Hepatology Publish Ahead of Print

DOI:10.1097/HEP.0000000000000842
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Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A

systematic review supporting the AASLD Practice Guideline

Keyur Patel1, Sumeet K Asrani2, Maria Isabel Fiel3, Deborah Levine4, Daniel H. Leung5, Andres
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Duarte-Rojo6, Jonathan A. Dranoff7, Tarek Nayfeh8, Bashar Hasan8, Tamar H. Taddei7, Yahya

Alsawaf8, Samer Saadi8, Abdul Mounaem Majzoub8, Apostolos Manolopoulos8, Muayad

Alzuabi8, Jingyi Ding8, Nigar Sofiyeva8, M. Hassan Murad8, Mouaz Alsawas8,9, Don C.
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Rockey10, Richard K. Sterling11

1
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Division of Gastroenterology and Hepatology, University Health Network, University of

Toronto, Toronto, ON, Canada; 2Division of Hepatology, Baylor University Medical Center,

Dallas, Texas 3Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of

Medicine at Mount Sinai, New York, NY; 4Department of Radiology, Beth Israel Deaconess

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 Medical Center, Boston, Harvard Medical School; 5Department of Pediatrics, Baylor College of

Medicine and Division of Gastroenterology, Hepatology and Nutrition, Texas Children’s

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Hospital, Houston, TX; 6Division of Gastroenterology, Hepatology and Nutrition, University of

Pittsburgh, Pittsburgh, Pennsylvania; 7Section of Digestive Diseases, Yale School of Medicine,

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New Haven, CT, and VA Connecticut Healthcare System, West Haven, CT; 8Mayo Clinic

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Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota; 9Department of Pathology,

University of Iowa, Iowa City, Iowa;10Digestive Disease Research Center, Medical University of

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South Carolina, Charleston, SC; 11Section of Hepatology, Virginia Commonwealth University,

Richmond, Virginia;
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Corresponding author:
Keyur Patel, MD, PhD
Division of Gastroenterology and Hepatology,
University Health Network,
University of Toronto,
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200 Elizabeth Street

Toronto, Ontario M5G2C4
Canada
Email: [email protected]
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List of Abbreviations

AASLD: American Association for the Study of Liver Diseases; AIH: autoimmune hepatitis;

ALD: alcohol-associated liver disease; APRI: AST-to-platelet ratio index; AUROC: Area Under

Receiver Operating Characteristic; CLD: chronic liver disease; DAA: direct acting antiviral;

DOR: diagnostic odds ratio; ELF: Enhanced liver fibrosis; F: Fibrosis (used in staging fibrosis

with stages F1 to F4); FIB-4: Fibrosis 4 index; GRADE: Grading of Recommendation

Assessment, Development and Evaluation; HCV: hepatitis C virus; HBV: hepatitis B virus; HIV:

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 human immunodeficiency virus; LR: likelihood ratio; METAVIR: meta-analysis of histological

data in viral hepatitis; NAFLD: non-alcoholic fatty liver disease; NFS: non-alcoholic fatty liver

disease fibrosis score; NPV: negative predictive value; NILDA: non-invasive liver disease
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assessments; PICO: patient, intervention, comparison and outcome; PSC: primary sclerosing

cholangitis, PBC: primary biliary cholangitis; PPV: positive predictive value; SVR: sustained
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virologic response;

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Conflicts of Interest

Keyur Patel consults and received grants from Gilead and Intercept. He consults for Galectin and
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Resalis. He advises Novo Nordisk. He received grants from Celgene, GENFIT,

GlaxoSmithKline, Madrigal, and Merck. Maria Isabel Fiel consults for Alexion, Progenity/Biora

Therapeutics, and Q32 Bio. Daniel H. Leung consults, advises, and received grants from Gilead.

He consults for AstraZeneca and Merck. He received grants from AbbVie, CF Foundation,
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Gilead, and Mirum. Andres Duarte-Rojo consults and received grants from Axcella Health. He

advises and received grants from Mallinckrodt. He received grants from AMRA Medical and
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Echosens. Tamar H. Taddei is on the board of AASLD. Don C. Rockey received grants paid to

his institution from Intercept, Freenome, Genfit, Gilead, Sequana Medical, Galectin, Novo

Nordisk, Pfizer, Durect, Axcella Therapeutics, Viking, Salix, Helio, Inventiva, Boehringer

Ingelheim, AstraZeneca, Ocelot Biological, Ipsen Madrigal, and Bio89. He consults for

Calliditas Therapeutics, Xeris Pharmaceuticals, and Takeda. He advises AstraZeneca, Merck,

Resolution Therapeutics, and Takeda. Richard K. Sterling received grants from Abbott, AbbVie,

Gilead, Roche and Zydus. The remaining authors have no conflicts to report.

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 Financial Support
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Funding for this systematic review was provided by the American Association for the Study of

Liver Diseases.
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ABSTRACT

Background and Aims

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Blood-based biomarkers have been proposed as an alternative to liver biopsy for non-invasive
liver disease assessment (NILDA) in chronic liver disease (CLD). Our aims for this systematic
review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in
combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4) and cirrhosis
(F4), as compared to biopsy in CLD.
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Approach and Results
We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE,
Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286
studies with 103,162 patients. The most frequently identified studies included the simple
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aminotransferase-to-platelet ratio index (APRI) and fibrosis (FIB)-4 markers (with low-to-
moderate risk of bias) in hepatitis B virus (HBV) and C virus (HCV), HIV-HCV/HBV co-
infection, and nonalcoholic fatty liver disease (NAFLD). Positive (LR+) and negative (LR )
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likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or
F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86
respectively; LR+ and LR for NAFLD F2-4, F3-4 and F4 were 2-65-3.37 and 0.37-0.39, 2.25-
6.76 and 0.07-0.87, and 3.90 and 0.15 respectively. Overall, proportional odds ratio indicated
FIB-4 <1.45 was better than APRI <0.5 for F2-4. FIB-4 >3.25 was also better than APRI >1.5
for F3-4 and F4. There was limited data for combined tests.
Conclusions Blood-based biomarkers are associated with small-to-moderate change in pre-test
probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV co-infection, and
NAFLD, with limited comparative or combination studies for other CLD.

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 INTRODUCTION

Hepatic fibrosis is a key measure of disease severity in chronic liver disease (CLD) with

important prognostic implications. In recent years there has been increased availability and
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greater acceptance of non-invasive liver disease assessment (NILDA) as an alternative to liver

biopsy for determination of fibrosis stage in CLD. Although histologic assessment remains the
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established standard for assessing injury, inflammation, and fibrosis stage, current blood-based

NILDA biomarkers may overcome the risks and sampling limitations associated with liver

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biopsy. The advent of simplified direct acting antiviral (DAA) therapeutic regimens in chronic

hepatitis C has now essentially eliminated the need for liver biopsy prior to antiviral therapy, and

NILDA is now routinely obtained to establish pre-treatment disease severity (1). With the
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increasing burden of nonalcoholic fatty liver disease (NAFLD), NILDA plays an increasingly

important role in the assessment of advanced fibrosis across diverse populations. Both

proprietary (i.e., patented) and non-proprietary blood-based tests for fibrosis assessment are

increasingly incorporated into routine clinical practice and adapted for all CLD (2).
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Blood-based NILDA biomarkers include a combination of either “direct markers”, that are

mostly complex proteins derived from myofibroblasts and extracellular matrix remodeling, or
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“indirect markers” that are relatively simple biochemical tests which estimate disease severity.

Although none of the current blood-based biomarkers are liver specific, potential advantages

compared to biopsy include cost, availability (for simple non-proprietary tests), inter-laboratory

reproducibility, repeat testing, and ease of use for routine clinical practice. However, an

important consideration is the reliability of currently available blood-based biomarkers to

accurately stage liver fibrosis and thus reduce the need for biopsy. Limitations in diagnostic

biomarker performance due to unreliable classification, disease heterogeneity, biopsy sampling,

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 or cohort spectrum effect have been reviewed previously (3). Interpretation of test results at

specified biomarker thresholds will depend on the practice setting (primary vs. specialist care),

and should account for limitations in NILDA study quality, variability in biomarker cutoffs,
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along with reported diagnostic accuracy.

Our study population included adult patients with CLD from hepatocellular (hepatitis C virus
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[HCV], hepatitis B virus [HBV], NAFLD, alcoholic-associated liver disease [ALD]) or

cholestatic disorders (primary sclerosing cholangitis [PSC], primary biliary cholangitis [PBC]).

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The role of serum‐based biomarker panels for assessment of hepatic fibrosis remains

unestablished in AIH(4).

Our objectives for this systematic review were to address three key questions (Table 1) as
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related to the accuracy of blood-based biomarkers for staging fibrosis, with liver biopsy as the

reference standard.

METHODS

This Systematic Review followed a predefined protocol developed by the NILDA writing group
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on behalf of the American Association for the Study of Liver Diseases (AASLD) Practice

Guideline Committee, and reported according to the Preferred Reporting Items for Systematic
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Reviews and Meta-Analyses (PRISMA) statement (5), http://links.lww.com/HEP/I342.

