Skip to main content
Top
Published in: BMC Medical Research Methodology 1/2011

Open Access 01-12-2011 | Research article

Progression of liver cirrhosis to HCC: an application of hidden Markov model

Authors: Nicola Bartolomeo, Paolo Trerotoli, Gabriella Serio

Published in: BMC Medical Research Methodology | Issue 1/2011

Login to get access

Abstract

Background

Health service databases of administrative type can be a useful tool for the study of progression of a disease, but the data reported in such sources could be affected by misclassifications of some patients' real disease states at the time. Aim of this work was to estimate the transition probabilities through the different degenerative phases of liver cirrhosis using health service databases.

Methods

We employed a hidden Markov model to determine the transition probabilities between two states, and of misclassification. The covariates inserted in the model were sex, age, the presence of comorbidities correlated with alcohol abuse, the presence of diagnosis codes indicating hepatitis C virus infection, and the Charlson Index. The analysis was conducted in patients presumed to have suffered the onset of cirrhosis in 2000, observing the disease evolution and, if applicable, death up to the end of the year 2006.

Results

The incidence of hepatocellular carcinoma (HCC) in cirrhotic patients was 1.5% per year. The probability of developing HCC is higher in males (OR = 2.217) and patients over 65 (OR = 1.547); over 65-year-olds have a greater probability of death both while still suffering from cirrhosis (OR = 2.379) and if they have developed HCC (OR = 1.410). A more severe casemix affects the transition from HCC to death (OR = 1.714). The probability of misclassifying subjects with HCC as exclusively affected by liver cirrhosis is 14.08%.

