Primary Billiary Cirrhosis STUDY

1. Primary Billiary CirrhosisSTUDY PubH5483 Correlated Data Analysis Final Project Fall, 2004 Soon Young Jang PBC STUDY

2. PBC - Background • What is Primary Billiary Cirrhosis (PBC) ? • Progressive chronic liver disease leading to cirrhosis and liver failure • Mostly women’s disease : 75 to 90% of Patients • Mostly occurs between fourth and sixth decades of life • Slow and predictable progress : 40-67% symptomatic disease development in approximately 5 to 7 years • No totally effective treatment in slowing the progress of PBC other than liver transplantation • Historical Stages : system by Ludwig et al and Scheuer based on the results of liver biopsy • Portal • Periportal • Septal • Cirrhosis In general, gradual progression over years from stage I to stage IV PBC STUDY

3. PBC - Background • Prognosis • Range from a few months to 20 years depending upon when the diagnosis is first made • The most reliable determinants of patient prognosis are : • Mayo risk score • Serum Bilirubin Level (SBL) • SBL and Prognosis • Constantly above 6 mg/dL, the mean survival rate is 2.1 years • Needed to be evaluated for possible liver transplantation • D-pencillamine : Hepatic copper decreasing and immunomodulatory potentials. • Scientific Questions • D-pencillamine impact on slowing the rate of increase in SBL and whether the effects are same among historical stages • The variability on the rate of increase in SBL among patients PBC STUDY

4. PBC - Method • Data : published by Terry Therneaus (June 10, 1999) • Repeatedly Measured Data : Mayo Clinic trial in PBC of the liver, originally conducted between January 1974 and May 1984, with extended follow-up to April 30, 1988. • For 312 patients who consented to participated in the randomized trial (D-Pencillamine Vs. Placebo), total of 1,945 patients visits. • Including patient’s id, survival time, status (Alive, Transplanted, and Dead), gender, age, treatment, 12 laboratory results and historical stage of each visit on the clinic with the days (of visit) from the enrollment • Exclusion of Observations with Missing Values • 32(10.26%) patients have missing values on either Serum Cholesterol or Platelet measurement at baseline, total of 264 observations • No evidence against “missing at random” assumption PBC STUDY

5. PBC – Method (Appendix)Analysis of Missing Observations Missing Observation By Survival Status Observed Mean Slope By Missing Status Welch Two Sample t-test : t(df=31.42)=-0.17, pValue=0.86 PBC STUDY

6. PBC - Method • Outcome of Interest • Change of serum bilirubin Level (SBL) from the baseline • Main Covariatesof Interest • Time : Visit in months from the enrollment ( day / 30.5 ) • Drug, randomly assigned • Stage determined at the baseline • Demographic Covariates • age, sex • Covariates for adjusting purpose • 11 laboratory results measured at the baseline PBC STUDY

7. PBC - Method • Analysis Model : General Linear Mixed Model • Covariance Structure • Random Intercept + Random Slope • No correlation was assumed between Random Intercept and Random Slope • Mean Model • No significant associations found between change in SBL and 11 other laboratory results at the baseline ( ) • Final Selected Mean Model • Diagnostic by residual analysis • EDA and Diagnostic using R ver1.8.1, Analysis using SAS ver8.2 PBC STUDY

8. PBC – Results Part I: Baseline Characteristics Table 1. Top: Categorical Baseline Characteristics (Frequency & Percent, chisq test) Bottom: Continuous Baseline Characteristics (Mean ± Std Dev, t test) PBC STUDY

9. PBC - Results • Summary of Data • Summary of Individual Regression Lines (Slopes Only) • Increasing rates across the historical stages • Large Standard Deviations Table 2. Mean of Individual Slope ( ± Std Dev mg/dL/month ) PBC STUDY

10. PBC - Results • Conclusion of Analysis: • No Significant Impact of D-pencillamine on the rate of increase in SBL • No different effects of D-pencillamine on the rate among the historical stages • The rate of increase in SBL across time significant differs by the historical stages determined at the enrollment (or when the diagnosis was made on) • Very large and highly significant Variability on the rate of change in SBL among individual patients. PBC STUDY

11. PBC – Results(Table 3)Estimated Slope and 95% Confidence Limits (mg/dL/month) PBC STUDY

12. PBC – Diagnostic: Predicted Vs. Observed Slope Figure I (a) Placebo (from Table 2 & 3) PBC STUDY

13. PBC – Diagnostic : Predicted Vs. Observed SlopeFigure I (b) D-Pencillamine (from Table 2 & 3) PBC STUDY

14. PBC – Diagnostic • Diagnostic Results • Comparison b/w Observed & Predicted Slopes (Figure I) • Outlying Clusters (Age and Stay under the study in years) --------------------------------------------------- ID Stay Status Drug Stage Age Sex b1 --------------------------------------------------- 67 7.6 Trans P III 51 F 0.61 100 1.5 Trans P IV 51 M 0.50 165 3.0 Trans D IV 53 M 0.50 --------------------------------------------------- • Normality and linearity assumptions checked by residual plots • Relatively good fit of cluster-specific predicted values on observed change (Figure II) PBC STUDY

15. PBC – Diagnostic (Figure II) PBC STUDY

16. PBC – Discussion (Figure III) PBC STUDY

17. PBC - Discussion • Prognosis of SBL by Survival Status (Figure III) • Limitation • Add-hoc analysis : Survival Data • Exclusion of observations with missing values • Main Question : D-Pencillamine effect  Prediction of SBL • Summary • No benefit of D-pencillamine to lowering the rate of increase in SBL, other literature indicates even harmful effect (toxic) • No recommendation of the use of D-pencillamine for the patients with PBC • Large variability of the rate of increase in SBL among patients • No practicality of using the model to predict the progress of SBL for each individual patients PBC STUDY

18. PBC - Reference • Dickson, et al., “Prognosis in Primary Biliary Cirrhosis: Model for Decision Making”, Hepatology 10:1-7 (1989) • Markus, et al., “Efficacy of Liver Transplantation in Patients with Primary Biliary Cirrhosis”, New England Journal of Medicine 320:1709-13 (1989) • Murtugh, et al., “Primary Biliary Cirrhosis: Prediction of Short-term Survival Based on Repeated Patient Visits”, Hepatology 20(1.1):126-34 (1994) • Bonnand, et al., “Clinical Significance of Serum Bilirubin Levels Under Ursodeoxycholic Acid Therapy in Patients With Primary Biliary Cirrhosis”, Hepatology, Hepatology 29(1):39-43 (1999) • Kim, et al., “Adaptation of the Mayo Primary Biliary Cirrhosis Natural History Model for Application in Liver Transplant Candidates”, Liver Transplantation 6(4):489-94 (2000) • Therneau, Terry, “Primary Biliary Cirrhosis, sequential data”, http://www.mayo.edu/hsr/people/therneau/book/data/pbcseq.html • Worman, H.J., “What is Primary Biliary Cirrhosis (PBC)?”, http://cpmcnet.columbia.edu/dept/gi/PBC.html • Pyrsopoulos, N.T., “Primary Biliary Cirrhosis”, http://www.emedicine.com/med/topic223.htm PBC STUDY