Search Strategy

A comprehensive search of several databases from each database’s inception to April 21, 2022.

The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-

Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled

Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search strategy was

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 designed and conducted by an experienced librarian with input from the study investigators.

Controlled vocabulary terms using Medical Subject Headings (MeSH) supplemented with

keywords was used to search for studies of non-invasive assessment of liver diseases. The search
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strategy used for this systematic review is detailed in the Supplementary Appendix,

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Study Selection

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Three PICO (Patient, Intervention, Comparison and Outcome) questions for this systematic

review were formulated by the writing group members with oversight by the AASLD Practice

Guidelines Committee (Table 1). We included studies that tested blood-based biomarker
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accuracy in patients with CLD, for the distinction between clinically significant fibrosis (F2-4),

advanced fibrosis (F3-4) and cirrhosis (F4) in CLD patients, as compared to liver histopathology

as the reference standard. We included only comparative studies that were published in English.

Non-proprietary and proprietary (commercially available and/or patented algorithm) blood-based

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biomarkers evaluated by the NILDA writing group included the following: AST-platelet ratio

index (APRI)(6), fibrosis-4 (FIB-4)(7), FibroTest/FibroSURE® (FT/FS)(BioPredictive, Paris,

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France; Labcorp, Burlington, NC)(8), Enhanced Liver Fibrosis TestTM (ELF)(Siemens

Healthineers AG, Erlangen, Germany)(9), FibroMeterTM (FM)(Echosens, Paris, France)(10),

FIBROSpect IITM (FSII)(Prometheus Labs, San Diego, CA)(11), Easy Liver Fibrosis Test

(eLIFT)(12), King’s Score(13), and HepaScoreTM (HS)(PathWest, UWA, Australia)(14).

We identified histopathologic fibrosis (F) stages based on METAVIR(15), or equivalent

classification according to other reported staging systems, including Scheuer(16), Batts-

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 Ludwig(17), Knodell(18), Ishak(19), Brunt(20), Kleiner(21), and Desmet(22). We excluded

studies with a sample size of less than 50 patients, mixed etiology of liver disease, reference

standard other than histopathology, unavailable threshold values for blood-based biomarker tests
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in detecting fibrosis stage, review studies, case reports or case series, and conference abstracts.

Two independent reviewers screened titles and abstracts of the studies for potential eligibility.
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The full articles of these included studies were reviewed by two independent reviewers, and

disagreement was resolved by consensus. We only included studies with adult patients, as there

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were very few studies identified for pediatric cohorts, with overall low quality of evidence for

sensitivity and specificity estimates.

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Data Extraction and Quality Assessment

Two independent reviewers completed the data extraction and studies included baseline

characteristics such as the year of publication, country of the study, setting, main institution,

study period, specific disease, inclusion and exclusion criteria, sample size, age group, sex, body
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mass index (BMI), staging system, days between the test and liver biopsy. To assess the risk of

bias in included studies, we used the quality assessment of diagnostic accuracy studies 2
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(QUADAS-2) tool(23).

Grading the Quality of evidence

We used the GRADE (Grading of Recommendations Assessment, Development, and Evaluation)

approach to rate certainty in the estimates. Quality of evidence derived from diagnostic studies

was considered to be high, but could be rated down for risk of bias or imprecision (based upon

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 the width of the upper and lower estimates of 95% confidence interval (CI) for sensitivity or

specificity, and low accuracy) (24, 25).

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Outcome Measures and Analysis

Outcomes were measures of diagnostic test accuracy (sensitivity, specificity, diagnostic odds
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ratio (DOR), positive likelihood ratio (LR+), negative likelihood ratio (LR )).We used Stata

version 17 (StataCorp, College Station, TX) to synthesize and pool sensitivity, specificity,

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positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio

(DOR) with 95% confidence intervals, after extracting the true positive, false positive, true

negative, and false negative rates across included studies. Instead of relying on statistical
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measures to explore heterogeneity, we stratified analysis by clinically meaningful covariates that

affect diagnostic accuracy, such as test type, cutoffs, disease etiology, and fibrosis stage(26). At

least four studies were required to generate pooled estimates and determine DOR and likelihood

ratios. If less than 4 studies were included, sensitivity, specificity, positive and negative
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predictive values were reported as ranges. Consideration of likelihood ratio allows for potential

clinical application based on pre-test probability, and interpretation from a nomogram. For
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example, LR+ 2, 5 and 10 and LR 0.5, 0.2 and 0.1 indicate a 15, 30, and 45% change in pre-

test probability for positive and negative tests to “rule-in” or “rule-out” a diagnosis, respectively

(27). DOR is the ratio of odds of disease with a positive test relative to the odds of disease in

subjects with a negative test, and useful for comparisons of diagnostic accuracy between tests for

statistical analysis in systematic reviews and meta-analyses, and is independent of disease

prevalence (28). We used a bivariate regression model to pool data across studies accounting for

the correlation between sensitivity and specificity. When comparing two serum biomarkers, we

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 used the proportional odds ratio (POR) of the two tests from the same study and pooled the DOR

using a random effects model (29).

For interpretation, one can compare the DOR for each test in each study (for example, DOR1 of
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APRI and DOR2 of FIB-4), and then calculate POR=DOR1/DOR2 for each study that compared

APRI vs. FIB-4. One can then pool PORs for all the studies with the same comparative tests to
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assess which test is better (for example, a confidence interval excluding 1 can suggest a

significant difference between tests).

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RESULTS

Description of the Evidence

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The search identified a total of 9,447 studies. After screening titles and abstracts, a total of 2,525

articles were included for full-text reviewing. After the application of inclusion and exclusion

criteria, a total of 286 studies were included, comprising data from 103,162 patients.

Characteristics of included studies are provided in the Supplementary Appendix,

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http://links.lww.com/HEP/I340. Forty-seven percent of the included studies (n=134) had a low

risk of bias, 128 studies (45%) had a moderate risk of bias, and 24 (8%) had high risk of bias.
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PICO 1. In adult patients with chronic liver disease, including hepatocellular (HCV, HIV-

HCV, HBV, HIV-HBV, NAFLD, ALD) or cholestatic (PSC, PBC) disorders, are blood-

based biomarker panels accurate in staging hepatic fibrosis (F0-1 vs. F2-4, F0-2 vs. F3-4,

F0-3 vs. F4) using histopathology as the reference?

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 Two hundred and seventy five studies assessed the accuracy of various blood-based biomarker

panels. This included 104 studies for HCV, 96 for HBV, 63 for NAFLD, 12 for HCV/HIV, 8 for

ALD, 3 studies for PBC, and one for HBV/HIV co-infection.

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Chronic Hepatitis C
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Overall, there were a greater number of studies in HCV for the simple non-proprietary tests FIB-

4 and APRI compared to proprietary tests (Table 2).

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Significant Fibrosis (F2-4)

Nonproprietary NILDA

Sixty-three studies reported the accuracy of APRI for staging HCV F2-4 fibrosis at different
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index score threshold (cut-off) values. A median APRI cutoff of 1 (range 0.7-1.2, n=17 studies)

had the highest DOR of 13.35 (6.7-26.57). Thirty-three studies reported FIB-4 for staging F2-4.

The upper FIB-4 cutoff of 3.25 (range 2.71-3.62, n=8 studies) was associated with the highest

DOR 9.71 (6.28-15.02). For HCV F2-4, the LR+ and LR range for non-proprietary blood-
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based tests across different cutoffs were 1.66-5.51 and 0.27-0.63, respectively.

Proprietary NILDA
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Thirteen studies reported FT/FS for staging HCV F2-4. A threshold of 0.3 (range 0.2-0.39, n=7

studies) was associated with a marginally higher DOR of 6.85 (5.48-8.56) than the FT/FS

recommended cutoff of 0.48 for F2-4 (Table 2).

For HCV F2-4, the LR+ and LR range for proprietary blood-based tests across different index

thresholds were 1.99-3.23 and 0.23-0.40 respectively.

Advanced Fibrosis (F3-4)

Non-proprietary NILDA

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 Forty-two studies reported on APRI for staging HCV F3-4 fibrosis at different cutoff values. A

median APRI cutoff of 1 (range 0.7-1.2, n=23 studies) was associated with the highest DOR of

9.73 (5.56-17.03). Thirty-five studies reported FIB-4 for staging HCV F3-4. The lower cutoff of
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1.45 (range 1.22-1.67, n=17 studies) was associated with the highest DOR of 14.44 (9.43-22.12).

For HCV F3-4, the LR+ and LR range for non-proprietary blood-based tests across different
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cutoffs were 2.05-5.60 and 0.20-0.55, respectively.

Proprietary NILDA

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FT/FS at the recommended threshold of 0.58 (range 0.52-0.6, n=4 studies) was associated with

DOR of 8.75 (6.30-12.16) (Table 2).

