Diagnostic accuracy of blood-based non-invasive tests for prediction of varices in pediatric portal-hypertension: A systematic review and meta-analysis

Table 1 Characteristics of included studies evaluating the diagnostic performance of aminotransferase-to-platelet ratio index and platelet count for prediction of oesophageal/gastric varices in pediatric portal hypertension, mean ± SD/median (25^th-75^th percentiles)/n (%)

Index test	Ref.	Study design/period	Sample size/gender	Age	Etiology of portal hypertension	Prevalence of varices	Interval between index test and reference standard	Any grade oesophageal/gastric varices						Clinically significant varices
								Cut-off value	TP	FP	FN	TN	AUROC	Cut-off value	TP	FP	FN	TN	AUROC
APRI	Colecchia et al[29], Italy, 2011	Prospective single-center (1990-2009)	31. Male = 13 (43)	12 ± 15.5 years	Cirrhotic. Biliary atresia-post KPE	48.3%	1 day	> 0.96	13	3	2	13	0.88
	Chongsrisawat et al[30], Thailand, 2011	Prospective single-center	73. Gender = NA	9.11 ± 5.64 years	Cirrhotic. Biliary atresia-post KPE	53.4%	NA	> 1.92	33	6	6	28	0.87
	Adami et al[34], Brazil, 2013	Retrospective single-center (2000-2011)	103. Male = 47 (45.7)	8.9 ± 4.7 years	Cirrhotic + non-cirrhotic	68.9%	Up to 3 months	> 1.4	45	11	26	21
	Isted et al[35], United Kingdom, 2015	Retrospective single-center (2004-2012)	195. Male = 83 (42.5)	55 (11-216) days	Cirrhotic. Biliary atresia post-KPE	21.5%	NA							≥ 1.64	29	57	13	96	0.72
	Voutilainen et al[36], Finland, 2016	Prospective single-center (2012-2015)	64. Male = 34 (53.1)	5.2 (2.1-13.9) years	Cirrhotic. Biliary atresia-post KPE (34.3%). IFALD (42.1%). Cholestatic liver disease (9.3%). Miscellaneous (14.3%)	21.8%	1 day	> 0.6	14	17	0	33	0.832
	Tomita et al[37], Japan, 2016	Prospective single-center (2011-2014)	16. Gender = NA	6.3 (0.7-33.5) years	Cirrhotic. Biliary atresia-post KPE	18.7%	Up to 3 months							> 4.87	2	0	1	13	0.72
	Witters et al[38], United Kingdom, 2017	Prospective single-center (2005-2014)	124. Male = 66 (53.2)	8.81 ± 5.60 years	Cirrhotic + non-cirrhotic	63.7%	Up to 6 months							> 1.603	48	20	31	25	0.61
	Adami et al[39], Brazil, 2018	Retrospective single-center (2000-2011)	98. Male = 46 (46.9)	9.1 ± 4.7 years	Cirrhotic. Autoimmune hepatitis (21.4%). Biliary atresia (26.5%). Sclerosing cholangitis (6.1%). Cystic fibrosis (6.1%). Idiopathic biliary cirrhosis (12.2%). Miscellaneous (27.5%)	32.6%	Up to 3 months							> 1.4	18	35	14	31
	Yoon et al[41], South Korea, 2019	Retrospective single-center (2015-2016)	22. Male = 10 (45.4)	10 (4-18) years	Cirrhotic. Biliary atresia-post KPE	27.2%	Up to 6 months	> 0.65	6	4	0	12	0.844
	Chiou et al[42], Singapore, 2019	Retrospective single-center (1989-2016)	72. Male = 35 (48.6)	NA	Cirrhotic. Biliary atresia-post KPE	22.2%	6 months							≥ 3	13	13	3	43	0.828
	Yokoyama et al[43], Japan, 2019	Prospective single-center (2018-2019)	34. Male = 11 (32.2)	5.2 ± 5.92 years	Cirrhotic. Biliary atresia-post KPE	41.1%	1-2 days							≥ 1.63	10	3	4	17	0.750
	Lampela et al[44], Finland, 2020	Prospective single-center (1989-2017)	45. Gender = NA	1.6 (0.7-14) years	Cirrhotic. Biliary atresia-post KPE	46.6%	None. Both done on same day							≥ 1.01	19	12	2	12	0.64
