Clinical prediction of HBV and HCV related hepatic fibrosis using machine learning

Clinical prediction of advanced hepatic fibrosis (HF) and cirrhosis has long been challenging due to the gold standard, liver biopsy, being an invasive approach with certain limitations. Less invasive blood test tandem with a cutting-edge machine learning algorithm shows promising diagnostic potential. In this study, we constructed and compared machine learning methods with the FIB-4 score in a discovery dataset (n = 490) of hepatitis B virus (HBV) patients. Models were validated in an independent HBV dataset (n = 86). We further employed these models on two independent hepatitis C virus (HCV) datasets (n = 254 and 230) to examine their applicability. In the discovery data, gradient boosting (GB) stably outperformed other methods as well as FIB-4 scores (p < .001) in the prediction of advanced HF and cirrhosis. In the HBV validation dataset, for classification between early and advanced HF, the area under receiver operating characteristic curves (AUROC) of GB model was 0.918, while FIB-4 was 0.841; for classification between non-cirrhosis and cirrhosis, GB showed AUROC of 0.871, while FIB-4 was 0.830. Additionally, GB-based prediction demonstrated good classification capacity on two HCV datasets while higher cutoffs for both GB and FIB-4 scores were required to achieve comparable specificity and sensitivity. Using the same parameters as FIB-4, the GB-based prediction system demonstrated steady improvements relative to FIB-4 in HBV and HCV cohorts with different cutoff values required in different etiological groups. A user-friendly web tool, LiveBoost, makes our prediction models freely accessible for further clinical studies and applications.

[1]  T. Ishikawa,et al.  Plasma amino acid profiles applied for diagnosis of advanced liver fibrosis in patients with chronic hepatitis C infection. , 2006, Hepatology research : the official journal of the Japan Society of Hepatology.

[2]  S. Easteal,et al.  Predicting the presence of hepatitis B virus surface antigen in Chinese patients by pathology data mining , 2013, Journal of medical virology.

[3]  E. Tapper,et al.  Use of Liver Imaging and Biopsy in Clinical Practice , 2017, The New England journal of medicine.

[4]  Michael S. Roberts,et al.  Enterohepatic Circulation , 2002, Clinical pharmacokinetics.

[5]  H. El‐Serag,et al.  Epidemiology of viral hepatitis and hepatocellular carcinoma. , 2012, Gastroenterology.

[6]  P. Bedossa,et al.  Age and platelet count: a simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus , 1997, Journal of viral hepatitis.

[7]  E. Segal,et al.  Personalized Nutrition by Prediction of Glycemic Responses , 2015, Cell.

[8]  N. Mcintyre,et al.  The BCAA/AAA ratio of plasma amino acids in three different groups of cirrhotics. , 1992, Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion.

[9]  Jens Keilwagen,et al.  PRROC: computing and visualizing precision-recall and receiver operating characteristic curves in R , 2015, Bioinform..

[10]  P. Thampanitchawong,et al.  Liver biopsy:complications and risk factors. , 1999, World journal of gastroenterology.

[11]  Atul J. Butte,et al.  Opening clinical trial data: are the voluntary data-sharing portals enough? , 2015, BMC Medicine.

[13]  R. Bataller,et al.  Amendment history : Corrigendum ( April 2005 ) Liver fibrosis Ramón Bataller , 2018 .

[14]  Qi Zhao,et al.  Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. , 2017, Nature materials.

[15]  G. Xie,et al.  Phospholipids are A Potentially Important Source of Tissue Biomarkers for Hepatocellular Carcinoma: Results of a Pilot Study Involving Targeted Metabolomics , 2019, Diagnostics.

[16]  A. Scrimgeour,et al.  Data sharing and the evolving role of statisticians , 2016, BMC Medical Research Methodology.

[17]  Leo Breiman,et al.  Random Forests , 2001, Machine Learning.

[18]  B. Ripley,et al.  Recursive Partitioning and Regression Trees , 2015 .

[19]  Guan-Tarn Huang,et al.  Changes in liver stiffness measurement using acoustic radiation force impulse elastography after antiviral therapy in patients with chronic hepatitis C , 2018, PloS one.

[20]  Max Kuhn,et al.  Building Predictive Models in R Using the caret Package , 2008 .

[21]  Wei-Yin Loh,et al.  Classification and regression trees , 2011, WIREs Data Mining Knowl. Discov..

[22]  M. Manns,et al.  A comparison of fibrosis progression in chronic liver diseases. , 2003, Journal of hepatology.