For HCV F3-4, the corresponding LR+ and LR range for proprietary blood-based tests across
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different index thresholds were 2.31-3.31 and 0.12-0.33.

Cirrhosis (F4)

Non-proprietary NILDA

Forty-four studies reported APRI for staging HCV F4 at cutoff values of 0.5-2. An APRI cutoff
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of 2 (range 2.0-4.3, n=18 studies) was associated with the highest DOR of 11.36 (7.96-16.21). A

median FIB-4 cutoff of 1.45 (range 1.17-2.0, n=8 studies) was associated with DOR of 12.54
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(9.92-15.85). For HCV F4, the corresponding LR+ and LR range for non-proprietary blood-

based tests across different cutoffs were 2.86-7.15 and 0.19-0.63,.

Proprietary NILDA

FT/FS at the validated index score threshold of 0.75 (range 0.7-0.81, n=5 studies), resulted in

DOR of 9.80 (7.16-13.41) (Table 2). For HCV F4, the corresponding LR+ and LR range for

proprietary blood-based tests across different index thresholds were 4.39-6.07 and 0.15-0.45.

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 Chronic Hepatitis B

Significant Fibrosis (F2-4)

Non-proprietary NILDA
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Seventy studies reported the accuracy of APRI in staging HBV F2-4 at similar index score

thresholds to HCV. The upper APRI cutoff of 1.5 (range 1.4-1.5, n=19 studies), was associated
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with DOR of 5.34 (3.84-7.41). Fifty-five studies reported the accuracy of FIB-4 in staging HBV

F2-4. The higher FIB-4 cutoff of 3.25 (range 3.22-4.9, n=10 studies) resulted in DOR of 7.85

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(4.30-14.36) (Table 2). For HBV F2-4, the corresponding LR+ and LR range for non-

proprietary blood-based tests across different cutoffs were 1.71-6.25 and 0.43-0.80.

Proprietary NILDA
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Relatively fewer studies were identified for proprietary tests.

Advanced Fibrosis (F3-4)

Forty studies reported the accuracy of APRI for staging F3-4 in patients with HBV infection. An

APRI cutoff of 1 (range 0.7-1.23, n=12 studies) was associated with DOR of 5.53 (3.97-7.70).
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Forty-two studies reported the accuracy of FIB-4 for F3-4, and median FIB-4 cutoff of 2.2 (range

1.88-2.65, n=10 studies) was associated with the highest DOR of 9.28 (5.7-15.11) (Table 2).
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For HBV F3-4, the LR+ and LR range for non-proprietary blood-based tests across different

cutoffs were 1.89-4.92 and 0.33-0.64 respectively. Very few studies were identified for

proprietary tests for staging HBV F3-4.

Cirrhosis (F4).

Forty-five studies reported the accuracy of APRI for staging F4 in patients with HBV infection.

The lower APRI cutoff of 0.5 (range 0.25-0.75, n=27 studies) was associated with DOR 6.26

(5.13-7.62). Thirty-nine studies reported the accuracy of FIB-4 for F4, and a lower median FIB-4

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 cutoff of 0.5 (range 0.37-0.72, n=5 studies) was associated with the highest DOR of 8.94 (5.18-

15.50) (Table 2). For HBV F4, the corresponding LR+ and LR range for non-proprietary

blood-based tests across different cutoffs were 1.32-4.19 and 0.15-0.86. Very few studies were
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identified for proprietary tests for staging F4.

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Nonalcoholic Fatty Liver Disease

Significant Fibrosis (F2-4)

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Ten studies reported the accuracy of APRI for staging NAFLD F2-4. The lower APRI cutoff of

0.5 (range 0.2-0.69, n=8 studies) resulted in DOR 7.24 (4.56-11.51). Thirteen studies reported

FIB-4 for F2-4, and a FIB-4 cutoff of 1.45 (range 1.1-1.74, n=8 studies) was associated with
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DOR 8.60 (6.04-12.24) (Table 2). For NAFLD F2-4, the LR+ and LR range for non-

proprietary tests were 2.65-3.37 and 0.37-0.39, respectively. Very few studies were identified for

proprietary tests for staging NAFLD F2-4.

Advanced Fibrosis (F3-4)

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Thirty-six studies reported the accuracy of APRI in staging NAFLD F3-4 fibrosis. An APRI

cutoff of 1 (range 0.76-1.0, n=17 studies) was associated with the highest DOR of 8.48 (6.74-
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10.66). Forty-nine studies reported the accuracy of FIB-4 for staging NAFLD F3-4 fibrosis. A

FIB-4 cutoff of 2.67 (n=23 studies) was associated with DOR of 9.98 (6.94-14.36). The lower

FIB-4 cutoff of 1.3 (n=18 studies) was associated with DOR of 7.81 (5.49 to 11.11) (Table 2).

For NAFLD F3-4, the LR+ and LR range for non-proprietary tests was 2.25-6.76 and 0.19-

0.87 respectively. There were fewer studies identified which reported the diagnostic accuracy of

proprietary tests for staging NAFLD F3-4 (Supplementary Appendix,

http://links.lww.com/HEP/I340).

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 Cirrhosis (F4)

There were very few studies that reported on non-proprietary or proprietary tests for staging

NAFLD F4 (Supplemental Appendix, http://links.lww.com/HEP/I340).

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Other Chronic Liver Disease

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HIV/HCV

Significant Fibrosis (F2-4)

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An APRI cutoff of 1.5 (range 1.3-1.54, n=8 studies) was associated with a DOR of 5.48 (3.92-

7.66). The corresponding LR+ and LR range for non-proprietary tests were 1.44-3.63 and

0.37-0.66. Fewer studies were identified for proprietary tests (Supplementary Table S1,
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http://links.lww.com/HEP/I341).

Advanced Fibrosis (F3-F4)

Very few studies reported on blood-based tests for HIV-HCV F3-4, including FIB-4 (n=3

studies) which was developed to predict advanced fibrosis in this specific population.
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(Supplementary Table S1, http://links.lww.com/HEP/I341).

Cirrhosis (F4)
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A lower APRI cutoff of 1 (range 0.76-1.11, n=4 studies) was associated with DOR 15.24 (5.79-

40.11). Very few studies were identified for proprietary tests (Supplementary Table S1,

http://links.lww.com/HEP/I341).

HIV/HBV

Advanced Fibrosis (F3-4)

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 In patients with HIV-HBV co-infection F3-4, a single study reported sensitivity of 0.63 and 0.5,

and specificity of 0.73 and 0.77, for APRI cutoffs of 0.42 (range 0.22-1.0) and FIB-4 1.76 (range

0.88-3.01), respectively (Supplementary Table S1, http://links.lww.com/HEP/I341).

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ALD
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Significant Fibrosis (F2-4)

Only a single study examined APRI in ALD F2-4. For FT/FS, an index threshold of 0.6 (range

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0.59-0.90, n=3 studies) was associated with sensitivity 0.43-0.59 and specificity 0.91-0.97

(Supplementary Table S1, http://links.lww.com/HEP/I341).

Advanced Fibrosis (F3-4) or Cirrhosis (F4)

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Very few studies were identified for non-proprietary tests for ALD F3-4 or F4.

For FT/FS and ALD F4, an index threshold of 0.75 (range 0.70-0.81, n=4 studies) was associated

with DOR 25.55 (12.3-53.02) (Supplementary Table S1, http://links.lww.com/HEP/I341).

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Cholestatic liver disease:

Significant Fibrosis (F2-4)

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Two studies reported APRI and FIB-4 for PBC F2-4, with resulting sensitivity and specificity

range of 0.58-0.89 and 0.39-0.80, respectively (Supplementary Table S1,

http://links.lww.com/HEP/I341).

Advanced Fibrosis (F3-4) and Cirrhosis (F4)

Three studies reported APRI, FIB-4 and ELF for PBC F3-4, with corresponding sensitivity and

specificity range of 0.63-0.90 and 0.58-0.84. A single study reported APRI and FIB-4 for PBC

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 F4, with resulting sensitivity and specificity of 0.91 and 0.50-0.77 respectively (Supplementary

Table S1, http://links.lww.com/HEP/I341).

There were no identified studies for blood-based markers to stage F2-4, F3-4 or F4 in other
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cholestatic liver disease

The overall quality of evidence for diagnostic estimates of PICO 1 was moderate since many of
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the included studies had high or medium risk of bias.

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PICO 2. In adult patients with chronic liver disease, including hepatocellular (HCV, HIV-

HCV, HBV, HIV-HBV, NAFLD, ALD) or cholestatic (PSC, PBC) disorders is any blood-

based biomarker panel superior to another biomarker panel in staging hepatic fibrosis (F0-
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1 vs. F2-4, F0-2 vs. F3-4, F0-3 vs. F4) using histopathology as the reference?

We assessed the performance characteristics of various blood-based NILDA in comparative

studies whereby more than one marker was examined in the same population. Limitations

included: 1) lack of comparison across all cutoffs; 2) few studies with non-proprietary markers as
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a comparator group; and 3) few studies for proprietary markers in comparison to one another.

