Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis.

BACKGROUND: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. METHODS: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <-1·455 vs -1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. FINDINGS: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. INTERPRETATION: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. FUNDING: Innovative Medicines Initiative 2.

Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study.

BACKGROUND AND AIMS: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. APPROACH AND RESULTS: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). CONCLUSIONS: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.

Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study.

BACKGROUND: The reference standard for detecting non-alcoholic steatohepatitis (NASH) and staging fibrosis-liver biopsy-is invasive and resource intensive. Non-invasive biomarkers are urgently needed, but few studies have compared these biomarkers in a single cohort. As part of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, we aimed to evaluate the diagnostic accuracy of 17 biomarkers and multimarker scores in detecting NASH and clinically significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and identify their optimal cutoffs as screening tests in clinical trial recruitment. METHODS: This was a comparative diagnostic accuracy study in people with biopsy-confirmed NAFLD from 13 countries across Europe, recruited between Jan 6, 2010, and Dec 29, 2017, from the LITMUS metacohort of the prospective European NAFLD Registry. Adults (aged ≥18 years) with paired liver biopsy and serum samples were eligible; those with excessive alcohol consumption or evidence of other chronic liver diseases were excluded. The diagnostic accuracy of the biomarkers was expressed as the area under the receiver operating characteristic curve (AUC) with liver histology as the reference standard and compared with the Fibrosis-4 index for liver fibrosis (FIB-4) in the same subgroup. Target conditions were the presence of NASH with clinically significant fibrosis (ie, at-risk NASH; NAFLD Activity Score ≥4 and F≥2) or the presence of advanced fibrosis (F≥3), analysed in all participants with complete data. We identified thres holds for each biomarker for reducing the number of biopsy-based screen failures when recruiting people with both NASH and clinically significant fibrosis for future trials. FINDINGS: Of 1430 participants with NAFLD in the LITMUS metacohort with serum samples, 966 (403 women and 563 men) were included after all exclusion criteria had been applied. 335 (35%) of 966 participants had biopsy-confirmed NASH and clinically significant fibrosis and 271 (28%) had advanced fibrosis. For people with NASH and clinically significant fibrosis, no single biomarker or multimarker score significantly reached the predefined AUC 0·80 acceptability threshold (AUCs ranging from 0·61 [95% CI 0·54-0·67] for FibroScan controlled attenuation parameter to 0·81 [0·75-0·86] for SomaSignal), with accuracy mostly similar to FIB-4. Regarding detection of advanced fibrosis, SomaSignal (AUC 0·90 [95% CI 0·86-0·94]), ADAPT (0·85 [0·81-0·89]), and FibroScan liver stiffness measurement (0·83 [0·80-0·86]) reached acceptable accuracy. With 11 of 17 markers, histological screen failure rates could be reduced to 33% in trials if only people who were marker positive had a biopsy for evaluating eligibility. The best screening performance for NASH and clinically significant fibrosis was observed for SomaSignal (number needed to test [NNT] to find one true positive was four [95% CI 4-5]), then ADAPT (six [5-7]), MACK-3 (seven [6-8]), and PRO-C3 (nine [7-11]). INTERPRETATION: None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis. However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort. FUNDING: The Innovative Medicines Initiative 2 Joint Undertaking.

Noninvasive tests for nonalcoholic fatty liver disease in a multi-ethnic population: The HELIUS study.

Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence and severity globally, prompting noninvasive testing, yet limited data exist on noninvasive liver tests (NITs) including transient elastography (TE) in ethnically diverse populations. Therefore, we studied prevalence and ethnic differences in NAFLD with NITs in the multi-ethnic HEalthy Life In an Urban Setting (HELIUS) cohort. NITs of liver steatosis (Fatty Liver Index [FLI]) and fibrosis (Fibrosis-4 index [FIB-4], and aspartate aminotransferase-to-platelet ratio [APRI]) were assessed in 10,007 participants. A subpopulation of 399 participants, selected on high-risk criteria for NAFLD (obesity, type 2 diabetes mellitus [T2DM], and/or elevated NITs), was examined with TE. FLI was ≥60 in 27.3% of 10,007 participants, indicating steatosis. Most participants (71.8%) had FIB-4 < 1.30, excluding advanced liver fibrosis, and 1.1% (n = 113) had high FIB-4 (FIB-4 ≥ 2.67), indicating likely advanced liver fibrosis. In the TE subpopulation, 37.8% and 17.3% had steatosis and fibrosis (continuation attenuation parameter [CAP] ≥ 280 dB/m, liver stiffness measurement [LSM] ≥ 7.0 kPa, respectively). Turkish participants had highest adjusted odds ratio (OR) for elevated LSM (1.72, 95% confidence interval [CI] 0.59-5.01) and Ghanaians the lowest (0.24, 95% CI 0.09-0.65). Ghanaians had lowest adjusted OR for elevated CAP: 0.18 (95% CI 0.09-0.37). In diabetics, CAP and LSM were 17.6% and 14.6% higher than in nondiabetics, respectively. Correlations of FIB-4 and APRI with LSM were absent and weak. Conclusion : Liver steatosis proxy FLI was elevated in 27.3% of this multi-ethnic population. In Turkish background and in those with T2DM, proxies for steatosis and fibrosis were high, whereas in Ghanaian background, NITs were generally low. Together, this warrants awareness for NAFLD among high-risk populations, taking ethnic background into account. The absence of clear correlation between FIB-4 and APRI with LSM questions the accuracy of these fibrosis NITs to detect advanced fibrosis in the general population.

Does aerobic exercise reduce NASH and liver fibrosis in patients with non-alcoholic fatty liver disease? A systematic literature review and meta-analysis.

Background: Exercise is an effective strategy for the prevention and regression of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD), but it is unclear whether it can reduce advanced stages of NAFLD, i.e., steatohepatitis and liver fibrosis. Furthermore, it is not evident which modality of exercise is optimal to improve/attenuate NAFLD. Objectives: The aim is to systematically review evidence for the effect of aerobic exercise (AE) on NAFLD, in particular non-alcoholic steatohepatitis (NASH) and liver fibrosis. Methods: A systematic literature search was conducted in Medline and Embase. Studies were screened and included according to predefined criteria, data were extracted, and the quality was assessed by Cochrane risk of bias tools by two researchers independently according to the protocol registered in the PROSPERO database (CRD42021270059). Meta-analyses were performed using a bivariate random-effects model when there were at least three randomized intervention studies (RCTs) with similar intervention modalities and outcome. Results: The systematic review process resulted in an inclusion a total of 24 studies, 18 RCTs and six non-RCTs, encompassing 1014 patients with NAFLD diagnosed by histological or radiological findings. Studies were grouped based on the type of AE: moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). A total of twelve meta-analyses were conducted. Compared to controls, MICT resulted in a mean difference (MD) in the NAFLD biomarkers alanine transaminase (ALT) and aspartate aminotransferase (AST) of -3.59 (CI: -5.60, -1.59, p<0.001) and -4.05 (CI: -6.39, -1.71, p<0.001), respectively. HIIT resulted in a MD of -4.31 (95% CI: -9.03, 0.41, p=0.07) and 1.02 (95% CI: -6.91, 8.94, p=0.8) for ALT and AST, respectively. Moreover, both AE types compared to controls showed a significantly lower magnetic resonance spectroscopy (MRS) determined liver fat with a MD of -5.19 (95% CI: -7.33, -3.04, p<0.001) and -3.41 (95% CI: -4.74, -2.08, p<0.001), for MICT and HIIT respectively. MICT compared to controls resulted in a significantly higher cardiorespiratory fitness (MD: 4.43, 95% CI: 0.31, 8.55, p=0.03). Conclusion: Liver fat is decreased by AE with a concomitant decrease of liver enzymes. AE improved cardiorespiratory fitness. Further studies are needed to elucidate the impact of different types of AE on hepatic inflammation and fibrosis. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier (CRD42021270059).

Analytical frameworks in colorectal cancer guidelines: development of methods for systematic reviews, their application and practical guidance for their use.

