1. Temporal Analysis of Platelet Data in Chronic Viral Hepatitis Dataset Shoji HiranoShusaku Tsumoto hirano@ieee.orgtsumoto@computer.org Department of Medical Informatics, Shimane University, School of Medicine, Japan

2. Outline Introduction Cluster analysis system for time-series medical data Experimental results 1. Cluster analysis of platelet (PLT) sequences 2. PLT-based analysis of the progress speed of liver fibrosis Conclusion & Future Work

3. Introduction Platelet (PLT) decrease in chronic viral hepatitis The liver plays an important role in generating platelets Bleeding is often observed on the patients at the terminal stage of liver cirrhosis Liver fibrosis -> dysfunction -> PLT decrease -> bleeding Use of PLT count as an noninvasive index for evaluating liver fibrosis [F0 (no fibrosis), F1, F2, F3, F4 (liver cirrhosis)] PLT counts correlate with fibrotic stage (Matsuura et al., J. Viral Hepat. 2000), according to PLT counts at the time of biopsy However, Time-series analysis of the PLT data have rarely been performed Features of temporal patterns/courses have not been examined

4. Introduction (cont ’ d) Difficulties in time series comparison Irregular sampling intervals, irregular sequence length Existence of events with different length and phase Difficult to find the corresponding pairs of points be compared 3-6M 4 years 1-2 Weeks IFN 6m 9 years

5. Cluster Analysis System 4 years 1-2 weeks PLT IFN 6 m 9 years IFN 6 m Seq １ Seq ２ Global Local Scale Similar Match Structural Dissimilarities Time-series Medical Data Multiscale Comparison Cluster representation of time series Grouping

6. Experiment 1: Cluster Analysis of PLT Sequences Objective Discovery of common temporal courses in platelet sequences Discovery of relations between platelet courses and fibrotic stages Used data Chronic hepatitis dataset provided by Chiba University Total 488 cases (Type B: 193, Type C w/o IFN: 99, Type C with IFN: 196) (Male 343, Female 145 (145:48, 61:38, 137:59)) Procedure Generate a dissimilarity matrix using the modified multi-scale matching Generate a dendrogram from the matrix using agglomerative hierarchical clustering (average linkage) and perform cluster analysis

7. Experiment 1 Cluster Constitution w.r.t. Fibrotic Stages Type C, IFN (total 196 cases) ※ clusters of N < 3 omitted F4 Major F1 Major

8. Experiment 1 Grouped Sequences F4, F3 major clusters (Type C, IFN) Cluster 5: N=11 (0/2/1/2/6) Normal H (350 x10^3 /ul ) Normal L (120 x10^3 /ul ) Cluster 8: N=40 (0/9/6/9/16) ※ first 16 cases 051015Y Number of cases (F0/F1/F2/F3/F4) Male 10, Female 1 Male 27, Female 13

9. Experiment 1 Grouped Sequences F1, F2 major clusters (Type C, IFN) Cluster 11: N=46 (2/24/9/9/3)Cluster 12: N=42 (1/22/10/6/3) ※ First 16 cases 051015Y Male 34, Female 12 Male 32, Female 10

10. Experiment 1 Grouped Sequences Clusters containing remarkable increase/decrease cases Cluster 4: N=4 (0/3/1/0/0) Cluster 6: N=3 (0/1/0/1/1) Cluster 10: N=5 (0/1/0/1/3) 051015Y Male 2, Female 2 Male 2, Female 1 Male 4, Female 1

11. Experiment 1 Relationships between PLT and GPT F4, F3 major clusters (Type C, IFN) Cluster 5: N=11 (0/2/1/2/6) Normal H (350 x10^3 /ul ) Normal L (120 x10^3 /ul ) 051015Y Normal H (40 IU/L) Normal L (7 IU/L) 051015Y PLT GPT

12. Experiment 1 Relationships between PLT and GPT F1, F2 major clusters (Type C, IFN) Cluster 11: N=46 (2/24/9/9/3) 051015Y PLT GPT ※ First 16 cases

13. Experiment 1 Relationships between PLT and GPT Clusters containing remarkable increase/decrease cases Cluster 4: N=4 (0/3/1/0/0) Cluster 6: N=3 (0/1/0/1/1) Cluster 10: N=5 (0/1/0/1/3) 051015Y PLT GPT PLT GPT PLT

14. Experiment 1 Summary Fibrotic stage and PLT course F4/F3 major clusters Lower PLT level, below the normal range Decreasing, or flat courses Some F1/F2 cases may follow similar courses (ex. Type C IFN cluster 5) F1/F2 major clusters Moderate PLT level within the normal range (ex. Type C with IFN clusters 11, 12, 23) Mildly decreasing, or flat courses PLT level may correspond to fibrotic stages (ex. Type C with IFN clusters 23 > 12 > 11 )

15. Experiment 1 Summary Fibrotic stage and PLT course Fast increase/decrease cases Some cases rapidly descent from normal range regardless of fibrotic stage (Type C with IFN clusters 4,6) Some cases rapidly ascent toward normal range (after IFN therapy)(Type C with IFN cluster 10) Relationships between PLT and GPT Chronically high GPT level may induce the descent of PLT, progressing the fibrotic stage Difficult interpretation of GPT patterns; high level followed by flat low level Cured cases or terminal cases ?