Ninety studies compared blood-based markers to APRI. This included 30 studies for HCV, 44
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for HBV, 6 for HIV-HCV, and 17 for NAFLD.

Analysis of Comparative Studies

Comparisons were only possible for non-proprietary APRI and FIB-4 and proprietary ELF,

FT/FS, and HS (Table 3). Eighty-six studies directly compared APRI with cutoff values of 0.5,

and 1.5, to other serum markers, including FIB-4 (cutoff 1.45 and 3.25), ELF (cutoff 9 and 9.8),

FT (cutoff 0.48), and HS (cutoff 0.5 and 0.84) (Table 3). Among non-proprietary markers, FIB-4

<1.45 (n=35 studies) was better than APRI <0.5 for F0-1 vs F2-4. FIB-4 >3.25 was better than

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 APRI >1.5 for F0-2 vs F3-4 (n=12 studies) and F0-3 vs F4 (n=4 studies). In most cases for other

select cutoffs, the performance of proprietary and non-proprietary tests compared to APRI was

not significantly different for F0-1 vs. F2-4, F0-2 vs F3-4, and F0-3 vs F4. The performance of
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proprietary and non- proprietary markers was similar for identifying F0-1 vs. F2-4 across all

etiologies.
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The quality of evidence for diagnostic estimates of PICO 2 was very low since many of the

included studies had high or medium risk of bias and diagnostic estimates were imprecise.

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PICO 3. In adult patients with chronic liver disease, including hepatocellular (HCV, HIV-

HCV, HBV, HIV-HBV, NAFLD, ALD) or cholestatic (PSC, PBC) disorders, is the
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combination of two blood-based biomarker panels superior to a single one for staging

fibrosis (F0-1 vs. F2-4, F0-2 vs. F3-4, F0-3 vs. F4) using histopathology as the reference?

Analyses supporting PICO 3 provided imprecise diagnostic estimates derived from studies with

high or unclear risk of bias. Only one study compared the performance and accuracy of two
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combined blood-based biomarkers (APRI and FIB-4) versus either biomarker alone in patients

with HBV (30). Other identified studies in viral hepatitis were combinations of imaging
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elastography and a blood-based biomarker, and not able to address this specific PICO question.

For ALD, PSC and PBC, no studies were identified that addressed the question of whether the

combination of blood-based markers is better than a single biomarker against liver histology.

DISCUSSION

Blood-based biomarkers continue to play an important role in decision-making and risk

stratification for patients with CLD. In this systematic review, based predominantly on studies

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 with moderate-to-high strength of evidence, we found that both indirect and direct, proprietary

and non-proprietary blood-based biomarkers were associated with: 1) positive likelihood ratio of

2-10 indicating a small-to-moderate (15-45%) increase in pre-test probability for detection of

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significant (F2-F4), advanced fibrosis (F3-F4) and cirrhosis (F4); and (2) negative likelihood

ratio >0.2, indicating a small (<30%) reduction in the probability of excluding F2-4, F3-4 and F4
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in CLD. Most identified studies were in patients with viral hepatitis, HIV-HCV co-infection, and

NAFLD. Diagnostic performance was comparable between both proprietary and nonproprietary

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direct and indirect tests, and there were insufficient data to allow for a determination if a

combination of blood-based markers had greater diagnostic accuracy compared to a single

biomarker.
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The limitations of liver biopsy as a reference standard are well-recognized, and prior modeling in

HCV infection has indicated that a perfect diagnostic marker for biopsy-detected fibrosis will not

exceed an AUROC of 0.9(31). As such, none of the tests in this systematic review tests achieved
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a pooled sensitivity and specificity >0.8 for F2-4 in CLD. However, some studies reported this

diagnostic benchmark at varying thresholds in advanced fibrosis and cirrhosis, for example, FIB-
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4 and HS for HCV F4, ELF for HIV-HCV and NAFLD F3-4, HS for NAFLD F4, FT/FS for

HBV F3-4 and F4, FT/FS, ELF, and FM for ALD F4.

There were a greater number of studies identified in chronic viral hepatitis and were

predominantly in untreated cohorts. We did not differentiate further between treatment-

experienced and treatment-naïve patients. Lower thresholds for blood-based biomarkers were

historically selected in HCV to optimize higher sensitivity and negative predictive value (NPV)

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 for “ruling out” F2-4. In the era of direct-acting antivirals, upper index thresholds to improve

specificity to “rule-in” in advanced fibrosis or cirrhosis allows for continued surveillance for

complications of end-stage liver disease. For HCV F3-4, lower thresholds for the simple tests
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APRI (0.5) and FIB-4 (1.45) resulted in high sensitivities of 0.82-0.86, and upper thresholds for

APRI (1.5) and FIB-4 (3.25) were associated with high specificity 0.85-0.90. For HCV F4, an
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upper threshold for APRI of 2 resulted in specificity of 0.94. However, our systematic review did

not account for “indeterminate” range scores, which are associated with simple tests such as

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APRI and FIB-4 in greater than one-third of patients, and require secondary confirmatory tests.

There were fewer studies identified for proprietary tests, but diagnostic performance for

advanced stages of fibrosis in HCV was similar to simple tests with high specificity, and
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comparable likelihood and diagnostic odds ratios. A meta-analysis of 172 studies evaluated

several direct and indirect blood-based biomarkers in HCV patients, with resulting AUROC and

LRs that also indicated moderate diagnostic usefulness for F2-4 and F4(32). With the caveat of

inherent population and disease heterogeneity, along with differences in fibrosis staging across
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CLD, the diagnostic performance of APRI and FIB-4 as individual tests for F2-4, F3-4 and F4

were similar for HBV and HCV, with comparatively fewer studies for proprietary tests.
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Diagnosis of advanced fibrosis in NAFLD has important prognostic implications, and in our

systematic review there were a greater number of identified studies reporting data for NAFLD

F3-4 compared to F2-4. Optimal test thresholds for selecting F3-4 using blood-based markers

vary between studies due to differences in population characteristics and disease prevalence

compared to the original test derivation cohort. Revised FIB-4 thresholds of ≤1.30 and ≥2.67

have been proposed as having higher predictive values for F3-4 in the Nonalcoholic

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 Steatohepatitis Clinical Research Network (NASH CRN) cohort(33). For NAFLD F3-4, both

FIB-4 ≥ 2.67 and ≥ 3.25 had specificity 0.95, but with higher DOR for FIB-4 ≥ 2.67. The lower

FIB-4 thresholds of 1.3 and 1.45 had pooled sensitivity of 0.82-0.86 for NAFLD F3-4, but with
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fewer studies and lower strength of evidence for the 1.45 cutoff validated for HIV co-infection

and viral hepatitis. Results from our comprehensive review of NAFLD Fibrosis Score (NFS) for
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F3-4 are reported in the Guidance document, and in a recent individual patient data meta-

analysis of 5735 NAFLD patients(34). APRI thresholds for NAFLD F3-4 have not been

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validated in independent test sets, but for the studies included in our systematic review, APRI

thresholds of ≤ 0.5 were associated with comparable LRs to FIB-4 ≤ 1.45. There were fewer

identified studies for NAFLD F3-4 using proprietary tests, but at upper index thresholds, ELF
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and FT/FS appeared to have comparable specificity to FIB-4. Several proprietary and other novel

blood-based biomarkers continue to be evaluated for their diagnostic utility for moderate-to-

advanced fibrosis in phase II and III NAFLD clinical therapeutic trials. Recent data from the

Liver Investigation Testing Marker Utility in Steatohepatitis (LITMUS) and Non-invasive

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Biomarkers for Metabolic Liver Disease (NIMBLE) biomarker consortia identified several

emerging blood-based biomarkers that met prespecified AUC thresholds for advanced fibrosis
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and at-risk NASH(35, 36). These studies will likely be included in future systematic reviews for

biomarker assessment of fibrosis in Metabolic-dysfunction associated steatotic liver disease.

Fewer studies were identified in ALD, but included a greater number of proprietary tests, with

FT/FS having good diagnostic performance for F4.

The performance of proprietary and non-proprietary tests as compared to APRI was not

significantly different for F0-1 vs. F2-4, F0-2 vs F3-4 and F0-3 vs F4 across select cutoffs.

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 Among non-proprietary tests, FIB-4 had better performance across disease etiology and stage of

fibrosis for select cutoffs. However, either test may be helpful for the assessment of fibrosis.

Diagnostic estimates were imprecise due moderate-high risk of bias, and multiple testing across
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relatively small number of studies is likely to increase error rates. Head-to-head testing was

primarily available for ELF, FT/FS and HS. Our study did not detect a difference for these PORs
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at a 5% significance level, although there were very few studies for proprietary markers.

