77, 92) |
AASL-HCC | 19 (17, 20) |
Toronto HCC Risk Index | 236 (197, 297) |
PLAN-B | 0.395 (0.306, 0.493) |
APA-B (n = 910) | 6 (3, 8) |
CAGE-B (n = 808) | 9 (8, 11) |
SAGE-B (n = 808) | 6 (6, 9) |
Variables | Without HCC (n = 1128) | HCC (n = 211) | p Value |
---|---|---|---|
Age (year) | 53 (47, 59) | 55 (50, 60) | 0.003 |
<40 | 83 (7.4) | 4 (1.9) | 0.004 |
40–50 | 295 (26.2) | 48 (22.7) | |
50–60 | 473 (41.9) | 105 (49.8) | |
60–70 | 220 (19.5) | 45 (21.3) | |
≥70 | 42 (3.7) | 9 (4.3) | |
Male sex | 605 (53.6) | 112 (53.1) | 0.942 |
Diabetes mellitus | 151 (13.4) | 39 (18.5) | 0.066 |
HBeAg positivity | 414 (36.7) | 100 (47.4) | 0.004 |
TDF use (vs. ETV) | 576 (51.1) | 108 (51.2) | >0.999 |
Platelet count (×103/μL) | 138 (102, 175) | 115 (87, 156) | <0.001 |
Total bilirubin (mg/dL) | 0.9 (0.7, 1.2) | 1.0 (0.7, 1.5) | 0.065 |
Serum albumin (g/dL) | 4.2 (3.9, 4.4) | 4.0 (3.4, 4.3) | <0.001 |
Prothrombin time (INR) | 1.04 (0.98, 1.11) | 1.05 (1.0, 1.16) | 0.007 |
Aspartate aminotransferase (IU/L) | 38 (27, 56) | 49 (37, 76) | <0.001 |
Alanine aminotransferase (IU/L) | 36 (24, 56) | 44 (30, 78) | 0.218 |
Alpha-fetoprotein (ng/mL) | 3.96 (2.59, 7.46) | 7.21 (4.66, 14.69) | <0.001 |
Liver stiffness value † (kPa) | 10.3 (6.9, 16.6) | 14.2 (10.0, 22.3) | <0.001 |
1 year after AVT (kPa) (n = 808) | 8.7 (6.1, 12.5) | 11.8 (8.65, 16.6) | <0.001 |
Follow-up and treatment duration (month) | 60.1 (38.1, 76.1) | 40.7 (24.6, 60.9) | <0.001 |
PAGE-B | 15 (12, 18) | 16 (13, 18) | <0.001 |
Modified PAGE-B | 12 (10, 14) | 13 (11, 15) | <0.001 |
Modified REACH-B | 9 (7, 11) | 11 (9, 12) | <0.001 |
CAMD | 14 (13, 16) | 15 (14, 16) | 0.022 |
aMAP | 66.8 (62.6, 71.1) | 69.4 (66.1, 72.6) | <0.001 |
HCC-RESCUE | 84 (76, 92) | 86 (79, 93) | 0.013 |
AASL-HCC | 19 (17, 20) | 20 (17, 22) | <0.001 |
Toronto HCC Risk Index | 236 (197, 297) | 247 (217, 297) | 0.001 |
PLAN-B | 0.382 (0.294, 0.479) | 0.434 (0.370, 0.527) | <0.001 |
APA-B (n = 910) | 5 (3, 8) | 7 (6, 10) | <0.001 |
CAGE-B (n = 808) | 9 (7, 11) | 11 (9, 12) | <0.001 |
SAGE-B (n = 808) | 6 (4, 9) | 8 (6, 11) | <0.001 |
Variable | Univariate | Multivariate Analysis | |
---|---|---|---|
p Value | p Value | Hazard Ratio (95% CI) | |
Age (year) | <0.001 | 0.003 | 1.023 (1.008, 1.038) |
Diabetes mellitus | 0.032 | 0.207 | 1.259 (0.881, 1.800) |
HBeAg positivity | 0.012 | 0.066 | 1.302 (0.982, 1.725) |
Platelet count (×103/μL) | <0.001 | 0.015 | 0.997 (0.994, 0.999) |
Total bilirubin (mg/dL) | 0.048 | 0.439 | 0.971 (0.901, 1.046) |
Serum albumin (g/dL) | <0.001 | <0.001 | 0.578 (0.446, 0.751) |