[23]  Pinelopi Manousou,et al.  A methodology for automated CPA extraction using liver biopsy image analysis and machine learning techniques , 2017, Comput. Methods Programs Biomed..

[24]  J. Kalbfleisch,et al.  A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C , 2003, Hepatology.

[25]  S. Pol,et al.  FIB‐4: An inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest , 2007, Hepatology.

[26]  J. Pignon,et al.  Bias and precision of methods for estimating the difference in restricted mean survival time from an individual patient data meta-analysis , 2016, BMC Medical Research Methodology.

[27]  R. Standish,et al.  Scoring of chronic hepatitis. , 2002, Clinics in liver disease.

[28]  Ping Liu,et al.  Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma* , 2011, Molecular & Cellular Proteomics.

[29]  V. de Lédinghen,et al.  Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study , 2005, Gut.

[30]  Andy Liaw,et al.  Classification and Regression by randomForest , 2007 .

[31]  Chengfu Xu,et al.  Association between serum free fatty acid levels and nonalcoholic fatty liver disease: a cross-sectional study , 2014, Scientific Reports.

[32]  Xavier Robin,et al.  pROC: an open-source package for R and S+ to analyze and compare ROC curves , 2011, BMC Bioinformatics.

[33]  박준용,et al.  Validation of FIB-4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus-infected patients , 2010 .

[34]  Daniel E. Zak,et al.  A prospective blood RNA signature for tuberculosis disease risk , 2016, The Lancet.

[35]  G. Tang,et al.  Indian Hedgehog: A Mechanotransduction Mediator in Condylar Cartilage , 2004, Journal of dental research.

[36]  Ian A. Rowe,et al.  Lessons from Epidemiology: The Burden of Liver Disease , 2017, Digestive Diseases.

[37]  H. Shousha,et al.  Data Mining and Machine Learning Algorithms Using IL28B Genotype and Biochemical Markers Best Predicted Advanced Liver Fibrosis in Chronic Hepatitis C. , 2017, Japanese journal of infectious diseases.

[38]  Ping Liu,et al.  Urinary metabolite variation is associated with pathological progression of the post-hepatitis B cirrhosis patients. , 2012, Journal of proteome research.

[39]  W John Boscardin,et al.  Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. , 2005, JAMA.

[40]  K. Hayashi,et al.  Predictive Ability of Laboratory Indices for Liver Fibrosis in Patients with Chronic Hepatitis C after the Eradication of Hepatitis C Virus , 2015, PloS one.

[41]  Jian Lu,et al.  Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis. , 2013, The Lancet. Oncology.

[42]  Zhi-Hua Zhou,et al.  Ensemble Methods: Foundations and Algorithms , 2012 .

[43]  Shi-Ming Lin,et al.  Differences in Liver Fibrosis Between Patients With Chronic Hepatitis B and C , 2015, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[44]  D. Mann,et al.  Clinical evidence for the regression of liver fibrosis. , 2012, Journal of hepatology.

[45]  Thomas Berg,et al.  FibroGENE: A gene-based model for staging liver fibrosis. , 2016, Journal of hepatology.

[46]  J. Montaner,et al.  Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection , 2006, Hepatology.

[47]  E. Schiff,et al.  Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection , 2002, American Journal of Gastroenterology.

[48]  G. Shiha,et al.  Diagnostic value of fibronectin discriminant score for predicting liver fibrosis stages in chronic hepatitis C virus patients. , 2013, Annals of hepatology.

[49]  Rebecca A. O'Leary,et al.  Classification and Regression Tree and Spatial Analyses Reveal Geographic Heterogeneity in Genome Wide Linkage Study of Indian Visceral Leishmaniasis , 2010, PloS one.

[50]  T. Saibara,et al.  Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population , 2011, BMC Gastroenterology.

[51]  Eric R. Ziegel,et al.  The Elements of Statistical Learning , 2003, Technometrics.

[52]  J. Hoofnagle,et al.  Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. , 1988, Gastroenterology.

[53]  G. Gerken,et al.  Lipid metabolism in the liver. , 2007, Zeitschrift fur Gastroenterologie.

[54]  Akin Ozçift,et al.  Random forests ensemble classifier trained with data resampling strategy to improve cardiac arrhythmia diagnosis. , 2011, Computers in biology and medicine.

[55]  Tom Fawcett,et al.  An introduction to ROC analysis , 2006, Pattern Recognit. Lett..

[56]  Sheng-Nan Lu,et al.  Comparisons of noninvasive indices based on daily practice parameters for predicting liver cirrhosis in chronic hepatitis B and hepatitis C patients in hospital and community populations , 2013, The Kaohsiung journal of medical sciences.