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We reported both diagnostic odds and likelihood ratios as both a comparative measure of

diagnostic accuracy and potential clinical application based on pre-test probability. However,

two tests with similar DOR can have substantially different sensitivities and specificities, and the
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application of DOR in clinical practice is more challenging where test selection is based on

predictive values and pre-test probability. Hence, our discussion of test performance in this

systematic review is based on likelihood ratios. Importantly, diagnostic measures such as LR and

DOR do not overcome limitations related to disease heterogeneity in study cohorts, and this
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systematic review indicates that diagnostic performance will vary across CLD etiology at similar

biomarker thresholds.
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There are several limitations to this systematic review. We excluded non-English language

studies, small or mixed disease cohorts with less than 50 participants. There were too few studies

in the pediatric population and our review was restricted to adults with CLD. However,

demographics of study population (e.g., age, gender, and race), reference standard quality

metrics such as blinded reporting of pathology data and biopsy length were considered

(Supplementary Appendix, http://links.lww.com/HEP/I340). However, due to population

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 variability, and non-reported test performance based on age and/or sex, we were unable to

objectively address variation of test accuracy with demographics across studies. Comparative

head-to-head studies in the same population were relatively limited, and prespecified test
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thresholds were either not reported, or variable cutoffs were used across studies that

compromised pooling of sensitivity and specificity. There remain limited data on comparative
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studies across proprietary markers. Furthermore, blood-based biomarker studies for fibrosis

staging in CLD have been developed in secondary or tertiary center cohorts with a higher

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prevalence of significant fibrosis(37), and there is limited data on applicability of these tests as a

screening tool in the primary care population where they are likely to have lower sensitivity and

positive predictive values. In these low prevalence community-based cohorts, blood-based

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biomarkers for fibrosis are likely to be selected based on several factors such as availability,

local resources, cost-effectiveness, and access to specialist care for secondary testing. However,

low prevalence community-based cohorts have lower pre-test probability compared to the test

derivation cohorts, and selection of test thresholds will impact predictive values. Other
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limitations were that we were unable to determine the accuracy of blood-based biomarkers in

post-treatment HCV cohorts following DAA treatment, as relevant studies in this systematic
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review were predominantly from the interferon-based treatment era, and biopsies are no longer

routinely performed as standard-of-care in HCV patients. Although FIB-4 is increasingly used in

clinical practice, historical studies have often used APRI as a comparator, likely due to

availability and accepted validation in viral hepatitis. Data on comparing markers in cholestatic

disease is lacking. Due to the absence of an adequate number and quality of studies, we were

unable to address if a combination of markers was superior to a single marker. However, data

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 from ongoing clinical trials should provide more information on the diagnostic accuracy of

combined versus single blood-based tests in NAFLD cohorts.

In summary, we found that blood-based biomarkers were associated with small-to-moderate

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improvement in pre-test probability for the diagnosis of F2-4, F3-4, and F4 in viral hepatitis,

HIV-HCV co-infection, and NAFLD. There were a limited number of studies in other CLD.
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Diagnostic performance was comparable between nonproprietary and proprietary direct and

indirect tests but we were not able to determine whether the diagnostic performance of two

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biomarkers was better compared to a single test. The diagnostic role of one biomarker compared

to another needs to be further evaluated in both low prevalence (primary care) and enriched

populations (tertiary centers). Blood-based biomarkers continue to be developed for the

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diagnosis of NAFLD advanced fibrosis with cross-sectional biopsy as the reference standard.

However, diagnostic test performance will need to be further validated, and optimal thresholds

defined for the different cohorts encountered in clinical practice, for example, in community and

minority populations, higher risk patients (e.g. morbidly obese, type II diabetes), and older
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patients with co-morbidities.

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278. Zhu X, Wang L-C, Chen E-Q, Chen X-B, Chen L-Y, Liu L, Lei X-Z, et al. Prospective
AC

evaluation of FibroScan for the diagnosis of hepatic fibrosis compared with liver biopsy/AST
platelet ratio index and FIB-4 in patients with chronic HBV infection. Digestive Diseases &
Sciences 2011;56:2742-2749.
279. Schmid P, Bregenzer A, Huber M, Rauch A, Jochum W, Mullhaupt B, Vernazza P, et al.
Progression of Liver Fibrosis in HIV/HCV Co-Infection: A Comparison between Non-Invasive
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280. Guillaume M, Moal V, Delabaudiere C, Zuberbuhler F, Robic M-A, Lannes A, Metivier
S, et al. Direct comparison of the specialised blood fibrosis tests FibroMeterV2G and Enhanced
Liver Fibrosis score in patients with non-alcoholic fatty liver disease from tertiary care centres.
Alimentary Pharmacology & Therapeutics 2019;50:1214-1222.
281. Trang T, Petersen JR, Snyder N. Non-invasive markers of hepatic fibrosis in patients co-
infected with HCV and HIV: comparison of the APRI and FIB-4 index. Clinica Chimica Acta
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282. Castera L, Winnock M, Pambrun E, Paradis V, Perez P, Loko MA, Asselineau J, et al.
Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms

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 combining these non-invasive tests for liver fibrosis staging in HIV/HCV coinfected patients:
ANRS CO13 HEPAVIH and FIBROSTIC collaboration. HIV Medicine 2014;15:30-39.
283. Kliemann DA, Wolff FH, Tovo CV, Alencastro PR, Ikeda MLR, Brandao ABM,
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284. Tural C, Tor J, Sanvisens A, Perez-Alvarez N, Martinez E, Ojanguren I, Garcia-

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D
TE
EP
C
AC

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 Table 1. Population, Intervention, Comparison and Outcomes (PICO) of Proposed

Questions

PICO 1 PICO 2 PICO 3

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Population Adults with Adults with Chronic Liver Adults with Chronic Liver
Chronic Liver Disease Disease
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

Disease

D
Intervention Single blood- Two blood-based biomarker Two blood-based biomarker
based panels panels

TE
biomarker
panel

Comparison Liver biopsy Biomarker panels compared Combination of Biomarker

to each other versus liver panels compared to single
EP
biopsy panel versus liver biopsy

Outcomes Significant Significant fibrosis (F2-4), Significant fibrosis (F2-4),

fibrosis (F2- Advanced fibrosis (F3-4), or Advanced fibrosis (F3-4), or
4), Advanced cirrhosis (F4) cirrhosis (F4)
C

fibrosis (F3-
4), or cirrhosis
AC

(F4)

PICO 1: In adult patients with chronic liver disease, including hepatocellular (HCV, HIV-
HCV, HBV, HIV-HBV, NAFLD, ALD) or cholestatic (PSC, PBC) disorders, are
blood-based biomarker panels accurate in staging hepatic fibrosis (F0-1 vs. F2-
4, F0-2 vs. F3-4, F0-3 vs. F4) using histopathology as the reference?

PICO 2: In adult patients with chronic liver disease, including hepatocellular (HCV, HIV-
HCV, HBV, HIV-HBV, NAFLD, ALD) or cholestatic (PSC, PBC) disorders is
any blood-based biomarker panel superior to another biomarker panel in staging

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 hepatic fibrosis (F0-1 vs. F2-4, F0-2 vs. F3-4, F0-3 vs. F4) using histopathology
as the reference?

PICO 3: In adult patients with chronic liver disease, including hepatocellular (HCV, HIV-
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HCV, HBV, HIV-HBV, NAFLD, ALD) or cholestatic (PSC, PBC) disorders, is

the combination of two blood-based biomarker panels superior to a single one
for staging fibrosis (F0-1 vs. F2-4, F0-2 vs. F3-4, F0-3 vs. F4) using
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

D
histopathology as the reference?

ALD, alcohol-associated liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; NAFLD,

TE
non-alcoholic fatty liver disease; PBC, primary biliary cholangitis; PSC, primary sclerosing

cholangitis
EP
C
AC

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 Table 2 Diagnostic Performance of Blood-based Biomarkers for Stages F2-4, F3-4 and F4
Stage F2-4
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Population Bi Select St (Re Pool Poole DOR (+)L (- Stren

om ed u fer ed d (rang R )LR gth of
ar cutoff di enc Sens Speci e) (rang (ran Evide
ke (rang es es) itivit ficity e) ge) nce*
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

r e) N y (95%

D
(95% CI)
CI)
HCV AP 0.5 4 (38 0.72 0.68( 5.44 2.23 0.41 Moder
RI (0.17 3 - (0.66 0.62 (4.39 (1.96 (0.35 ate

TE
to 80) to to to to to
0.67) 0.78) 0.73) 6.75) 2.54) 0.48)

1 1 (45 0.76 0.81 13.35 3.99 0.30 Moder

(0.7 7 , (0.69 (0.70 (6.7 (2.46 (0.22 ate
EP
to 58, to to to to to
1.2) 65, 0.82) 0.88) 26.57) 6.48) 0.40)
72,
74,
78,
81-
91)
C

1.5 2 (39 0.40 0.93 8.37 5.45 0.65 High

(1.4 3 , (0.33 (0.88 (5.32 (3.53 (0.59
to 40, to to to to to
AC

1.54) 42, 0.47) 0.96) 13.16) 8.38) 0.72)