Prothrombin time (INR) | 0.014 | 0.589 | 0.829 (0.420, 1.636) |
Liver stiffness value † (kPa) | <0.001 | 0.026 | 1.012 (1.002, 1.024) |
Scoring Systems | Harrell’s c-Index (95% CI) | Integrated AUC * (95% CI) | TDAUC at 1 Year (95% CI) | TDAUC at 2 Year (95% CI) | TDAUC at 3 Year (95% CI) | TDAUC at 5 Year (95% CI) | TDAUC at 8 Year (95% CI) |
---|---|---|---|---|---|---|---|
PAGE-B | 0.605 (0.568, 0.644) | 0.573 (0.536, 0.609) | 0.674 (0.513, 0.835) | 0.689 (0.624, 0.754) | 0.658 (0.601, 0.714) | 0.596 (0.547, 0.644) | 0.568 (0.475, 0.661) |
Modified PAGE-B | 0.640 (0.601, 0.676) | 0.611 (0.577, 0.644) | 0.747 (0.592, 0.902) | 0.714 (0.650, 0.777) | 0.701 (0.648, 0.754) | 0.630 (0.581, 0.678) | 0.641 (0.550, 0.732) |
Modified REACH-B | 0.667 (0.630, 0.702) | 0.643 (0.606, 0.674) | 0.662 (0.516, 0.808) | 0.732 (0.670, 0.795) | 0.704 (0.654, 0.753) | 0.663 (0.616, 0.709) | 0.608 (0.515, 0.700) |
CAMD | 0.565 (0.528, 0.604) | 0.553 (0.517, 0.588) | 0.674 (0.545, 0.804) | 0.626 (0.556, 0.697) | 0.603 (0.545, 0.661) | 0.553 (0.506, 0.600) | 0.576 (0.482, 0.671) |
aMAP | 0.603 (0.564, 0.641) | 0.610 (0.573, 0.645) | 0.725 (0.571, 0.879) | 0.713 (0.653, 0.774) | 0.706 (0.655, 0.758) | 0.630 (0.582, 0..678) | 0.629 (0.536, 0.722) |
HCC-RESCUE | 0.588 (0.547, 0.623) | 0.560 (0.524, 0.593) | 0.761 (0.646, 0.876) | 0.692 (0.630, 0.754) | 0.645 (0.591, 0.700) | 0.571 (0.523, 0.619) | 0.513 (0.416, 0.610) |
AASL-HCC | 0.616 (0.578, 0.655) | 0.590 (0.557, 0.623) | 0.798 (0.679, 0.916) | 0.724 (0.662, 0.787) | 0.680 (0.625, 0.735) | 0.603 (0.553, 0.653) | 0.578 (0.486, 0.670) |
Toronto HCC Risk Index | 0.603 (0.564, 0.641) | 0.572 (0.537, 0.608) | 0.693 (0.591, 0.794) | 0.709 (0.651, 0.768) | 0.667 (0.613, 0.721) | 0.589 (0.541, 0.637) | 0.536 (0.437, 0.634) |
PLAN-B | 0.638 (0.600, 0.675) | 0.613 (0.578, 0.650) | 0.634 (0.489, 0.779) | 0.727 (0.658, 0.797) | 0.691 (0.638, 0.743) | 0.625 (0.576, 0.673) | 0.462 (0.365, 0.560) |
APA-B (n = 910) † | 0.661 (0.615, 0.703) | 0.655 (0.618, 0.691) | 0.608 (0.447, 0.769) | 0.651 (0.573, 0.729) | 0.664 (0.603, 0.725) | 0.679 (0.626, 0.732) | 0.718 (0.604, 0.832) |
CAGE-B (n = 808) ‡ | 0.621 (0.571, 0.675) | 0.622 (0.579, 0.661) | - | 0.645 (0.533, 0.757) | 0.679 (0.606, 0.753) | 0.679 (0.606, 0.753) | 0.675 (0.556, 0.794) |
SAGE-B (n = 808) ‡ | 0.639 (0.587, 0.691) | 0.637 (0.593, 0.678) | - | 0.659 (0.540, 0.777) | 0.705 (0.633, 0.777) | 0.610 (0.547, 0.674) | 0.667 (0.546, 0.786) |
Risk Stratification | Patient No. (%) | Cumulative Incidence of HCC | Log Rank p Value | Log Rank p Value vs. | |||||