OBJECTIVES: Analytical frameworks are graphical representation of the key questions answered by a systematic review and can support the development of guideline recommendations. Our objectives were to a) conduct a systematic review to identify, describe and compare all analytical frameworks published as part of a systematic and guideline development process related to colorectal cancer (CRC), and b) to use this case study to develop guidance on how to conduct systematic reviews of analytical frameworks. METHODS: We developed a search strategy to identify eligible studies in Medline and Embase from 1996 until December 2020. We also manually searched guideline databases and websites to identify all guidelines and systematic reviews in CRC that used an analytical framework. We assessed the quality of the guidelines using the Appraisal of Guidelines for Research and Evaluation II tool. The systematic review was registered in International Prospective Register of Systematic Reviews, registration CRD42020172117. RESULTS: We screened 34,505 records and identified 1,166 guidelines and 3,127 systematic reviews on CRC of which five met our inclusion criteria. These five publications included four analytical frameworks in colorectal cancer (one update). We also describe our methodological approach to systematic reviews for analytical frameworks and underlying concepts for developing analytical framework using a bottom-up or top-down approach. CONCLUSION: Few guidelines and systematic reviews are utilizing analytical frameworks in the development of recommendations. Development of analytical frameworks should begin with a systematic search for existing analytical frameworks and follow a structured conceptual approach for their development to support guideline recommendations. Our methods may be helpful in achieving these objectives.

Clinicians' Perspectives on Barriers and Facilitators for the Adoption of Non-Invasive Liver Tests for NAFLD: A Mixed-Method Study.

(1) Background: Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) and the limitations of liver biopsies, multiple non-invasive tests (NITs) have been developed to identify non-alcoholic fatty liver disease (NAFLD) patients at-risk of progression. The availability of these new NITs varies from country to country, and little is known about their implementation and adoption in routine clinical practice. This study aims to explore barriers and facilitators that influence the adoption of NAFLD NITs, from healthcare professionals' perspectives. (2) Methods: A cross-sectional study was performed using an exploratory mixed-methods approach. Twenty-seven clinicians from eight different countries with different specialties filled in our questionnaire. Of those, 16 participated in semi-structured interviews. Qualitative and quantitative data were collected and summarized using the recently published Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework for new medical technologies in healthcare organizations. (3) Results: Several factors were reported as influencing the uptake of NITs for NAFLD in clinical practice. Among those: insufficient awareness of tests; lack of practical guidelines and evidence for the performance of tests in appropriate patient populations and care settings; and absence of sufficient reimbursement systems were reported as the most important barriers. Other factors, most notably 'local champions', proper functional payment systems, and sufficient resources in academic hospitals, were indicated as important facilitating factors. (4) Conclusions: Clinicians see the adoption of NITs for NAFLD as a complex process that is modulated by several factors, such as robust evidence, practical guidelines, a proper payment system, and local champions. Future research could explore perspectives from other stakeholders on the adoption of NITs.

Systematic Review with Meta-Analysis: Diagnostic Accuracy of Pro-C3 for Hepatic Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77-0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73-0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD.

Systematic Review with Meta-Analyses: Diagnostic Accuracy of FibroMeter Tests in Patients with Non-Alcoholic Fatty Liver Disease.

Early detection of liver fibrosis is crucial to select the correct care path for patients with non-alcoholic fatty liver disease (NAFLD). Here, we systematically review the evidence on the performance of FibroMeter versions in detecting different levels of fibrosis in patients with NAFLD. We searched four databases (Medline, Embase, the Cochrane library, and Web of Science) to find studies that included adults with NAFLD and biopsy-confirmed fibrosis (F1 to F4), compared with any version of FibroMeter. Two independent researchers screened the references, collected the data, and assessed the methodological quality of the included studies. We used a bivariate logit-normal random effects model to produce meta-analyses. From 273 references, 12 studies were eligible for inclusion, encompassing data from 3425 patients. Meta-analyses of the accuracy in detecting advanced fibrosis (F ≥ 3) were conducted for FibroMeter Virus second generation (V2G), NAFLD, and vibration controlled transient elaFS3stography (VCTE). FibroMeter VCTE showed the best diagnostic accuracy in detecting advanced fibrosis (sensitivity: 83.5% (95%CI 0.58-0.94); specificity: 91.1% (95%CI 0.89-0.93)), followed by FibroMeter V2G (sensitivity: 83.1% (95%CI 0.73-0.90); specificity: 84.4% (95%CI 0.62-0.95)) and FibroMeter NAFLD (sensitivity: 71.7% (95%CI 0.63-0.79); specificity: 82.8% (95%CI 0.71-0.91)). No statistically significant differences were found between the different FibroMeter versions. FibroMeter tests showed acceptable sensitivity and specificity in detecting advanced fibrosis in patients with NAFLD, but an urge to conduct head-to-head comparison studies in patients with NAFLD of the different FibroMeter tests remains.