Conclusions

The hidden Markov model allowing for misclassification is well suited to analyses of health service databases, since it is able to capture bias due to the fact that the quality and accuracy of the available information are not always optimal. The probability of evolution of a cirrhotic subject to HCC depends on sex and age class, while hepatitis C virus infection and comorbidities correlated with alcohol abuse do not seem to have an influence.
Appendix
Available only for authorised users
Literature
1.
go back to reference Di Bisceglie AM: Hepatitis C and hepatocellular carcinoma. Hepatology. 1997, 26 (3 suppl 1): 34S-38S. 10.1002/hep.510260706.CrossRefPubMed Di Bisceglie AM: Hepatitis C and hepatocellular carcinoma. Hepatology. 1997, 26 (3 suppl 1): 34S-38S. 10.1002/hep.510260706.CrossRefPubMed
2.
go back to reference Fattovich G, Stroffolini T, Zagni I, Donato F: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004, 127: S35-S50. 10.1053/j.gastro.2004.09.014.CrossRefPubMed Fattovich G, Stroffolini T, Zagni I, Donato F: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004, 127: S35-S50. 10.1053/j.gastro.2004.09.014.CrossRefPubMed
3.
go back to reference Putter H, Fiocco M, Geskus RB: Tutorial in biostatistics: competing risks and multi-state models. Statistics in Medicine. 2007, 26: 2389-2430. 10.1002/sim.2712.CrossRefPubMed Putter H, Fiocco M, Geskus RB: Tutorial in biostatistics: competing risks and multi-state models. Statistics in Medicine. 2007, 26: 2389-2430. 10.1002/sim.2712.CrossRefPubMed
4.
go back to reference Serio G, Morabito A: Considerations on a staging process for chronic diseases. Rivista di Statistica Applicata. 1988, 21 (23): 335-348. Serio G, Morabito A: Considerations on a staging process for chronic diseases. Rivista di Statistica Applicata. 1988, 21 (23): 335-348.
5.
go back to reference Serio G, Morabito A: Stochastic survival model with covariates in cancer. Modelling of Biomedical Systems. 1986, 91-96. Serio G, Morabito A: Stochastic survival model with covariates in cancer. Modelling of Biomedical Systems. 1986, 91-96.
6.
go back to reference Chen HH, Duffy SW, Tabar L: A Markov chain method to estimate the tumour progression rate from preclinical to clinical phase, sensitivity and positive predictive value for mammography in breast cancer screening. The Statistician. 1996, 45 (3): 307-317. 10.2307/2988469.CrossRef Chen HH, Duffy SW, Tabar L: A Markov chain method to estimate the tumour progression rate from preclinical to clinical phase, sensitivity and positive predictive value for mammography in breast cancer screening. The Statistician. 1996, 45 (3): 307-317. 10.2307/2988469.CrossRef
7.
go back to reference Jackson CH, Sharples LD: Hidden Markov models for the onset and progression of bronchiolitis obliterans syndrome in lung transplant recipients. Statistics in Medicine. 2002, 21: 113-128. 10.1002/sim.886.CrossRefPubMed Jackson CH, Sharples LD: Hidden Markov models for the onset and progression of bronchiolitis obliterans syndrome in lung transplant recipients. Statistics in Medicine. 2002, 21: 113-128. 10.1002/sim.886.CrossRefPubMed
8.
go back to reference Clogg CC: Latent class models: recent developments and prospects for the future. Handbook of Statistical Modeling in the Social Sciences. Edited by: Arminger G, Clogg CC, Sobel ME. 1995, Plenum, New York, 311-359.CrossRef Clogg CC: Latent class models: recent developments and prospects for the future. Handbook of Statistical Modeling in the Social Sciences. Edited by: Arminger G, Clogg CC, Sobel ME. 1995, Plenum, New York, 311-359.CrossRef
9.
go back to reference MacDonald IL, Zucchini W: Hidden Markov Models and Other Models for Discrete-valued Time Series. 1997, Chapman and Hall: New York MacDonald IL, Zucchini W: Hidden Markov Models and Other Models for Discrete-valued Time Series. 1997, Chapman and Hall: New York
10.