---|---|---|---|---|---|---|---|---|---|
1 Year | 2 Year | 3 Year | 5 Year | 8 Year | |||||
All Patients | 1339 (100) | 12 (0.9) | 49 (3.8) | 91 (7.4) | 155 (14.6) | 203 (31.7) | |||
PAGE-B | |||||||||
Low (0–9) | 113 (8.4) | 0 (0.0) | 0 (0.0) | 2 (2.2) | 6 (8.5) | 10 (24.7) | 0.025 | Int | 0.200 |
Int (10–17) | 951 (71.0) | 7 (0.7) | 31 (3.4) | 57 (6.5) | 105 (13.9) | 142 (32.3) | High | 0.030 | |
High (18–25) | 275 (20.5) | 5 (1.8) | 18 (6.8) | 32 (12.9) | 44 (19.3) | 51 (30.4) | Low | 0.020 | |
Modified PAGE-B | |||||||||
Low (0–8) | 120 (9.0) | 0 (0.0) | 0 (0.0) | 2 (2.0) | 6 (7.3) | 9 (19.4) | <0.001 | Int | 0.200 |
Int (9–12) | 642 (47.9) | 2 (0.3) | 13 (2.1) | 25 (4.2) | 56 (11.4) | 79 (24.9) | High | <0.001 | |
High (13–21) | 577 (43.1) | 10 (1.8) | 36 (6.4) | 64 (12.1) | 93 (19.7) | 115 (42.4) | Low | 0.002 | |
Modified REACH-B | |||||||||
Low (0–6) | 185 (13.8) | 0 (0.0) | 0 (0.0) | 2 (1.3) | 8 (6.7) | 12 (19.8) | <0.001 | Int | 0.020 |
Int (7–11) | 846 (63.2) | 8 (1.0) | 24 (2.9) | 49 (6.3) | 86 (12.8) | 116 (28.9) | High | <0.001 | |
High (12–16) | 308 (23.0) | 4 (1.3) | 25 (8.4) | 40 (14.0) | 61 (24.0) | 75 (45.1) | Low | <0.001 | |
CAMD | |||||||||
Low (0–7) | - | - | - | - | - | 0.003 | - | ||
Int (8–13) | 408 (30.5) | 2 (0.5) | 8 (2.0) | 19 (5.1) | 33 (10.2) | 44 (21.4) | |||
High (14–23) | 931 (69.5) | 10 (1.1) | 41 (4.6) | 72 (8.4) | 122 (16.5) | 159 (36.3) | |||
aMAP | |||||||||
Low (1–50) | 14 (1.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | - | 0.003 | Int | 0.400 |
Int (50–60) | 142 (10.6) | 0 (0.0) | 1 (0.7) | 3 (2.4) | 5 (5.1) | 8 (14.2) | High | 0.002 | |
High (60–100) | 1183 (88.3) | 12 (1.0) | 48 (4.2) | 88 (8.1) | 150 (15.8) | 195 (33.8) | Low | 0.100 | |
HCC-RESCUE | |||||||||
Low ( ≤ 64) | 43 (3.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (3.1) | 2 (9.2) | 0.070 | Int | 0.080 |
Int (65–84) | 637 (47.6) | 2 (0.3) | 11 (1.8) | 31 (5.4) | 65 (13.5) | 93 (33.9) | High | 0.200 | |
High (≥85) | 659 (49.2) | 10 (1.5) | 38 (5.9) | 60 (9.8) | 89 (16.3) | 108 (30.8) | Low | 0.050 | |
AASL-HCC | |||||||||
Low (0–5) | - | - | - | - | - | - | 0.003 | - | |
Int (6–19) | 763 (57.0) | 2 (0.3) | 10 (1.6) | 29 (4.5) | 66 (11.7) | 96 (29.0) | |||
High (20–29) | 576 (43.0) | 10 (1.8) | 27 (6.6) | 50 (11.2) | 77 (18.4) | 95 (35.3) | |||
Toronto HCC Risk Index | |||||||||
Low (0–120) | 45 (3.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (26.2) | 0.030 | Int | 0.100 |
Int (120–240) | 635 (47.4) | 3 (0.5) | 9 (1.5) | 25 (4.4) | 59 (12.4) | 90 (32.4) | High | 0.050 | |