	Kumar et al[46], India, 2020	Prospective single-center (2018-2019)	59. Gender = NA	NA	Cirrhotic. Wilson disease (25%). Autoimmune hepatitis (16%). Biliary atresia (11%). Cholestatic liver disease (8%). Miscellaneous (40%)	54.2%	Up to 1 week	≥ 1.5	26	7	6	20	0.81
	Lopes et al[48], Brazil, 2021	Retrospective single-center (2004-2018)	158. Male = 70 (44.3)	5.38 (2.08-11.52) years	Cirrhotic. Biliary atresia (35.4%). Autoimmune hepatitis (27.8%). Sclerosing cholangitis (14.5%). Alpha1-antitrypsin deficiency (8.2%). Cryptogenic cirrhosis (6.3%). Miscellaneous (7.5%)	18.9%	Up to 3 months							≥ 1.4	26	63	4	65	0.744
	Rahmani et al[49], Iran, 2021	Prospective single-center	98. Male = 66 (67.3)	9.48± 4.9 years	Cirrhotic	43.8%	NA	≥ 0.45	33	18	10	37	0.799
	Poddar et al[16], India, 2023	Retrospective single-center (2010-2022)	110. Male = 75 (68.1)	12 (8-24) months	Cirrhotic. Biliary atresia	31.8%	None							≥ 2	29	28	6	47	0.720
	Yokoyama et al[50], Japan, 2024	Prospective single-center (2018-2022)	53. Male = 17	4 (0-18) years	Cirrhotic. Biliary atresia-post KPE	52.8%	Up to 1 month							≥ 1.476	22	5	6	20	0.826
Platelet count	Gana et al[32], Multicentric, 2011	Prospective multi-center (2007-2010)	108. Male = 53 (48)	11 ± 5.4 years	Cirrhotic + non-cirrhotic	68.5%	Up to 3 weeks	< 1.15 lakh/mm3	60	10	14	24	0.790
	Alcantara et al[33], Brazil, 2012	Prospective. Single-center (2007-2011)	35. Gender = NA	Median: 11 years	Cirrhotic. Autoimmune hepatitis (54.2%). Biliary atresia (28.5%). Miscellaneous (17.1%)	48.5%	Up to 3 months	< 1.19 lakh/mm3	13	3	4	15	0.830
	Adami et al[34], Brazil, 2013	Retrospective single-center (2000-2011)	103. Male = 47 (45.7)	8.9 ± 4.7 years	Cirrhotic + non-cirrhotic	68.9%	Up to 3 months	< 1.15 lakh/mm3	48	6	23	26	0.820
	Adami et al[39], Brazil, 2018	Retrospective single-center (2000-2011)	98. Male = 46 (46.9)	9.1 ± 4.7 years	Cirrhotic	32.6%	Up to 3 months							< 115 × 109/L	21	30	11	36	0.67
	Chiou et al[42], Singapore, 2019	Retrospective single-center (1989-2016)	72. Male = 35 (48.6)	NA	Cirrhotic. Biliary atresia post-KPE	22.2%	6 months							< 100 × 109/L	12	11	4	45	0.800
	Alam et al[45], Bangladesh, 2019	Prospective single-center (2016-2018)	84. Male = 44 (52.4)	9.7 ± 3.2 years	Cirrhotic. Wilson disease (65.4%). Hepatitis B/C (7.1%). Autoimmune hepatitis (7.1%). Biliary atresia (5.9%). Miscellaneous (14.2%)	71.4%-EV. 55%-CSV	None	< 1 lakh/mm3	26	1	34	23	0.740	< 100 × 109/L	17	9	16	18	0.640
	Vadlapudi et al[47], India, 2020	Prospective single-center (2017-2018)	55. Male = 33 (60)	9.37 ± 3.12 years	Non-cirrhotic Extrahepatic portal vein thrombosis	87.2%	NA							< 117 × 109/L	37	3	11	4	0.568
	Lopes et al[48], Brazil, 2021	Retrospective single-center (2004-2018)	158. Male = 70 (44.3)	5.38 (2.08-11.52) years	Cirrhotic	18.9%	Up to 3 months							< 100 × 109/L	13	21	17	107	0.709
	Rahmani et al[49], Iran, 2021	Prospective single-center	98. Male = 66 (67.3)	9.48 ± 4.9 years	Cirrhotic	43.8%	NA	< 1.1 lakh/mm3	36	18	7	37	0.833
	Poddar et al[16], India, 2023	Retrospective single-center (2010-2022)	110. Male = 75 (68.1)	12 (8–24) months	Cirrhotic. Biliary atresia	31.8%	None							< 150 × 109/L	26	25	9	50	0.690
	Yokoyama et al[50], Japan, 2024	Prospective single-center (2018-2022)	53. Male = 17	4 (0-18) years	Cirrhotic. Biliary atresia post-KPE	52.8%	Up to 1 month							< 141 × 109/L	20	10	8	15	0.721