FibroTest for Evaluating Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review and Meta-Analysis.

(1) Background: FibroTest™ is a multi-marker panel, suggested by guidelines as one of the surrogate markers with acceptable performance for detecting fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). A number of studies evaluating this test have been published after publication of the guidelines. This study aims to produce summary estimates of FibroTest™ diagnostic accuracy. (2) Methods: Five databases were searched for studies that evaluated FibroTest™ against liver biopsy as the reference standard in NAFLD patients. Two authors independently screened the references, extracted data, and assessed the quality of included studies. Meta-analyses of the accuracy in detecting different levels of fibrosis were performed using the bivariate random-effects model and the linear mixed-effects multiple thresholds model. (3) Results: From ten included studies, seven were eligible for inclusion in our meta-analysis. Five studies were included in the meta-analysis of FibroTest™ in detecting advanced fibrosis and five in significant fibrosis, resulting in an AUC of 0.77 for both target conditions. The meta-analysis of three studies resulted in an AUC of 0.69 in detecting any fibrosis, while analysis of three other studies showed higher accuracy in cirrhosis (AUC: 0.92). (4) Conclusions: Our meta-analysis showed acceptable performance (AUC > 0.80) of FibroTest™ only in detecting cirrhosis. We observed more limited performance of the test in detecting significant and advanced fibrosis in NAFLD patients. Further primary studies with high methodological quality are required to validate the reliability of the test for detecting different fibrosis levels and to compare the performance of the test in different settings.

Application of weighting methods for presenting risk-of-bias assessments in systematic reviews of diagnostic test accuracy studies.

BACKGROUND: An assessment of the validity of individual diagnostic accuracy studies in systematic reviews is necessary to guide the analysis and the interpretation of results. Such an assessment is performed for each included study and typically reported at the study level. As studies may differ in sample size and disease prevalence, with larger studies contributing more to the meta-analysis, such a study-level report does not always reflect the risk of bias in the total body of evidence. We aimed to develop improved methods of presenting the risk of bias in the available evidence on diagnostic accuracy of medical tests in systematic reviews, reflecting the relative contribution of the study to the body of evidence in the review. METHODS: We applied alternative methods to represent evaluations with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2), weighting studies according to their relative contribution to the total sample size or their relative effective sample size. We used these methods in four existing systematic reviews of diagnostic accuracy studies, including 9, 13, 22, and 32 studies, respectively. RESULTS: The risk-of-bias summaries for each domain of the QUADAS-2 checklist changed in all four sets of studies after replacing unit weights for the studies with relative sample sizes or with the relative effective sample size. As an example, the risk of bias was high in the patient selection domain in 31% of the studies in one review, unclear in 23% and low in 46% of studies. Weighting studies according to the relative sample size changed the corresponding proportions to 4%, 4%, and 92%, respectively. The difference between the two weighting methods was small and more noticeable when the reviews included a smaller number of studies with wider range of sample size. CONCLUSIONS: We present an alternative way of presenting the results of risk-of-bias assessments in systematic reviews of diagnostic accuracy studies. Weighting studies according to their relative sample size or their relative effective sample size can be used as more informative summaries of the risk of bias in the total body of available evidence. SYSTEMATIC REVIEW REGISTRATIONS: Not applicable.

Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). METHODS: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. RESULTS: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. CONCLUSIONS: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. LAY SUMMARY: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring.

Study designs for comparative diagnostic test accuracy: A methodological review and classification scheme.