45,
49,
54,
56,
58,
60,
62,
69,
70,
72,
74,
78,
79,

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reproduction of this article prohibited.
 92-
98)
2 4 (45 0.42 0.92 8.80 5.51 0.63 High
, (0.22 (0.78 (4.40 (2.58 (0.45
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58, to to to to to
78, 0.65) 0.98) 17.62) 11.74 0.86)
99) )
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FI 1.45 1 (38 0.73 0.72 6.95 2.62 0.38 High

D
B- (1.26 3 , (0.68 (0.67 (5.84 (2.25 (0.34
4 to 42, to to to to to
1.61) 46- 0.77) 0.77) 8.27) 3.04) 0.42)
49,

TE
57,
66,
79,
83,
90,
99,
EP
100
)
3.25 8 (42 0.60 0.87 9.71 4.52 0.47 Moder
(2.71 , (0.46 (0.76 (6.28 (2.84 (0.36 ate
to 49, to to to to to
C

3.62) 76, 0.72) 0.93) 15.02) 7.18) 0.60)

79,
86,
92,
AC

97,
101
)
Fib 0.3 7 (43 0.78 0.66 6.85 2.31 0.34 High
ro (0.2 , (0.72 (0.60 (5.48 (1.99 (0.28
Te to 48, to to to to to
st 0.39) 58, 0.82) 0.73) 8.56) 2.69) 0.40)
71,
102
-
104
)

Copyright © 2024 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized
reproduction of this article prohibited.
 0.48 7 (55 0.71 0.73 6.68 2.66 0.40 Moder
(0.4 , (0.62 (0.68 (5.21 (2.36 (0.32 ate
to 70, to to to to to
0.5) 80, 0.78) 0.78) 8.55) 3.00) 0.50)
95,
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103
,
105
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D
106
)
Fib 0.5 4 (48 0.85 0.64 10.10 2.34 0.23 Moder

TE
ro (0.41 , (0.62 (0.40 (6.41 (1.50 (0.11 ate
Me to 55, to to to to to
ter 0.59) 75, 0.95) 0.82) 15.92) 3.67) 0.49)
80)
He 0.32 4 (48 0.79 0.60 5.72 1.99 0.35 Moder
pa (0.25 , (0.58 (0.48 (3.22 (1.75 (0.19 ate
EP
Sc to 55, to to to to to
ore 0.34) 107 0.91) 0.71) 10.17) 2.27) 0.64)
,
108
)
C

0.5 5 (58 0.70 0.78 8.52 3.23 0.38 Moder

(0.5 , (0.62 (0.69 (6.40 (2.45 (0.31 ate
to 80, to to to to to
0.55) 107 0.78) 0.85) 11.33) 4.27) 0.47)
AC

,
109
,
110
)
HBV AP 0.5 6 (85 0.74 0.59 4.08 1.79 0.43 Moder
RI (0.2 1 , (0.71 (0.53 (3.65 (1.64 (0.41 ate
to 101 to to to to to
0.66) , 0.78) 0.64) 4.56) 1.96) 0.47)
111
-
169
)

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reproduction of this article prohibited.
 1 1 (11 0.47 0.84 4.60 2.90 0.63 Moder
(0.71 6 1, (0.35 (0.79 (3.62 (2.62 (0.52 ate
to 113 to to to to to
1.2) , 0.60) 0.96 5.85) 3.22) 0.77)
120
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,
123
,
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127

D
,
136
,
139

TE
,
142
,
144
,
157
EP
,
168
,
170
-
174
C

)
1.5 1 (95 0.25 0.94 5.34 4.24 0.80 Moder
(1.4 9 , (0.17 (0.91 (3.84 (3.18t (0.71 ate
AC

to 113 to to to o to
1.5) , 0.36) 0.96) 7.41) 5.64) 0.88)
114
,
120
,
121
,
124
,
133
,
136
,

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reproduction of this article prohibited.
 137
,
141
,
142
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,
144
,
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149

D
,
157
,
161

TE
,
162
,
175
-
177
EP
)
2 3 (11 0.13 0.89 - - - High
(1.8 3, to to
to 170 0.59 0.99
2.25) ,
177
C

)
FI (85 0.60 0.76 4.69 2.46 0.53 Moder
AC

B- , (0.55 (0.72 (4.10 (2.56 (0.48 ate

2 to
4 114 to to to to
3 0.65)
, 0.79) 5.35) 2.71) 0.58)
116
,
1.45 118
(1.20 ,
to 120
1.76) ,
132
,
133
,
139
-

Copyright © 2024 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized
reproduction of this article prohibited.
 142
,
149
,
152
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,
157
-
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162

D
,
164
,
169

TE
,
174
,
178
)
EP
(11 0.24 0.96 7.85 6.25 0.80 Moder
4, (0.12 (0.92 (4.30 (3.65 (0.67 ate
1 to
120 to to to to
0 0.41)
, 0.98) 14.36) 10.71 0.94)
133 )
,
141
C

,
3.25 142
(3.22 ,
AC

to 155
4.9) ,
161
,
162
,
170
,
179
)
He 0.32 (13 0.74 0.64 4.99 2.04 0.41 High
pa to 0, (0.57 (0.53 (2.06 (1.42 (0.23
4 to
0.52 141
, 0.85)

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reproduction of this article prohibited.
 Sc 150 to to to to
ore , 0.73) 12.09) 2.93) 0.72)
180
)
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Ki (10 0.66 0.70 4.69 2.04 0.41 Moder

ng’ 1, (0.56 (0.63 (3.39 (1.42 (0.23 ate
s 149 to to to to to
, 0.75) 0.77) 6.49) 2.93) 0.72)
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4.22
153

D
to 5
,
8.16
154
,

TE
159
)
NAFLD AP 0.5 8 (18 0.74 0.72 7.24 2.65 0.37 Moder
RI (0.2 1- (0.68 (0.61 (4.56 (1.87 (0.30 ate
to 188 to to to to to
0.69) ) 0.79) 0.81) 11.51) 3.75) 0.44)
EP
FI 8 (18 0.69 0.80 8.60 3.37 0.39 Moder
B- 1- (0.57 (0.72 (6.04 (2.67 (0.29 ate
4 1.45 184 to to to to to
(1.1 , 0.79) 0.85) 12.24) 4.25) 0.53)
to 186
C

1.74) -
189
)
AC

Stage F3-4
Biomarker Selected Studies (References) Pooled Pooled DOR (+)LR (-)LR St
cutoff (range) N Sensitivity Specificity (range) (range) (range) Ev
(95% CI) (95% CI)
HCV AP 1 (38 0.82 0.60 6.92 2.05 0.30 High
RI 0.5 6 , (0.70 (0.51 (3.95 (1.73 (0.18
(0.08 41, to to to to to
to 45, 0.90) 0.68) 12.13) 2.41) 0.49)
0.67) 46,
49,

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reproduction of this article prohibited.
 55,
58,
59,
66,
67,
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74,
79,
190
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

D
193
)
2 (44 0.75 9.73 3.09 0.32 Moder

TE
3 , (0.68 (5.56 (2.25 (0.24 ate
45, to to to to
50, 0.82) 17.03) 4.24) 0.42)
51,
56,
58,
EP
61,
74, 0.76
1
76, (0.70
(0.7
77, to
to
84, 0.81)
1.2)
88,
91,
C

96,
191
,
AC

194
-
201
)
1 (45 0.85 6.87 3.71 0.54 Moder
3 , (0.80 (5.14 (2.94 (0.45 ate
48, 0.54 to to to to
1.5 56, 0.90) 9.16) 4.76) 0.65)
(0.44
(1.3 58, to
to 79, 0.63)
1.75) 83,
85,
92,
97,

Copyright © 2024 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized
reproduction of this article prohibited.
 190
,
192
,
193
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,
202
)
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2 (2 6 (45 0.51 0.90 9.58 5.24 0.55 High

D
to , (0.35 (0.86 (6.89
(4.26 (0.41
2.1) 49, to to to
to to
58, 0.66) 0.94) 13.33)
6.46) 0.73)

TE
94,
196
,
200
)
FI 1 (38 0.86 0.70 14.44 2.88 0.20 Moder
EP
B- 7 , (0.80 (0.63 (9.43 (2.33 (0.14 ate
4 39, to to to to to
41, 0.91) 0.77) 22.12) 3.56) 0.28)
49,
51,
62,
C

66,
75,
79,
1.45
AC

99,
(1.22
190
to
,
1.67)
194
,
195
,
199
,
203
-
205
)

Copyright © 2024 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized
reproduction of this article prohibited.
 1 (39 0.55 0.90 11.11 5.60 0.50 Moder
7 , (0.47 (0.86 (8.36 (4.11 (0.44 ate
48, to to to to to
49, 0.62) 0.94) 14.78) 7.62) 0.58)
62,
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76,
79,
81,
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91,