APRI: Aspartate aminotransferase to platelet ratio index; EV: Esophageal/gastric varices; KPE: Kasai portoenterostomy; CSV: Clinically significant varices; TP: True positive; FP: False positive; TN: True negative; FN: False negative; AUROC: Area under receiver operating characteristic curve; NA: Not available.

Table 2 Characteristics of included studies evaluating the diagnostic performance of various non-invasive blood-test-based indices for the prediction of oesophageal/gastric varices in pediatric portal hypertension, mean ± SD/median (25^th-75^th percentiles)/n (%)

Index test	Ref.	Study design/period	Sample size/gender	Age	Prevalence of varices	Etiology of portal hypertension	Interval between index test and reference standard	Any grade oesophageal/gastric varices						Clinically significant varices
								Cut-off value	TP	FP	FN	TN	AUROC	Cut-off value	TP	FP	FN	TN	AUROC
Clinical prediction rule	Gana et al[31], Canada, 2010	Retrospective single-center (2000-2007)	51. Male= 25 (49)	Mean (range): 11 (0.2-17) years	33.3%	Cirrhotic + non-cirrhotic	Up to 6 months	≤ 116	14	4	3	30	0.93
	Gana et al[32], Multicentric, 2011	Prospective multi-center (2007-2010)	108. Male = 53 (48)	11 ± 5.4 years	68.5%	Cirrhotic + non-cirrhotic	Up to 3 weeks	≤ 116	60	9	14	25	0.80
	Adami et al[34], Brazil, 2013	Retrospective single-center (2000-2011)	103. Male = 47 (45.7)	8.9 ± 4.7 years	68.9%	Cirrhotic + non-cirrhotic	Up to 3 months	≤ 114	53	7	18	25	0.77
	Isted et al[35], United Kingdom, 2015	Retrospective single-center (2004-2012)	195. Male = 83 (42.5)	55 (11-216) days	21.5%	Cirrhotic. Biliary atresia post-KPE	NA							≤ 114	29	55	13	98	0.74
	Tomita et al[37], Japan, 2016	Prospective single-center (2011-2014)	16	Median (range): 6.3 (0.7-33.5) years	18.7%	Cirrhotic. Biliary atresia-post KPE	Up to 3 months							≤ 106	2	2	1	11	0.76
	Witters et al[38], United Kingdom, 2017	Prospective single-center (2005-2014)	124. Male = 66 (53.2)	8.81 ± 5.60 years	63.7%	Cirrhotic + non-cirrhotic	Up to 6 months							≤ 114	60	18	19	27	0.73
	Adami et al[39], Brazil, 2018	Retrospective single-center (2000-2011)	98. Male= 46 (46.9)	9.1 ± 4.7 years	32.6%	Cirrhotic	Up to 3 months							≤ 114	26	31	6	35	0.65
	Sutton et al[40], United Kingdom, 2018	Prospective single-center (2015-2016)	67. Male= 32 (47.7)	8.5 (0.3-18) years	56.7%	Cirrhotic + non-cirrhotic	None							≤ 106.3	17	10	21	19	0.54
	Yokoyama et al[43], Japan, 2019	Prospective single-center (2018-2019)	34. Male= 11 (32.2)	5.2 ± 5.92 years	41.1%	Cirrhotic. Biliary atresia-post KPE	1-2 days							≤ 120.3	12	7	2	13	0.782
	Lampela et al[44], Finland, 2020	Prospective single-center (1989-2017)	45. Gender = NA	1.6 (0.7-14) years	46.6%	Cirrhotic. Biliary atresia-post KPE	None. Both done on same day							≤ 105	11	4	10	20	0.69