High (240–366) | 659 (49.2) | 9 (1.4) | 40 (6.3) | 66 (10.9) | 96 (17.6) | 111 (31.5) | Low | 0.040 | |
PLAN-B | |||||||||
Low (0.075–0.250) | 190 (20.9) | 1 (0.5) | 1 (0.5) | 2 (1.1) | 6 (4.9) | 10 (12.1) | <0.001 | Int | <0.001 |
Int (0.250–0.500) | 832 (91.4) | 6 (0.7) | 20 (2.5) | 47 (6.2) | 95 (14.6) | 127 (33.4) | High | 0.020 | |
High (0.500–1.000) | 317 (34.8) | 5 (1.6) | 28 (9.2) | 42 (14.3) | 54 (20.2) | 66 (35.8) | Low | <0.001 | |
APA-B (n = 910) † | |||||||||
Low (0–5) | 437 (48.0) | 2 (0.5) | 8 (1.9) | 16 (4.0) | 27 (7.5) | 34 (19.5) | <0.001 | Int | <0.001 |
Int (6–9) | 306 (33.6) | 4 (1.3) | 21 (7.3) | 33 (11.9) | 50 (20.1) | 63 (40.6) | High | 0.050 | |
High (10–15) | 167 (18.4) | 4 (2.5) | 11 (6.8) | 24 (15.6) | 38 (27.3) | 50 (66.7) | Low | <0.001 | |
CAGE-B (n = 808) ‡ | |||||||||
Low | 41 (5.1) | - | 0 (0.0) | 0 (0.0) | 1 (3.1) | 1 (3.1) | 0.001 | Int | 0.080 |
Int | 468 (57.9) | - | 6 (1.3) | 17 (3.8) | 40 (11.2) | 51 (26.8) | High | 0.003 | |
High | 299 (37.0) | - | 6 (2.0) | 22 (7.9) | 37 (14.9) | 56 (45.7) | Low | 0.010 | |
SAGE-B (n = 808) ‡ | |||||||||
Low | 198 (24.5) | - | 0 (0.0) | 1 (0.6) | 8 (5.4) | 11 (14.0) | <0.001 | Int | 0.003 |
Int | 450 (55.7) | - | 8 (1.8) | 24 (5.5) | 47 (13.0) | 62 (33.7) | High | 0.002 | |
High | 160 (19.8) | - | 4 (2.5) | 14 (9.5) | 23 (17.8) | 35 (50.5) | Low | <0.001 |
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Lee, J.S.; Lim, T.S.; Lee, H.W.; Kim, S.U.; Park, J.Y.; Kim, D.Y.; Ahn, S.H.; Lee, H.W.; Lee, J.I.; Kim, J.K.; et al. Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis. Diagnostics 2023, 13, 3. https://doi.org/10.3390/diagnostics13010003
Lee JS, Lim TS, Lee HW, Kim SU, Park JY, Kim DY, Ahn SH, Lee HW, Lee JI, Kim JK, et al. Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis. Diagnostics. 2023; 13(1):3. https://doi.org/10.3390/diagnostics13010003
Chicago/Turabian StyleLee, Jae Seung, Tae Seop Lim, Hye Won Lee, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Hyun Woong Lee, Jung Il Lee, Ja Kyung Kim, and et al. 2023. "Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis" Diagnostics 13, no. 1: 3. https://doi.org/10.3390/diagnostics13010003
APA StyleLee, J. S., Lim, T. S., Lee, H. W., Kim, S. U., Park, J. Y., Kim, D. Y., Ahn, S. H., Lee, H. W., Lee, J. I., Kim, J. K., Min, I. K., & Kim, B. K. (2023). Suboptimal Performance of Hepatocellular Carcinoma Prediction Models in Patients with Hepatitis B Virus-Related Cirrhosis. Diagnostics, 13(1), 3. https://doi.org/10.3390/diagnostics13010003