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1.  Non-Markov Multistate Modeling Using Time-Varying Covariates, with Application to Progression of Liver Fibrosis due to Hepatitis C Following Liver Transplant* 
Multistate modeling methods are well-suited for analysis of some chronic diseases that move through distinct stages. The memoryless or Markov assumptions typically made, however, may be suspect for some diseases, such as hepatitis C, where there is interest in whether prognosis depends on history. This paper describes methods for multistate modeling where transition risk can depend on any property of past progression history, including time spent in the current stage and the time taken to reach the current stage. Analysis of 901 measurements of fibrosis in 401 patients following liver transplantation found decreasing risk of progression as time in the current stage increased, even when controlled for several fixed covariates. Longer time to reach the current stage did not appear associated with lower progression risk. Analysis of simulation scenarios based on the transplant study showed that greater misclassification of fibrosis produced more technical difficulties in fitting the models and poorer estimation of covariate effects than did less misclassification or error-free fibrosis measurement. The higher risk of progression when less time has been spent in the current stage could be due to varying disease activity over time, with recent progression indicating an “active” period and consequent higher risk of further progression.
doi:10.2202/1557-4679.1213
PMCID: PMC2836212  PMID: 20305705
fibrosis; hepatitis C; liver transplant; memoryless assumptions; multistate modeling
2.  Estimating Complex Multi-State Misclassification Rates for Biopsy-Measured Liver Fibrosis in Patients with Hepatitis C* 
For both clinical and research purposes, biopsies are used to classify liver damage known as fibrosis on an ordinal multi-state scale ranging from no damage to cirrhosis. Misclassification can arise from reading error (misreading of a specimen) or sampling error (the specimen does not accurately represent the liver). Studies of biopsy accuracy have not attempted to synthesize these two sources of error or to estimate actual misclassification rates from either source. Using data from two studies of reading error and two of sampling error, we find surprisingly large possible misclassification rates, including a greater than 50% chance of misclassification for one intermediate stage of fibrosis. We find that some readers tend to misclassify consistently low or consistently high, and some specimens tend to be misclassified low while others tend to be misclassified high. Non-invasive measures of liver fibrosis have generally been evaluated by comparison to simultaneous biopsy results, but biopsy appears to be too unreliable to be considered a gold standard. Non-invasive measures may therefore be more useful than such comparisons suggest. Both stochastic uncertainty and uncertainty about our model assumptions appear to be substantial. Improved studies of biopsy accuracy would include large numbers of both readers and specimens, greater effort to reduce or eliminate reading error in studies of sampling error, and careful estimation of misclassification rates rather than less useful quantities such as kappa statistics.
doi:10.2202/1557-4679.1139
PMCID: PMC2810974  PMID: 20104258
fibrosis; hepatitis C; kappa statistic; latent variables; misclassification
3.  Estimating Complex Multi-State Misclassification Rates for Biopsy-Measured Liver Fibrosis in Patients with Hepatitis C 
For both clinical and research purposes, biopsies are used to classify liver damage known as fibrosis on an ordinal multi-state scale ranging from no damage to cirrhosis. Misclassification can arise from reading error (misreading of a specimen) or sampling error (the specimen does not accurately represent the liver). Studies of biopsy accuracy have not attempted to synthesize these two sources of error or to estimate actual misclassification rates from either source. Using data from two studies of reading error and two of sampling error, we find surprisingly large possible misclassification rates, including a greater than 50% chance of misclassification for one intermediate stage of fibrosis. We find that some readers tend to misclassify consistently low or consistently high, and some specimens tend to be misclassified low while others tend to be misclassified high. Non-invasive measures of liver fibrosis have generally been evaluated by comparison to simultaneous biopsy results, but biopsy appears to be too unreliable to be considered a gold standard. Non-invasive measures may therefore be more useful than such comparisons suggest. Both stochastic uncertainty and uncertainty about our model assumptions appear to be substantial. Improved studies of biopsy accuracy would include large numbers of both readers and specimens, greater effort to reduce or eliminate reading error in studies of sampling error, and careful estimation of misclassification rates rather than less useful quantities such as kappa statistics.
doi:10.2202/1557-4679.1139
PMCID: PMC2810974  PMID: 20104258

Results 1-3 (3)