	Diéguez Hernández-Vaquero et al[51], Spain, 2024	Retrospective single-center	45 UGIE (in 18 patients). Male = 11 (61.1)1	NA	80%	Non-cirrhotic. Extrahepatic portal vein thrombosis	Up to 6 months							≤ 115	8	0	28	9	0.815
	Jezequel et al[52], France, 2025	Retrospective single-center (2020-2024)	58. Male = 28 (48.3)	9.20 (4.0-14.3) years	53.4%	Cirrhotic + non-cirrhotic. Biliary atresia (32.8%). Autoimmune hepatitis (19%). Portal vein thrombosis (13.8%). Wilson disease (5.2%). Miscellaneous (29.2%)	NA	≤ 116.4	23	6	8	21	0.71
Varice prediction rule	Isted et al[35], United Kingdom, 2015	Retrospective single-center (2004-2012)	195. Male = 83 (42.5)	55 (11-216) days	21.5%	Cirrhotic. Biliary atresia post-KPE	NA							≤ 7.2	36	44	6	109	0.75
	Tomita et al[37], Japan, 2016	Prospective single-center (2011-2014)	16. Gender = NA	Median (range): 6.3 (0.7-33.5) years	18.7%	Cirrhotic. Biliary atresia post-KPE	Up to 3 months							≤ 7.16	3	3	0	10	0.85
	Witters et al[38], United Kingdom, 2017	Prospective single-center (2005-2014)	124. Male = 66 (53.2)	8.81 ± 5.60 years	63.7%	Cirrhotic. Biliary atresia post-KPE	Up to 6 months							≤ 3.63	63	18	16	27	0.72
	Chiou et al[42], Singapore, 2019	Retrospective single-center (1989-2016)	72. Male = 35 (48.6)	NA	22.2%	Cirrhotic. Biliary atresia post-KPE	6 months							≤ 3	13	8	3	48	0.833
	Lampela et al[44], Finland, 2020	Prospective single-center (1989-2017)	45. Gender = NA	1.6 (0.7-14) years	46.6%	Cirrhotic. Biliary atresia post-KPE	None. Both done on same day							≤ 2.76	16	10	5	14	0.720
	Lopes et al[48], Brazil, 2021	Retrospective single-center (2004-2018)	158. Male = 70 (44.3)	5.38 (2.08-11.52) years	18.9%	Cirrhotic	Up to 3 months							≤ 7.2	25	66	5	62	0.752
	Diéguez Hernández-Vaquero et al[51], Spain, 2024	Retrospective single-center	45 UGI. (in 18 patients). Male = 11 (61.1)	NA	80%	Non-cirrhotic. Extrahepatic portal vein thrombosis	Up to 6 months							≤ 7.3	24	0	12	9	0.858
King’s variceal prediction score (K-VaPS)	Witters et al[38], United Kingdom, 2017	Prospective single-center (2005-2014)	124. Male = 66 (53.2)	8.81 ± 5.60 years	63.7%	Cirrhotic + non-cirrhotic	Up to 6 months							≤ 76	57	12	22	33	0.77
	Sutton et al[40], United Kingdom, 2018	Prospective single-center (2015-2016)	67. Male = 32 (47.7)	Median (range): 8.5 (0.3-18) years	56.7%	Cirrhotic + non-cirrhotic	None							≤ 75.2	15	11	23	18	0.48
	Yokoyama et al[43], Japan, 2019	Prospective single-center (2018-2019)	34. Male = 11 (32.2)	5.2 ± 5.92 years	41.1%	Cirrhotic. Biliary atresia-post KPE	1-2 days							≤ 96.1	10	5	4	15	0.775
	Lampela et al[44], Finland, 2020	Prospective single-center (1989-2017)	45. Gender = NA	1.6 (0.7-14) years	46.6%	Cirrhotic. Biliary atresia-post KPE	None. Both done on same day							≤ 68	14	8	7	16	0.670
	Diéguez Hernández-Vaquero et al[51], Spain, 2024	Retrospective single-center	45 UGIE (in 18 patients). Male = 11 (61.1)1	NA	80%	Non-cirrhotic. Extrahepatic portal vein thrombosis	Up to 6 months							≤ 76	2	0	34	9	0.753