OBJECTIVES: (1) To identify and classify comparative diagnostic test accuracy (DTA) study designs; (2) to describe study design labels used by authors of comparative DTA studies. METHODS: We performed a methodological review of 100 comparative DTA studies published between 2015 and 2017, randomly sampled from studies included in 238 comparative DTA systematic reviews indexed in MEDLINE in 2017. From each study report, we extracted six design elements characterizing participant flow and the labels used by authors. RESULTS: We identified a total of 46 unique combinations of study design features in our sample, based on six design elements characterizing participant flow. We classified the studies into five study design categories based on how participants were allocated to receive each index test: 'fully paired' (n=79), 'partially paired, random subset' (n=0), 'partially paired, nonrandom subset' (n=2), 'unpaired randomized' (n=1) and 'unpaired nonrandomized' (n=3). The allocation method used in 15 studies was unclear. Sixty-one studies reported, in total, 29 unique study design labels but only four labels referred to specific design features of comparative studies. CONCLUSION: Our classification scheme can help systematic review authors define study eligibility criteria, assess risk of bias, and communicate the strength of the evidence. A standardized labelling scheme could be developed to facilitate communication of specific design features.

Diagnostic accuracy of fibrosis tests in children with non-alcoholic fatty liver disease: A systematic review.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children. Even at young age, it can progress to liver fibrosis. Given the drawbacks of liver biopsy, there is a need for non-invasive methods to accurately stage liver fibrosis in this age group. In this systematic review, we evaluate the diagnostic accuracy of non-invasive methods for staging liver fibrosis in children with NAFLD. METHODS: We searched MEDLINE, Embase, Web of Science and the Cochrane Library, for studies that evaluated the performance of a blood-based biomarker, prediction score or imaging technique in staging liver fibrosis in children with NAFLD, using liver biopsy as the reference standard. RESULTS: Twenty studies with a total of 1787 NAFLD subjects were included, which evaluated three prediction scores, five simple biomarkers, two combined biomarkers and six imaging techniques. Most studies lacked validation. Substantial heterogeneity of studies and limited available study data precluded a meta-analysis of the few fibrosis tests evaluated in more than one study. The most consistent accuracy data were found for transient elastography by FibroScan®, ELF test and ultrasound elastography, with an area under the receiver operating characteristics curve varying between 0.92 and 1.00 for detecting significant fibrosis. CONCLUSION: Due to the lack of validation, the accuracy and clinical utility of non-invasive fibrosis tests in children with NAFLD remains uncertain. As studies have solely been performed in tertiary care settings, accuracy data cannot directly be translated to screening populations.

Prognostic accuracy of FIB-4, NAFLD fibrosis score and APRI for NAFLD-related events: A systematic review.

BACKGROUND & AIMS: Fibrosis is the strongest predictor for long-term clinical outcomes among patients with non-alcoholic fatty liver disease (NAFLD). There is growing interest in employing non-invasive methods for risk stratification based on prognosis. FIB-4, NFS and APRI are models commonly used for detecting fibrosis among NAFLD patients. We aimed to synthesize existing literature on the ability of these models in prognosticating NAFLD-related events. METHODS: A sensitive search was conducted in two medical databases to retrieve studies evaluating the prognostic accuracy of FIB-4, NFS and APRI among NAFLD patients. Target events were change in fibrosis, liver-related event and mortality. Two reviewers independently performed reference screening, data extraction and quality assessment (QUAPAS tool). RESULTS: A total of 13 studies (FIB-4:12, NFS: 11, APRI: 10), published between 2013 and 2019, were retrieved. All studies were conducted in a secondary or tertiary care setting, with follow-up ranging from 1 to 20 years. All three markers showed consistently good prognostication of liver-related events (AUC from 0.69 to 0.92). For mortality, FIB-4 (AUC of 0.67-0.82) and NFS (AUC of 0.70-0.83) outperformed APRI (AUC of 0.52-0.73) in all studies. All markers had inconsistent performance for predicting change in fibrosis stage. CONCLUSIONS: FIB-4, NFS, and APRI have demonstrated ability to risk stratify patients for liver-related morbidity and mortality, with comparable performance to a liver biopsy, although more head-to-head studies are needed to validate this. More refined models to prognosticate NAFLD-events may further enhance performance and clinical utility of non-invasive markers.

Reporting of test comparisons in diagnostic accuracy studies: A literature review.