go back to reference Scheike TH, Zhang M: Direct Modelling of Regression Effects for Transition Probabilities in Multistate Models. Scandinavian Journal of Statistics. 2007, 34: 17-32. 10.1111/j.1467-9469.2006.00544.x.CrossRef Scheike TH, Zhang M: Direct Modelling of Regression Effects for Transition Probabilities in Multistate Models. Scandinavian Journal of Statistics. 2007, 34: 17-32. 10.1111/j.1467-9469.2006.00544.x.CrossRef
11.
go back to reference Cox D: Regression Models and Life-Tables. Journal of the Royal Statistical Society, Series B. 1972, 34: 187-220. Cox D: Regression Models and Life-Tables. Journal of the Royal Statistical Society, Series B. 1972, 34: 187-220.
12.
go back to reference Jackson CH, Sharples LD, Thompson SG, Duffy SW, Couto E: Multistate Markov models for disease progression with classification error. Journal of the Royal Statistical Society, Series D - The Statistician. 2003, 52 (2): 193-209. 10.1111/1467-9884.00351.CrossRef Jackson CH, Sharples LD, Thompson SG, Duffy SW, Couto E: Multistate Markov models for disease progression with classification error. Journal of the Royal Statistical Society, Series D - The Statistician. 2003, 52 (2): 193-209. 10.1111/1467-9884.00351.CrossRef
13.
go back to reference Bureau A, Shiboski S, Hughes JP: Applications of continuous time hidden Markov models to the study of misclassified disease outcomes. Statistics in Medicine. 2003, 22: 441-462. 10.1002/sim.1270.CrossRefPubMed Bureau A, Shiboski S, Hughes JP: Applications of continuous time hidden Markov models to the study of misclassified disease outcomes. Statistics in Medicine. 2003, 22: 441-462. 10.1002/sim.1270.CrossRefPubMed
14.
go back to reference Kalbfleisch JD, Lawless JF: The analysis of panel data under a Markov assumption. Journal of the American Statistical Association. 1985, 80 (392): 863-871. 10.2307/2288545.CrossRef Kalbfleisch JD, Lawless JF: The analysis of panel data under a Markov assumption. Journal of the American Statistical Association. 1985, 80 (392): 863-871. 10.2307/2288545.CrossRef
15.
go back to reference Kay R: A Markov model for analysing cancer markers and disease states in survival studies. Biometrics. 1986, 42: 855-865. 10.2307/2530699.CrossRefPubMed Kay R: A Markov model for analysing cancer markers and disease states in survival studies. Biometrics. 1986, 42: 855-865. 10.2307/2530699.CrossRefPubMed
16.
go back to reference Cox DR, Miller HD: The Theory of Stochastic Processes. 1965, Chapman and Hall, London Cox DR, Miller HD: The Theory of Stochastic Processes. 1965, Chapman and Hall, London
17.
go back to reference Grambsch P, Therneau T: Proportional Hazards Tests and Diagnostics Based on Weighted Residuals. Biometrika. 1994, 81: 515-26. 10.1093/biomet/81.3.515.CrossRef Grambsch P, Therneau T: Proportional Hazards Tests and Diagnostics Based on Weighted Residuals. Biometrika. 1994, 81: 515-26. 10.1093/biomet/81.3.515.CrossRef
18.
go back to reference Schoenfeld D: Chi-squared goodness of fit test for the proportional hazards regression model. Biometrika. 1981, 67: 147-53. Schoenfeld D: Chi-squared goodness of fit test for the proportional hazards regression model. Biometrika. 1981, 67: 147-53.
19.
go back to reference Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987, 40: 373-383. 10.1016/0021-9681(87)90171-8.CrossRefPubMed Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987, 40: 373-383. 10.1016/0021-9681(87)90171-8.CrossRefPubMed
20.
go back to reference Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9- CM administrative databases. J Clin Epidemiol. 1992, 45: 613-619. 10.1016/0895-4356(92)90133-8.CrossRefPubMed Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9- CM administrative databases. J Clin Epidemiol. 1992, 45: 613-619. 10.1016/0895-4356(92)90133-8.CrossRefPubMed
21.
go back to reference Ryder SD: Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut. 2003, 52 (Suppl. III): iii1-8.PubMedPubMedCentral Ryder SD: Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut. 2003, 52 (Suppl. III): iii1-8.PubMedPubMedCentral
23.