¹In this study, total number of upper gastrointestinal endoscopy was used for the calculation of diagnostic accuracy instead of the number of patients.

KPE: Kasai portoenterostomy; TP: True positive; FP: False positive; TN: True negative; FN: False negative; AUROC: Area under receiver operating characteristic curve; NA: Not available; UGIE: Upper gastrointestinal endoscopy.

Table 3 Diagnostic accuracy of various blood-based parameters/indices for the prediction of any varices and clinically significant varices in pediatric portal hypertension

Index test	Target condition	No. of study cohorts	Pooled sensitivity (95%CI)	Pooled specificity (95%CI)	Diagnostic odds ratio (95%CI)	PLR (95%CI)	NLR (95%CI)	AUC	Pre-test probability (%)	Post-test probability (+) (%)	Post-test probability (-) (%)
APRI	EV	7	0.77 (0.71-0.83)	0.71 (0.65-0.77)	11.15 (4.75-33.09)	2.85 (2.06-4.07)	0.26 (0.11-0.46)	0.795	25	47	10
									50	73	24
									75	89	49
	CSV	10	0.72 (0.67-0.77)	0.61 (0.57-0.65)	5.91 (2.91-18.62)	2.23 (1.57-4.94)	0.38 (0.24-0.55)	0.776	25	38	13
									50	65	32
									75	85	58
Platelet count	EV	5	0.69 (0.63-0.75)	0.77 (0.69-0.83)	9.23 (3.40-25.67)	3.30 (1.94-6.34)	0.36 (0.19-0.62)	0.834	25	50	12
									50	75	29
									75	90	55
	CSV	7	0.66 (0.59-0.72)	0.72 (0.67-0.76)	4.25 (1.95-8.56)	2.1 (1.38-3.14)	0.5 (0.33-0.71)	0.714	25	61	5
									50	83	15
									75	93	34
CPR	EV	4	0.78 (0.71-0.83)	0.80 (0.71-0.86)	12.91 (5.72-28.50)	3.68 (2.14-6.17)	0.29 (0.19-0.43)	0.848	25	70	6
									50	87	17
									75	95	38
	CSV	8	0.62 (0.56-0.68)	0.65 (0.59-0.70)	3.76 (1.74-8.40)	2.0 (1.35-3.26)	0.54 (0.32-0.79)	0.717	25	37	16
									50	64	37
									75	84	64
VPR	CSV	7	0.79 (0.73-0.84)	0.65 (0.60-0.70)	9.19 (4.06-21.7)	2.64 (1.73-5.11)	0.29 (0.19-0.44)	0.864	25	43	10
									50	70	24
									75	87	49
K-VaPS	CSV	5	0.52 (0.45-0.59)	0.72 (0.63-0.79)	2.43 (0.72-8.17)	1.72 (0.78-3.16)	0.72 (0.36-1.08)	0.727	25	38	18
									50	65	40
									75	85	67