D
93,
3.25
97,
(3.21
190
to
,

TE
3.97)
196
,
201
,
202
,
EP
204
-
206
)
Fib 0.32 4 (55 0.87 0.62 11.00 2.31 0.21 High
ro (0.29 , (0.82 (0.56 (6.85 (1.95 (0.15
C

Te to 58, to to to to to
st 0.46) 102 0.91) 0.68) 17.68) 2.74) 0.30)
,
AC

207
)
0.58 4 (48 0.75 0.74 8.75 2.93 0.33 High
(0.52 , (0.58 (0.59 (6.30 (2.04 (0.22
to 58, to to to to to
0.6) 102 0.87) 0.86) 12.16) 4.20) 0.52)
,
106
)
EL 9.13 4 (66 0.92 0.66 21.49 2.68 0.12 High
F to , (0.87 (0.49 (8.43 (1.70 (0.07
9.49 208 to to to to to
- 0.95) 0.79) 54.75) 4.21) 0.22)

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 210
)
He 0.5 6 (48 0.79 0.76 11.92 3.31 0.28 Moder
pa to , (0.69 (0.71 (6.22 (2.56 (0.18 ate
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Sc 0.6 55, to to to to to
ore 58, 0.86) 0.81) 22.84) 4.27) 0.43)
107
-
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109

D
)
HBV AP 0.5 2 (10 0.77 0.59 4.86 1.89 0.39 Moder
RI (0.12 7 1, (0.71 (0.51 (4.10 (1.63 (0.34 ate

TE
to 114 to to to to to
0.69) , 0.82) 0.68) 5.74) 2.21) 0.45)
116
,
119
,
EP
122
,
125
,
130
,
C

132
,
135
AC

,
140
,
144
,
148
,
152
,
153
,
165
,
176
,

Copyright © 2024 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized
reproduction of this article prohibited.
 178
,
201
,
211
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-
219
)
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1 1 (85 0.67 0.73 5.53 2.49 0.45 Moder

D
(0.7 2 , (0.61 (0.65 (3.97 (1.96 (0.38 ate
to 144 to to to to to
1.23) , 0.72) 0.80) 7.70) 3.15) 0.53)

TE
147
,
150
,
151
,
EP
156
,
173
,
176
,
201
C

,
216
,
AC

220
,
221
)
1.5 6 (13 0.45 0.87 5.17 3.31 0. 64 Moder
(1.27 8, (0.27 (0.80 (2.78 (2.30 (0.47 ate
to 155 to to to to to 0.
1.74) , 0.64) 0.91) 9.64) 4.77) 88)
172
,
176
,
213
,

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 216
)
FI 1.45 1 (10 0.67 0.69 4.66 2.20 0.47 Moder
B- (1.3 8 1, (0.61 (0.61 (3.63 (1.78 (0.73 ate
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4 to 116 to to to to to
1.65) , 0.72) 0.807 5.97) 2.71) 0.52)
121 7
,
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124

D
,
125
,

TE
144
,
147
,
151
,
EP
152
,
172
,
178
,
201
C

,
211
-
AC

214
,
216
,
222
)
2.2 1 (85 0.53 0.89 9.28 4.92 0.53 Moder
(1.88 0 , (0.44 (0.81 (5.70 (3.04 (0.46 ate
to 138 to to to to to
2.65) , 0.61) 0.94) 15.11) 7.98) 0.61)
140
,
144
,

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reproduction of this article prohibited.
 176
,
201
,
216
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,
221
-
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223

D
)
3.25 1 (12 0.26 0.96 8.95 6.85 0.77 High
(3.25 1 1, (0.14 (0.89 (5.67 (3.91 (0.65

TE
to 124 to to to to to
5.76) , 0.44) 0.99) 14.13) 12.01 0.90)
144 )
,
155
,
EP
165
,
176
,
213
,
216
C

,
218
,
AC

222
,
224
)
NAFLD AP 0.5 1 (18 0.78 0.65 6.59 2.25 0.34 Moder
RI (0.15 9 1, (0.71 (0.58 (5.05 (1.92 (0.28 ate
to 182 to to to to to
0.7) , 0.83) 0.72) 8.61) 2.63) 0.42)
188
,
198
,
225
-

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reproduction of this article prohibited.
 239
)
1 1 (18 0.53 0.88 8.48 4.50 0.53 Moder
(0.76 7 3, (0.42 (0.83 (6.74 (3.57 (0.44 ate
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to 1) 184 to to to to to
, 0.64) 0.92) 10.66) 5.68) 0.65)
199
,
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226

D
,
229
,

TE
234
,
238
-
248
)
EP
1.5 8 (22 0.15 0.97 6.17 5.37 0.87 High
9, (0.10 (0.94 (3.75 (3.23 (0.82
232 to to to to to
, 0.23) 0.99) 10.14) 8.93) 0.93)
235
,
C

237
,
248
AC

-
251
)
FI 1.3 1 (19 0.82 0.64 7.81 2.25 0.29 Moder
B- 8 9, (0.73 (0.52 (5.49 (1.77 (0.21 ate
4 229 to to to to to
, 0.88) 0.74) 11.11) 2.87) 0.39)
235
,
236
,
238
-
240

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reproduction of this article prohibited.
 ,
242
,
245
,
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247
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252
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259
)
1.45 4 (23 0.86 0.78 21.11 3.91 0.19 Low

TE
7, (0.70 (0.64 (5.54 (2.15 (0.08
243 to to to to to
, 0.94) 0.88) 80.45) 7.10) 0.44)
260
,
261
EP
)
1.45 1 (18 0.75 0.78 10.19 3.33 0.33 Moder
(1.45 8 1- (0.67 (0.70 (7.26 (2.57 (0.26 ate
to 2) 183 to to to to to
, 0.81) 0.84) 14.29) 4.30) 0.41)
188
C

,
189
,
AC

225
,
226
,
230
,
231
,
234
,
237
,
243
,
246

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reproduction of this article prohibited.
 ,
258
,
260
-
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263
)
2.67 2 (18 0.36 0.95 9.98 6.76 0.68 Moder
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3 4, (0.29 (0.92 (6.94 (4.70 (0.61 ate

D
229 to to to to to
, 0.44) 0.97) 14.36) 9.71) 0.75)
232

TE
,
235
,
236
,
238
EP
,
240
,
245
,
247
-
C

250
,
253
AC

-
259
,
262
,
264
-
266
)
3.25 1 (22 0.26 0.95 6.66 5.16 0.78 High
0 9, (0.14 (0.90 (2.54 (2.26 (0.64
237 to to to to to
, 0.43) 0.98) 17.47) 0.94)
239

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reproduction of this article prohibited.
 , 11.77
242 )
-
244
,
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251
,
261
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D
265
,
266
)

Biomarker
Stage F4
Selected Studies (References) TE Pooled Pooled DOR (+)LR (-)LR Str
EP
N Sensitivity Specificity Ev
cutoff (range) (range) (range) (range)
(95% CI) (95% CI)

HCV AP 0.5 6 (50 0.81 0.72 10.96 2.86 0.26 Moder

RI (0.44 , (0.72 (0.66 (6.63 (2.39 (0.18 ate
C

to 59, to to to to to
0.75) 61, 0.88) 0.76) 18.12) 3.42) 0.39)
64,
68,
AC

79)
1 2 (38 0.76 0.75 9.99 3.12 0.31 High
(0.76 0 , (0.72 (0.71 (8.17 (2.68 (0.27
to 41, to to to to to
1.14) 43, 0.80) 0.80) 12.23) 3.63) 0.36)
44,
46,
49,
51,
54,
55,
62,
69,

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reproduction of this article prohibited.
 72,
76,
91,
201
,
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267
-
271
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D
1 (72 0.70 0.82 10.55 3.82 0.36 High
2 , (0.59 (0.76 (6.37 (2.93 (0.26
73, to to to to to

TE
77, 0.80) 0.86) 17.47) 4.99) 0.51)
79,
81,
1.5
83-
(1.27
85,
to
89,
1.73)
EP
201
,
267
,
272
)
C

2 1 (49 0.41 0.94 11.36 7.15 0.63 High

8 ,
(2.0 (0.32 (0.91 (7.96- (4.98 (0.55
54,
to - - 16.21) - -
AC

62,
4.3) 0.50) 0.97) 10.27 0.72)
66,
)
69,
72,
74,
80,
92,
93,
95,
96,
98,
267
,
269
,

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reproduction of this article prohibited.
 270
,
273
,
274
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)
FI 8 (38 0.88 0.63 12.54 2.39 0.19 Moder
B- , (0.80 (0.51 (9.92 (1.86 (0.13 ate
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4 43, to to to to to

D
49, 0.93) 0.74) 15.85) 3.07) 0.27)
1.45 51,
(1.17 54,

TE
to 2) 79,
205
,
268
)
9 (49 0.73 0.79 10.19 3.48 0.34 Moder
EP
, (0.68 (0.75 (8.20 (3.00 (0.29 ate
54, to to to to to
64, 0.78) 0.83) 12.66) 4.04) 0.40)
3.25 77,
(2.95 79,
to 85,
C