16. Experiment 2: PLT-based Analysis of Progress Speed of Liver Fibrosis Assumption: Diminishing PLT (below the normal low limit; NL) for long time -> F4 stage Using PLT-based stage estimation and biopsy information, we analyzed Years for reaching F4 stage Years elapsed between stages 1Y Normal Low (NL) Normal High (NH) PLT diminishing below the NL MID 466 (7.92Y) F4(PLT) F1(biopsy)

17. Experiment 2 Preprocess: Sequence Selection Excluded sequences 1. No biopsy information 2. Short: # of exam < 3, or duration of exam < 2Y 3. Inhomogeneous: SD of exam intervals > 1Y Interval 14 Y Inhomogeneous seq. Interval 1M MID 215 Normal Low (NL) Normal High (NH)

18. Experiment 2 Preprocess: Sequence Smoothing Removal of short-term changes Convolution with Gaussian kernel with 6M width(  =2.8)

19. Experiment 2 Discrimination of Diminishing Cases Criteria 1. Keeps diminished PLT counts (below the normal level) at least for 6 month 2. Once diminished, never maintain normal PLT level for 6 month at any time until the last examination 1Y 6 M Diminished Case MID 466 Normal Low (NL) Normal High (NH)

20. Experiment 2 Discrimination of Diminished Cases Criteria 1. Keeps diminished PLT count (below the normal level) at least for 6 month 2. Once diminished, never maintain normal PLT level for 6 month at any time until the last examination 6 M Not Diminished Case 6 M Recovery MID 37 Normal Low (NL) Normal High (NH)

21. Experiment 2 Selection Results PLT data exist, but no biopsy information available # of exam < 3, or Duration of exam < 2Y SD of exam interval > 1Y Not diminished below NL Excluded from Analysis Subject for Analysis Selection Results (Total 720 Cases) Numbers in (): ratio (%)

22. Experiment 2 Years for Reaching F4: Two Measures First-exam basis:Years from the first PLT examination First-biopsy basis ： Years from the first biopsy Fibrotic stage at starting date: stage observed at the first biopsy Years = 0 if the date for diminishment is earlier than the first biopsy Diminished date (below NL) F4 (PLT) First biopsy F1 (biopsy) First PLT exam F1 (stage at first biopsy) First-exam basis First-biopsy basis MID 216 Normal Low (NL) Normal High (NH)

23. Experiment 2 Years for Reaching F4: Summary for 97 Diminishing Cases (First-exam basis)

24. Experiment 2 Years for Reaching F4: Summary for 97 Diminishing Cases (First-biopsy Basis)

25. Experiment 2 Years Elapsed between Stages: Summary for 97 Diminishing Cases (First-biopsy Basis)

26. Experiment 2 Summary PLT-based estimation about years for reaching F4 and years elapsed between stages Assumption: Diminishing PLT (below NL) over long time -> F4 stage Keeps diminished PLT below NL at least for 6 month Cannot maintain normal PLT level over 6 month at any time from the time it diminished below NL to the last examination Analyzed a total of 97 diminished cases (31 Type B, 40 Type C with IFN, 26 Type C w/o IFN cases) Years for F4:2.95 Y (av. 97 cases, first-exam basis) 2.22 Y (av. 97 cases, first-biopsy basis) Years between stages: 1.60 Y/stage （ av. 97 cases, first-biopsy basis)

27. Conclusion Presented the results of temporal analysis of platelet data in chronic viral hepatitis dataset Findings: Temporal courses of PLT might be classified into some patterns according to their levels and trends which might be further related to fibrotic stages. In some exacerbating cases, liver fibrosis may proceed a few times faster than the natural courses. Further validation of the clinical reasonability of the results Application of the analysis scheme on other items/datasets. Future Work

28. Cluster Constitution w.r.t. Fibrotic Stages Type C w/o IFN (total 99 cases)

29. Grouped Sequences F4, F3 Major Clusters (Type C, w/o IFN) Cluster 3: N=47 (1/27/6/7/6) ※ First 16 cases Cluster 1: N=22 (0/4/4/5/9) ※ First 16 cases 051015Y Male 14, Female 8 Male 27, Female 20

30. Relationships between PLT and GPT F4, F3 major clusters (Type C, w/o IFN) Cluster 1: N=22 (0/4/4/5/9) ※ First 16 cases 051015Y PLT GPT ※ First 16 cases