title: Progression of biopsy-measured liver fibrosis in untreated patients with hepatitis C infection: non-Markov multistate model analysis.
abstract: BACKGROUND
  Fibrosis stages from liver biopsies reflect liver damage from hepatitis C infection, but analysis is challenging due to their ordered but non-numeric nature, infrequent measurement, misclassification, and unknown infection times.
  
  
  METHODS
  We used a non-Markov multistate model, accounting for misclassification, with multiple imputation of unknown infection times, applied to 1062 participants of whom 159 had multiple biopsies. Odds ratios (OR) quantified the estimated effects of covariates on progression risk at any given time.
  
  
  RESULTS
  Models estimated that progression risk decreased the more time participants had already spent in the current stage, African American race was protective (OR 0.75, 95% confidence interval 0.60 to 0.95, p = 0.018), and older current age increased risk (OR 1.33 per decade, 95% confidence interval 1.15 to 1.54, p = 0.0002). When controlled for current age, older age at infection did not appear to increase risk (OR 0.92 per decade, 95% confidence interval 0.47 to 1.79, p = 0.80). There was a suggestion that co-infection with human immunodeficiency virus increased risk of progression in the era of highly active antiretroviral treatment beginning in 1996 (OR 2.1, 95% confidence interval 0.97 to 4.4, p = 0.059). Other examined risk factors may influence progression risk, but evidence for or against this was weak due to wide confidence intervals. The main results were essentially unchanged using different assumed misclassification rates or imputation of age of infection.
  
  
  CONCLUSIONS
  The analysis avoided problems inherent in simpler methods, supported the previously suspected protective effect of African American race, and suggested that current age rather than age of infection increases risk. Decreasing risk of progression with longer time already spent in a stage was also previously found for post-transplant progression. This could reflect varying disease activity, with recent progression indicating active disease and high risk, while longer time already spent in a stage indicates quiescent disease and low risk.
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Bacchetti
authors.forename: Ross
authors.initials: R
authors.lastname: Boylan
authors.forename: Jacquie
authors.initials: J
authors.lastname: Astemborski
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Shruti H
authors.initials: SH
authors.lastname: Mehta
authors.forename: David L
authors.initials: DL
authors.lastname: Thomas
authors.forename: Norah A
authors.initials: NA
authors.lastname: Terrault
authors.forename: Alexander
authors.initials: A
authors.lastname: Monto
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000473:pathology; D001706:Biopsy; D018450:Disease Progression; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications* / Q000473:pathology*; D008390:Markov Chains; D008875:Middle Aged; D008954:Models, Biological; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013997:Time Factors; D055815:Young Adult