Routine laboratory model for identifying significant fibrosis in chronic hepatitis B

Table 1 Baseline characteristics of the study cohorts, median (interquartile range)/n (%)

	Variable1	Development	External (First Affiliated Hospital of Zhejiang University)	National Health and Nutrition Examination Survey (population-based)
Clinical features	Age (years)	41.0 (16.0)	38.0 (17.0)	48.5 (18.8)
	Sex (male)	765 (65.6)	367 (59.1)	1284 (54.1)
	Body mass index (kg/m2)	23.1 (4.4)	22.2 (4.2)	24.7 (5.6)
	Height (cm)	167.0 (11.5)	168.0 (12.0)	165.3 (14.2)
	Weight (kg)	64.0 (14.8)	61.0 (16.0)	73.2 (23.4)
Hepatitis B virus virology	Hepatitis B surface antigen, log10 (IU/mL)	2.4 (1.4)	3.6 (1.7)
Liver function tests	Alanine aminotransferase (U/L)	36.0 (35.0)	43.0 (58.0)	57.7 (55.3)
	Aspartate aminotransferase (U/L)	32.0 (22.0)	31.0 (29.0)	35.0 (23.5)
	Gamma-glutamyl transferase (U/L)	27.0 (28.0)	27.0 (38.0)	21.0 (18.0)
	Alkaline phosphatase (U/L)	87.5 (36.0)	72.0 (32.0)	67.0 (28.0)
	Albumin (g/L)	43.1 (5.6)	44.7 (7.0)	38.1 (3.5)
	Globulin (g/L)	28.1 (5.6)	26.6 (5.6)	30.0 (10.0)
	White blood cell count (109/L)	5.4 (2.1)	5.4 (2.1)	5.1 (6.5)
	Red blood cell count (1012/L)	4.7 (0.8)	4.7 (0.8)	4.6 (0.7)
Blood routine characteristics	Platelet count (109/L)	176.0 (78.0)	190.0 (71.0)	205.5 (80.5)
	Mean corpuscular volume (fL)	91.0 (5.8)	90.2 (5.5)	89.7 (7.0)
	Total cholesterol (mmol/L)	4.3 (1.2)	4.1 (1.2)	3.9 (0.7)
Metabolic indicators	High density lipoprotein-cholesterol (mmol/L)	1.2 (0.4)	1.2 (0.5)	1.1 (0.3)
	Low-density lipoprotein-cholesterol (mmol/L)	2.5 (0.9)	2.3 (1.0)	2.4 (0.6)

¹Continuous variables are presented as median (interquartile range), and categorical variables as n (%). The development cohort and the biopsy-confirmed external validation cohort (First Affiliated Hospital of Zhejiang University) included adults with chronic hepatitis B who underwent liver biopsy with fibrosis staged according to the Scheuer system. The population-based cohort was derived from National Health and Nutrition Examination Survey 2011-2020 and included individuals with evidence of hepatitis B virus exposure. Quantitative hepatitis B surface antigen was available only in the hospital-based cohorts and is therefore reported for descriptive purposes only. Hepatitis B surface antigen was not included in model development or external evaluation because it was not consistently available/derivable across cohorts (including National Health and Nutrition Examination Survey). Cross-cohort harmonization refers to the final model predictors and preprocessing rules, which were uniformly applied across datasets.

Table 2 Observed prevalence of significant fibrosis across model-defined risk strata within the fibrosis-4 indeterminate zone (n = 129)

Group	n	S ≥ 21	S ≥ 2 (%)
Low risk	54	7	13.0
Uncertain	39	14	35.9
High risk	36	27	75.0

¹S ≥ 2 denotes significant fibrosis according to the Scheuer staging system.

Values are presented as number of patients and percentage within each stratum.

Table 3 Discriminative performance of the machine-learning model across cohorts

Cohort1	AUC (95%CI)	Sensitivity (95%CI)	Specificity (95%CI)	PPV	NPV	F1 (95%CI)
Development	0.8528 (0.8301-0.8722)	0.8088 (0.7711-0.8449)	0.7077 (0.6735-0.7394)	0.6212	0.8619	0.7027 (0.6708-0.7337)
External (First Affiliated Hospital of Zhejiang University)	0.8379 (0.8000-0.8721)	0.7290 (0.6506-0.7949)	0.7361 (0.6966-0.7778)	0.4788	0.8909	0.5780 (0.5151-0.6383)
National Health and Nutrition Examination Survey (surrogate-labeled)	0.817 (0.800-0.833)

¹Area under the receiver operating characteristic curve with 95% confidence intervals is reported for the development cohort and the biopsy-confirmed external validation cohort (First Affiliated Hospital of Zhejiang University), together with sensitivity, specificity, positive predictive value, negative predictive value, and F1-score (with 95% confidence intervals where applicable) evaluated at the pre-specified operating point used in the main analysis. For the National Health and Nutrition Examination Survey exploratory cohort, fibrosis status was derived using an aspartate aminotransferase to platelet ratio index/fibrosis-4-based surrogate phenotyping algorithm rather than histology; therefore, only area under the curve (95% confidence interval) is presented as the primary measure of discrimination for this surrogate-labeled outcome, and threshold-dependent metrics are not reported.

PPV: Positive predictive value; NPV: Negative predictive value; AUC: Area under the curve; CI: Confidence interval.