Comparative accuracy studies evaluate the relative performance of two or more diagnostic tests. As any other form of research, such studies should be reported in an informative manner, to allow replication and to be useful for decision-making. In this study we aimed to assess whether and how components of test comparisons were reported in comparative accuracy studies. We evaluated 100 comparative accuracy studies, published in 2015, 2016 or 2017, randomly sampled from 238 comparative accuracy systematic reviews. We extracted information on 20 reporting items, pertaining to the identification of the test comparison, its validity, and the actual results of the comparison. About a third of the studies (n = 36) did not report the comparison as a study objective or hypothesis. Although most studies (n = 86) reported how participants had been allocated to index tests, we could often not evaluate whether test interpreters had been blinded to the results of other index tests (n = 40; among 59 applicable studies), nor could we identify the sequence of index tests (n = 52; among 90 applicable studies) or the methods for comparing measures of accuracy (n = 59). Two-by-four table data (revealing the agreement between index tests) were only reported by 9 of 90 paired comparative studies. More than half of the studies (n = 64) did not provide measures of statistical imprecision for comparative accuracy. Our findings suggest that components of test comparisons are frequently missing or incompletely described in comparative accuracy studies included in systematic reviews. Explicit guidance for reporting comparative accuracy studies may facilitate the production of full and informative study reports.

Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: A systematic review and meta-analysis.

INTRODUCTION: Association between elevated cytokeratin 18 (CK-18) levels and hepatocyte death has made circulating CK-18 a candidate biomarker to differentiate non-alcoholic fatty liver from non-alcoholic steatohepatitis (NASH). Yet studies produced variable diagnostic performance. We aimed to provide summary estimates with increased precision for the accuracy of CK-18 (M30, M65) in detecting NASH and fibrosis among non-alcoholic fatty liver disease (NAFLD) adults. METHODS: We searched five databases to retrieve studies evaluating CK-18 against a liver biopsy in NAFLD adults. Reference screening, data extraction and quality assessment (QUADAS-2) were independently conducted by two authors. Meta-analyses were performed for five groups based on the CK-18 antigens and target conditions, using one of two methods: linear mixed-effects multiple thresholds model or bivariate logit-normal random-effects model. RESULTS: We included 41 studies, with data on 5,815 participants. A wide range of disease prevalence was observed. No study reported a pre-defined cut-off. Thirty of 41 studies provided sufficient data for inclusion in any of the meta-analyses. Summary AUC [95% CI] were: 0.75 [0.69-0.82] (M30) and 0.82 [0.69-0.91] (M65) for NASH; 0.73 [0.57-0.85] (M30) for fibrotic NASH; 0.68 (M30) for significant (F2-4) fibrosis; and 0.75 (M30) for advanced (F3-4) fibrosis. Thirteen studies used CK-18 as a component of a multimarker model. CONCLUSIONS: For M30 we found lower diagnostic accuracy to detect NASH compared to previous meta-analyses, indicating a limited ability to act as a stand-alone test, with better performance for M65. Additional external validation studies are needed to obtain credible estimates of the diagnostic accuracy of multimarker models.

Risk of bias assessment of test comparisons was uncommon in comparative accuracy systematic reviews: an overview of reviews.

OBJECTIVES: Comparative diagnostic test accuracy systematic reviews (DTA reviews) assess the accuracy of two or more tests and compare their diagnostic performance. We investigated how comparative DTA reviews assessed the risk of bias (RoB) in primary studies that compared multiple index tests. STUDY DESIGN AND SETTING: This is an overview of comparative DTA reviews indexed in MEDLINE from January 1st to December 31st, 2017. Two assessors independently identified DTA reviews including at least two index tests and containing at least one statement in which the accuracy of the index tests was compared. Two assessors independently extracted data on the methods used to assess RoB in studies that directly compared the accuracy of multiple index tests. RESULTS: We included 238 comparative DTA reviews. Only two reviews (0.8%, 95% confidence interval 0.1 to 3.0%) conducted RoB assessment of test comparisons undertaken in primary studies; neither used an RoB tool specifically designed to assess bias in test comparisons. CONCLUSION: Assessment of RoB in test comparisons undertaken in primary studies was uncommon in comparative DTA reviews, possibly due to lack of existing guidance on and awareness of potential sources of bias. Based on our findings, guidance on how to assess and incorporate RoB in comparative DTA reviews is needed.