Temporal Analysis of Platelet Data in Chronic Viral Hepatitis Dataset

Shoji Hirano Shusaku Tsumotohirano@ieee.org tsumoto@computer.org

Department of Medical Informatics, Shimane University, School of Medicine, Japan

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

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 l

iver 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 He

pat. 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

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 pointsbe compared

3-6M 4 years1-2 Weeks

IFN 6m

9 years

Cluster Analysis System

4 years1-2 weeks

PLT

IFN 6 m

9 years

IFN 6 m

Seq １ Seq ２

Global

Local

Sc

ale

Similar

Match

Structural Dissimilarities

Time-series Medical Data

Multiscale Comparison

Cluster representation of time seriesGrouping

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 matchin

g Generate a dendrogram from the matrix using agglomerative hierarchi

cal clustering (average linkage) and perform cluster analysis

Experiment 1

Cluster Constitution w.r.t. Fibrotic Stages

Type C, IFN (total 196 cases)

F0 F1 F2 F3 F44 0 3 1 0 0 45 0 2 1 2 6 116 0 1 0 1 1 38 0 9 6 9 16 409 0 3 0 0 0 310 0 1 0 1 3 511 2 24 8 9 3 4612 1 22 10 6 3 4220 0 4 1 0 0 522 0 2 0 0 1 323 1 13 4 1 0 19

Number of Cases / Fibrosis StageCLUSTER Total N

※ clusters of N < 3 omitted

F4 Major

F1 Major

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

0 5 10 15Y

Number of cases (F0/F1/F2/F3/F4)

Male 10, Female 1 Male 27, Female 13

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 cases0 5 10 15YMale 34, Female 12 Male 32, Female 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)

0 5 10 15Y

Male 2, Female 2

Male 2, Female 1

Male 4, Female 1

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)

0 5 10 15Y

Normal H (40 IU/L)Normal L (7 IU/L)

0 5 10 15Y

PLTPLT GPTGPT

Experiment 1

Relationships between PLT and GPT

F1, F2 major clusters (Type C, IFN)Cluster 11: N=46 (2/24/9/9/3)

0 5 10 15Y

PLTPLT GPTGPT

※First 16 cases※First 16 cases

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)

0 5 10 15Y

PLTPLT

GPTGPT

GPTGPT

PLTPLT

GPTGPT

PLTPLT

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 )

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 ?

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)

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)

Experiment 2

Preprocess: Sequence Smoothing

Removal of short-term changes Convolution with Gaussian kernel with 6M width(=2.8)

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)

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)

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 fromAnalysis

Subject forAnalysis

Selection Results (Total 720 Cases)

Numbers in (): ratio (%)

NotDiminishing Diminishing

222(30.8) 82(11.4) 28(3.9) 291(40.4) 97(13.5) 720

TotalSubject for DiscreminationNo biopsy

Info Short Inhomo-geneous

Experiment 2Years 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 biopsyF1 (biopsy)

First PLT examF1 (stage at first biopsy)

First-exam basis

First-biopsy basis

MID 216

Normal Low (NL)

Normal High (NH)

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

Mean Median SDB 1 5 2.36 0.00 3.53 3

2 9 5.04 1.79 6.29 23 8 2.44 0.66 3.62 34 9 1.43 0.00 2.56 5

B subtotal 31 2.89 0.56 4.38 13C with IFN 0 1 13.08 13.08 - 0

1 8 4.05 3.87 3.15 22 6 3.89 3.70 3.90 23 10 2.26 2.30 2.43 44 15 1.84 0.00 3.02 8

40 2.98 2.32 3.46 16C w/ o IFN 1 7 4.29 4.50 3.52 2

2 2 4.05 4.05 5.72 13 5 2.49 0.12 3.64 24 12 2.21 0.00 3.15 7

26 2.97 0.65 3.42 12Total 97 2.95 1.19 3.73 41

C with IFN subtotal

C w/ o IFN subtotal

Type Years=0cases

Years for reaching F4 (First-exam basis)(Y)Stage Cases

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

Mean Median SDB 1 5 3.70 3.71 3.46 1

2 9 4.26 2.85 5.45 33 8 2.12 0.22 3.72 34 9 1.31 0.00 2.54 5

B subtotal 31 2.77 0.52 4.00 12C with IFN 0 1 13.08 13.08 - 0

1 8 2.44 2.38 2.36 22 6 2.54 0.83 3.42 33 10 1.99 2.14 2.05 34 15 2.01 0.00 3.51 9

40 2.44 1.18 3.30 17C w/ o IFN 1 7 1.47 1.17 1.76 3

2 2 3.70 3.70 5.24 13 5 2.27 0.00 3.54 34 12 0.26 0.00 0.54 9

26 1.23 0.00 2.27 16Total 97 2.22 0.44 3.34 45

C with IFN subtotal

C w/ o IFN subtotal

Years for reaching F4 (First-biopsy basis)(Y) Years=0casesType Stage Cases

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

Mean Median SDB 1 5 1.23 1.24 1.51

2 9 2.13 1.42 2.733 8 2.12 0.22 3.724 9 - - -

B subtotal 31 1.92 0.62 2.80C with IFN 0 1 3.27 3.27 -

1 8 0.81 0.79 0.792 6 1.27 0.41 1.713 10 1.99 2.14 2.054 15 - - -

40 1.49 1.07 1.66C w/ o IFN 1 7 0.49 0.39 0.58

2 2 1.85 1.85 2.623 5 2.27 0.00 3.544 12 - - -

26 1.32 0.20 2.30Total 97 1.60 0.80 2.25

C with IFN subtotal

C w/ o IFN subtotal

Years between stages (Y/ stage)Type Stage Cases

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 t

he 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)

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 acc

ording 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/dataset

s.

Future Work

Cluster Constitution w.r.t. Fibrotic Stages

Type C w/o IFN (total 99 cases)

F0 F1 F2 F3 F41 0 4 4 5 9 222 0 1 0 1 1 33 1 27 6 7 6 474 0 1 0 0 0 15 0 11 2 0 0 136 2 11 0 0 0 13

CLUSTER Number of Cases / Fibrosis Stage Total N

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 cases0 5 10 15YMale 14, Female 8 Male 27, Female 20

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 cases0 5 10 15Y

PLTPLT GPTGPT

※First 16 cases