4.32) 92,
201
,
AC

206
)
Fib 0.75 5 (43 0.61 0.86 9.80 4.39 0.45 Moder
ro (0.7 , (0.50 (0.79 (7.16 (3.25 (0.35 ate
Te to 80, to to to to to
st 0.81) 95, 0.72) 0.91) 13.41) 5.94) 0.57)
106
,
270
)
He 0.84 4 (80 0.87 0.86 41.52 6.07 0.15 Low
pa (0.75 , (0.70 (0.72 (7.55 (2.75 (0.05
107 to to to
- 0.95)

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 Sc to 109 to 228.5 13.40 to
ore 0.84) ) 0.93) 0) ) 0.41)
HBV AP 0.5 2 (85 0.84 0.54 6.26 1.82 0.29 Moder
RI (0.25 7 , (0.79 (0.44 (5.13 (1.56 (0.24 ate
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to 118 to to to to to
0.7) , 0.89) 0.63) 7.62) 2.12) 0.35)
120
,
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122

D
,
123
,

TE
126
,
127
,
129
,
EP
130
,
132
,
140
,
144
C

,
148
,
AC

149
,
152
,
153
,
157
,
158
,
163
,
169
,

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reproduction of this article prohibited.
 176
,
177
,
201
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,
218
,
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275

D
-
277
)

TE
1 2 (10 0.52 0.82 4.88 2.86 0.58 Moder
(0.77 3 1, (0.43 (0.76 (3.60 (2.31 (0.50 ate
to 120 to to to to to
1.22) , 0.61) 0.86) 6.63) 3.56) 0.68)
121
,
EP
123
-
128
,
133
,
135
C

,
139
,
AC

144
,
147
,
149
,
151
,
157
,
165
,
177
,

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reproduction of this article prohibited.
 275
-
278
)
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1.5 6 (12 0.38 0.85 3.42 2.51 0.73 High

(1.27 7, (0.27 (0.75 (2.57 (1.89 (0.65
to 150 to to to to to
1.68) , 0.50) 0.91) 4.55) 3.33) 0.83)
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

176

D
,
201
,

TE
275
,
276
)
1 (95 0.21 0.92 3.09 2.65 0.86 High
8 , (0.14 (0.88 (2.37 (2.16 (0.79
EP
121 to to to to to
, 0.31) 0.95) 4.02) 3.32) 0.93)
123
-
125
,
C

133
,
137
AC

2 (2 ,
to 144
5.1) ,
149
,
155
,
157
,
172
,
176
,
177
,

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reproduction of this article prohibited.
 218
,
275
-
277
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)
FI 0.5 5 (14 0.96 0.28 8.94 1.32 0.15 Moder
B- (0.37 8, (0.89 (0.13 (5.18 (1.06 (0.09 ate
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

4 to 157 to to to to to

D
0.72) , 0.98) 0.49) 15.50) 1.66) 0.25)
177
,

TE
218
,
277
)
1.45 2 (12 0.76 0.72 7.97 2.69 0.34 High
(0.8 7 0, (0.69 (0.66 (6.17 (2.29 (0.27
EP
to 122 to to to to to
1.97) , 0.81) 0.77) 10.29) 3.16) 0.42)
123
,
125
,
C

127
,
130
AC

,
132
,
135
,
139
,
140
,
144
,
147
,
149
,

Copyright © 2024 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc. Unauthorized
reproduction of this article prohibited.
 151
,
153
,
157
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,
158
,
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163

D
,
172
,
176

TE
,
201
,
218
,
222
EP
,
223
,
276
-
278
C

)
3.25 9 (11 0.46 0.92 9.85 5.77 0.59 High
(3.25 8, (0.17 (0.75 (4.39 (2.82 (0.33
AC

to 139 to to to to to
7.9) , 0.78) 0.98) 22.12) 11.81 1.05)
155 )
,
165
,
177
,
218
,
222
,
223
,

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reproduction of this article prohibited.
 277
)
NAFLD FI 0.92 4 (18 0.88 0.77 25.32 3.90 0.15 Moder
B- to 2, (0.73 (0.68 (10.81 (2.80 (0.07 ate
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4 2.2 183 to to to to to
, 0.95) 0.85) 59.33) 5.42) 0.35)
189
,
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263

D
)
DOR, diagnostic odds ratio; (+) LR, positive likelihood ratio; (-)LR, negative likelihood ratio;
APRI, AST-Platelet Ratio Index; CI, confidence interval; ELF, Enhanced Liver Fibrosis; HCV,

TE
Hepatitis C Virus; HBV, Hepatitis B virus; HIV-HCV, Human Immunodeficiency Virus-HCV
co-infection; NAFLD, non-alcoholic fatty liver disease; ALD, alcohol-associated liver disease;
PBC, Primary Biliary Cholangitis
EP
C
AC

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 Table 3: Proportional Odds Ratio for comparative studies with two serum tests
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ELF FIB-4 FT/FS HS

F0-1 vs. F2-4 APRI Cutoff: 9 Cutoff: 1.45 Cutoff: 0.48 Cutoff: 0.5
(0.5)
Studies = Studies= Studies = Studies =
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

D
6(62, 65, 66,35(38, 42, 46- 4(55, 80, 279, 3(58, 80,
160, 279, 49, 57, 66, 79, 282) 279)
280) 85, 114, 116,
118, 120, 132,

TE
133, 139-142, POR: 0.51 POR: 1.26
POR: 0.97 149, 151, 152, (95%CI: 0.15 to (95%CI:
(95%CI: 0.59 159-162, 169, 1.69) 0.67 to 2.36)
to 1.60) 187, 188, 279,
281)
EP
*POR: 0.85
(95%CI: 0.73
to 0.99)

APRI Cutoff: 9 Cutoff: 3.25 Cutoff: 0.48 Cutoff: 0.84

C

(1.5)
Studies = Studies= Studies = Studies =
4(62, 98, 13(42, 49, 79, 3(95, 279, 282) 3(58, 141,
AC

160, 279) 92, 97, 114, 279)

120, 133, 141,
142, 161, 162, POR: 1.71
POR: 0.90 283) (95%CI: 0.46 to POR: 1.76
(95%CI: 0.47 POR: 1.21 6.35) (95%CI:
to 1.70) (95%CI: 0.74 0.72 to 4.27)
to 1.98)

F0-2 Vs F3-4 APRI Cutoff: 9 Cutoff: 1.45 Cutoff: 0.48 Cutoff: 0.5
(0.5)
Studies = Studies= Studies = Studies =
1(66) 21(38, 41, 49, 1(182) 3(55, 58,
79, 116, 125, 130)
144, 149, 153,
157, 158, 163,
181, 182, 188,

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 0.44 (95%CI: 201, 211-214, POR: 0.63 POR: 0.60
0.10 to 1.95) 216, 218, 225, (95%CI: 0.23 to (95%CI:
226, 230, 231, 1.72) 0.27 to 1.31)
237, 277, 284)
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POR: 0.80
(95%CI: 0.60
to 1.06)
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

D
APRI Cutoff: 3.25 Cutoff: 0.84
(1.5)
Studies= Studies =
12(48, 79, 97, 1(58)

TE
176, 190, 202,
213, 216, 229,
237, 251, 284) POR: 2.53
(95%CI:
0.76 to 8.45)
*POR: 0.58
EP
(95%CI: 0.42
to 0.81)
F0-3 Vs F4 APRI Cutoff: 1.45
(0.5)
Studies=
18(79, 120,
C

122, 123, 130,

132, 140, 144,
149, 153, 157,
158, 163, 176,
AC

201, 218, 276,

277)

POR: 0.86
(95%CI: 0.69
to 1.08)
APRI Cutoff: 3.25
(1.5)
Studies=
4(77, 79, 85,
201)

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 *POR: 0.47
(95%CI: 0.33
to 0.66)
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APRI, AST-Platelet Ratio Index; ELF, Enhanced Liver Fibrosis; HCV, Hepatitis C Virus; HBV,
Hepatitis B virus; HIV-HCV, Human Immunodeficiency Virus-HCV co-infection; NAFLD, non-
alcoholic fatty liver disease; POR, Proportional Odds Ratio (95% CI).
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/21/2024

D
Table 3 Legend: The proportional odds ratio compares the diagnostic odds ratio (DOR) of one
test (DOR1), in this case APRI, as compared to another test (DOR2) (ELF, FIB-4, FT/FS, HS) in
the same study/population. PORs are pooled for all the studies with the same comparative tests
allowing an assessment of which test has better diagnostic performance. For example, a 95%

TE
confidence interval that excludes 1 can suggest a significant difference between tests. In most
comparisons, there was no difference in diagnostic performance between two selected tests.
*Significant POR (95%CI) are shown in bold; FIB-4 (1.45) was significantly better than APRI
(0.5) for F2-4; FIB-4 (3.25) was better than APRI (1.5) for F3-4 and F4
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