go back to reference Duffy SW, Chen HH: Estimation of mean sojourn time in breast cancer screening using a Markov chain model of entry to and exit from preclinical detectable phase. Statistics in Medicine. 1995, 14: 1531-1543. 10.1002/sim.4780141404.CrossRefPubMed Duffy SW, Chen HH: Estimation of mean sojourn time in breast cancer screening using a Markov chain model of entry to and exit from preclinical detectable phase. Statistics in Medicine. 1995, 14: 1531-1543. 10.1002/sim.4780141404.CrossRefPubMed
24.
go back to reference Zaman SN, Melia WM, Johnson RD, Portmann BC, Johnson PJ, Williams R: Risk factors in development of hepatocellular carcinoma in cirrhosis: prospective study of 613 patients. Lancet. 1985, 1: 1357-60. 10.1016/S0140-6736(85)91785-4.CrossRefPubMed Zaman SN, Melia WM, Johnson RD, Portmann BC, Johnson PJ, Williams R: Risk factors in development of hepatocellular carcinoma in cirrhosis: prospective study of 613 patients. Lancet. 1985, 1: 1357-60. 10.1016/S0140-6736(85)91785-4.CrossRefPubMed
25.
go back to reference Sarbah SA, Gramlich T, Younoszai A, et al: Risk factors for hepatocellular carcinoma in patients with cirrhosis. Dig Dis Sci. 2004, 49: 850-853. 10.1023/B:DDAS.0000030098.75759.32.CrossRefPubMed Sarbah SA, Gramlich T, Younoszai A, et al: Risk factors for hepatocellular carcinoma in patients with cirrhosis. Dig Dis Sci. 2004, 49: 850-853. 10.1023/B:DDAS.0000030098.75759.32.CrossRefPubMed
26.
go back to reference Degos F, Christidis C, Ganne-Carrie N, Farmachidi JP, Degott C, Guettier C, Trinchet JC, Beaugrand M, Chevret S: Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut. 2000, 47: 131-136. 10.1136/gut.47.1.131.CrossRefPubMedPubMedCentral Degos F, Christidis C, Ganne-Carrie N, Farmachidi JP, Degott C, Guettier C, Trinchet JC, Beaugrand M, Chevret S: Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut. 2000, 47: 131-136. 10.1136/gut.47.1.131.CrossRefPubMedPubMedCentral
27.
go back to reference Ioannou GN, Splan MF, Weiss NS, McDonald GB, Beretta L, Lee SP: Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2007, 5: 938-945. 10.1016/j.cgh.2007.02.039. 945.e1-945.e4CrossRefPubMed Ioannou GN, Splan MF, Weiss NS, McDonald GB, Beretta L, Lee SP: Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2007, 5: 938-945. 10.1016/j.cgh.2007.02.039. 945.e1-945.e4CrossRefPubMed
28.
go back to reference Fattovich G, Giustina G, Degos F, et al: Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997, 112: 463-472. 10.1053/gast.1997.v112.pm9024300.CrossRefPubMed Fattovich G, Giustina G, Degos F, et al: Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997, 112: 463-472. 10.1053/gast.1997.v112.pm9024300.CrossRefPubMed
29.
go back to reference Colombo M, de Franchis R, Del Ninno E, et al: Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med. 1991, 325: 675-680. 10.1056/NEJM199109053251002.CrossRefPubMed Colombo M, de Franchis R, Del Ninno E, et al: Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med. 1991, 325: 675-680. 10.1056/NEJM199109053251002.CrossRefPubMed
30.
go back to reference N'Kontchou G, Paries J, Htar MT, et al: Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis. Clin Gastroenterol Hepatol. 2006, 4: 1062-1068.CrossRefPubMed N'Kontchou G, Paries J, Htar MT, et al: Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis. Clin Gastroenterol Hepatol. 2006, 4: 1062-1068.CrossRefPubMed
31.
go back to reference Sangiovanni A, Del Ninno E, Fasani P, De Fazio C, Ronchi G, Romeo R, Morabito A, de Franchis R, Colombo M: Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 2004, 126: 1005-1014. 10.1053/j.gastro.2003.12.049.CrossRefPubMed Sangiovanni A, Del Ninno E, Fasani P, De Fazio C, Ronchi G, Romeo R, Morabito A, de Franchis R, Colombo M: Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 2004, 126: 1005-1014. 10.1053/j.gastro.2003.12.049.CrossRefPubMed
32.
go back to reference Benvegnù L, Chemello L, Noventa F, Fattovich G, Pontisso P, Alberti A: Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis. Cancer. 1998, 83: 901-909.CrossRefPubMed Benvegnù L, Chemello L, Noventa F, Fattovich G, Pontisso P, Alberti A: Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis. Cancer. 1998, 83: 901-909.CrossRefPubMed