EV: Esophageal/gastric varices; CSV: Clinically significant varices; APRI: Aspartate aminotransferase to platelet ratio index; CPR: Clinical prediction rule; VPR: Varices prediction rule; K-VaPS: King’s variceal prediction score; PLR: Positive likelihood ratio; NLR: Negative likelihood ratio; AUC: Area under receiver operating characteristic curve.

Table 4 Summary of findings table for certainty of evidence by Grading of Recommendations, Assessment, Development and Evaluation approach for diagnostic accuracy of blood-based non-invasive tests as a predictor of varices in pediatric portal hypertension

Diagnostic test for the target condition	No. of studies (n = No. of participants)	Study design	Accuracy parameter	Risk of bias	Indirectness	Inconsistency	Imprecision	Publication bias	Overall certainty of evidence
APRI for EV	7 studies (n = 450)	Cross-sectional	Sensitivity	Serious1	Not serious	Serious2	Not serious	None	Low
			Specificity	Serious1	Not serious	Not serious	Not serious	None	Moderate
APRI for CSV	10 studies (n = 892)	Cross-sectional	Sensitivity	Serious1	Not serious	Not serious	Serious3	None	Low
			Specificity	Serious1	Not serious	Serious2	Not serious	None	Low
Platelet count for EV	5 studies (n = 368)	Cross-sectional	Sensitivity	Serious1	Not serious	Serious2	Not serious	None	Low
			Specificity	Serious1	Not serious	Serious2	Not serious	None	Low
Platelet count for CSV	7 studies (n = 612)	Cross-sectional	Sensitivity	Serious1	Not serious	Not serious	Not serious	None	Moderate
			Specificity	Serious1	Not serious	Serious2	Serious3	None	Very low
CPR for EV	4 studies (n = 320)	Cross-sectional	Sensitivity	Serious1	Not serious	Not serious	Not serious	None	Moderate
			Specificity	Serious1	Not serious	Not serious	Not serious	None	Moderate
CPR for CSV	8 studies (n = 624)	Cross-sectional	Sensitivity	Serious1	Not serious	Serious2	Serious3	None	Very low
			Specificity	Serious1	Not serious	Serious2	Not serious	None	Low
VPR for CSV	7 studies (n = 655)	Cross-sectional	Sensitivity	Serious1	Not serious	Not serious	Serious3	None	Low
			Specificity	Serious1	Not serious	Serious2	Not serious	None	Low
K-VaPS for CSV	5 studies (n = 315)	Cross-sectional	Sensitivity	Serious1	Not serious	Serious2	Not serious	None	Low
			Specificity	Serious1	Not serious	Not serious	Not serious	None	Moderate

¹As per the Quality Assessment of Diagnostic Accuracy Studies-2 tool, some of the included studies have high risk of bias across flow and timing domain.

²As there is substantial heterogeneity I² > 60%, we downgraded by one level, as we could not conduct meta-regression for all possible covariates.

³We downgraded by one level due to the wide confidence intervals around the accuracy parameters of some of the included studies.

EV: Esophageal/gastric varices; CSV: Clinically significant varices; APRI: Aspartate aminotransferase to platelet ratio index; CPR: Clinical prediction rule; VPR: Varices prediction rule; K-VaPS: King’s variceal prediction score.