33.
go back to reference Bolondi L, Sofia S, Siringo S, Gaiani S, Casali A, Zironi G, Piscaglia F, Gramantieri L, Zanetti M, Sherman M: Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut. 2001, 48: 251-259. 10.1136/gut.48.2.251.CrossRefPubMedPubMedCentral Bolondi L, Sofia S, Siringo S, Gaiani S, Casali A, Zironi G, Piscaglia F, Gramantieri L, Zanetti M, Sherman M: Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut. 2001, 48: 251-259. 10.1136/gut.48.2.251.CrossRefPubMedPubMedCentral
34.
go back to reference La Vecchia C, Negri E, Decarli A, et al: Diabetes mellitus and the risk of primary liver cancer. Int J Cancer. 1997, 73: 204-207. 10.1002/(SICI)1097-0215(19971009)73:2<204::AID-IJC7>3.0.CO;2-#.CrossRefPubMed La Vecchia C, Negri E, Decarli A, et al: Diabetes mellitus and the risk of primary liver cancer. Int J Cancer. 1997, 73: 204-207. 10.1002/(SICI)1097-0215(19971009)73:2<204::AID-IJC7>3.0.CO;2-#.CrossRefPubMed
35.
go back to reference El-Serag HB, Tran T, Everhart JE: Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004, 126: 460-468. 10.1053/j.gastro.2003.10.065.CrossRefPubMed El-Serag HB, Tran T, Everhart JE: Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004, 126: 460-468. 10.1053/j.gastro.2003.10.065.CrossRefPubMed
36.
go back to reference London WT, McGlynn KA: Liver cancer. Cancer Epidemiology and Prevention. Edited by: Schottenfeld D, Fraumeni JF Jr. 1996, New York: Oxford University Press, 772-93. London WT, McGlynn KA: Liver cancer. Cancer Epidemiology and Prevention. Edited by: Schottenfeld D, Fraumeni JF Jr. 1996, New York: Oxford University Press, 772-93.
37.
go back to reference Kumar M, Kumar R, Hissar SS, Saraswat MK, Sharma BC, Sakhuja P, Sarin SK: Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: a case -control study of 213 hepatocellular carcinoma patients from India. J Gastroenterol Hepatol. 2007, 22 (7): 1104-11. 10.1111/j.1440-1746.2007.04908.x.CrossRefPubMed Kumar M, Kumar R, Hissar SS, Saraswat MK, Sharma BC, Sakhuja P, Sarin SK: Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: a case -control study of 213 hepatocellular carcinoma patients from India. J Gastroenterol Hepatol. 2007, 22 (7): 1104-11. 10.1111/j.1440-1746.2007.04908.x.CrossRefPubMed
38.
go back to reference Pradat P, Voirin N, Tillmann HL, Chevallier M, Trepo C: Progression to cirrhosis in hepatitis C patients: an age-dependent process. Liver Int. 2007, 27 (3): 335-339. 10.1111/j.1478-3231.2006.01430.x.CrossRefPubMed Pradat P, Voirin N, Tillmann HL, Chevallier M, Trepo C: Progression to cirrhosis in hepatitis C patients: an age-dependent process. Liver Int. 2007, 27 (3): 335-339. 10.1111/j.1478-3231.2006.01430.x.CrossRefPubMed
39.
go back to reference Brookhart MA, Hubbard AE, Van Der Laan MJ, Colford JM, Eisenberg JN: Statistical estimation of parameters in a disease transmission model: analysis of a Cryptosporidium outbreak. Statistics in Medicine. 2002, 21: 3627-38. 10.1002/sim.1258.CrossRefPubMed Brookhart MA, Hubbard AE, Van Der Laan MJ, Colford JM, Eisenberg JN: Statistical estimation of parameters in a disease transmission model: analysis of a Cryptosporidium outbreak. Statistics in Medicine. 2002, 21: 3627-38. 10.1002/sim.1258.CrossRefPubMed
40.
go back to reference Cooper B, Lipsitch M: The analysis of hospital infection data using hidden Markov models. Biostatistics. 2004, 5 (2): 223-237. 10.1093/biostatistics/5.2.223.CrossRefPubMed Cooper B, Lipsitch M: The analysis of hospital infection data using hidden Markov models. Biostatistics. 2004, 5 (2): 223-237. 10.1093/biostatistics/5.2.223.CrossRefPubMed
Metadata
Title
Progression of liver cirrhosis to HCC: an application of hidden Markov model
Authors
Nicola Bartolomeo
Paolo Trerotoli
Gabriella Serio
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Medical Research Methodology / Issue 1/2011
Electronic ISSN: 1471-2288
DOI
https://doi.org/10.1186/1471-2288-11-38

Other articles of this Issue 1/2011

BMC Medical Research Methodology 1/2011 Go to the issue