Introduction

Data Mining in Genomics: the dawn

of personalized medicine

Gregory Piatetsky-Shapiro

KDnuggetswww.KDnuggets.com/gps.html

Connecticut College, October 15, 2003

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Overview

Data Mining and Knowledge Discovery

Genomics and Microarrays

Microarray Data Mining

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Trends leading to Data Flood

More data is generated:

Bank, telecom, other business transactions ...

Scientific Data: astronomy, biology, etc

Web, text, and e-commerce

More data is captured:

Storage technology faster and cheaper

DBMS capable of handling bigger DB

http://www.cultindustries.com/new/html/frame.html

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Transformed Data

Patternsand

Rules

Target Data

RawData

Knowledge

Data MiningTransformation

Interpretation& Evaluation

Selection& Cleaning

Integration

Understanding

Knowledge Discovery Process

DATAWarehouse

Knowledge

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Major Data Mining Tasks Classification: predicting an item class

Clustering: finding clusters in data

Associations: e.g. A & B & C occur frequently

Visualization: to facilitate human discovery

Summarization: describing a group

Estimation: predicting a continuous value

Deviation Detection: finding changes

Link Analysis: finding relationships

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Major Application Areas for Data Mining Solutions

Advertising Bioinformatics Customer Relationship Management (CRM) Database Marketing Fraud Detection eCommerce Health Care Investment/Securities Manufacturing, Process Control Sports and Entertainment Telecommunications Web

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Genome, DNA & Gene ExpressionAn organism’s genome is the “program” for

making the organism, encoded in DNA

Human DNA has about 30-35,000 genes

A gene is a segment of DNA that specifies how to make a protein

Cells are different because of differential gene expression About 40% of human genes are expressed at one time

Microarray devices measure gene expression

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Molecular Biology Overview

Cell Nucleus

Chromosome

ProteinGraphics courtesy of the National Human Genome Research Institute

Gene (DNA)Gene (mRNA), single strand

Geneexpression

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Affymetrix Microarrays

50um

1.28cm

~107 oligonucleotides,half Perfectly Match mRNA (PM), half have one Mismatch (MM)Gene expression computed from PM and MM

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Affymetrix Microarray Raw Image

Gene ValueD26528_at 193D26561_cds1_at -70D26561_cds2_at 144D26561_cds3_at 33D26579_at 318D26598_at 1764D26599_at 1537D26600_at 1204D28114_at 707

Scannerenlarged section of raw image

raw data


Microarray Potential Applications

New and better molecular diagnostics

New molecular targets for therapy few new drugs, large pipeline, …

Outcome depends on genetic signature best treatment?

Fundamental Biological Discovery finding and refining biological pathways

Personalized medicine ?!


Microarray Data Mining ChallengesAvoiding false positives, due to

too few records (samples), usually < 100

too many columns (genes), usually > 1,000

Model needs to be robust in presence of noise

For reliability need large gene sets; for diagnostics or drug targets, need small gene sets

Estimate class probability

Model needs to be explainable to biologists


False Positives in Astronomy

cartoon used with permission


Preparation

2-Class Multi-Class

Clustering

CATs: Clementine Application Templates CATs - examples of

complete data mining processes

Microarray CAT


Key Ideas

Capture the complete process

X-validation loop w. feature selection inside

Randomization to select significant genes

Internal iterative feature selection loop

For each class, separate selection of optimal gene sets

Neural nets – robust in presence of noise

Bagging of neural nets


Microarray Classification

Train data Feature and Parameter Selection

EvaluationTest data

Data Model Building


Classification: External X-val

Train data Feature and Parameter Selection

EvaluationTest data

Gene Data

T r a i n

FinalTest

Data Model Building

Final Model

Final Results


Measuring false positives with randomization

ClassGene

178105

41747133

1122

Class

178105

41747133

2112

RandClass

2112Randomize

500 times

Bottom 1% T-value = -2.08

Select potentially interesting genes at 1%

Gene


Gene Reduction improves Classificationmost learning algorithms look for non-linear

combinations of features -- can easily find many spurious combinations given small # of records and large # of genes

Classification accuracy improves if we first reduce # of genes by a linear method, e.g. T-values of mean difference

Heuristic: select equal # genes from each class

Then apply a favorite machine learning algorithm


Iterative Wrapper approach to selecting the best gene set Test models using 1,2,3, …, 10, 20, 30, 40, ...,

100 top genes with x-validation.

Heuristic 1: evaluate errors from each class; select # number of genes from each class that minimizes error for that class

For randomized algorithms, average 10+ Cross-validation runs!

Select gene set with lowest average error


Clementine stream for subset selection by x-validation


Microarrays: ALL/AML Example

Leukemia: Acute Lymphoblastic (ALL) vs Acute Myeloid (AML), Golub et al, Science, v.286, 1999 72 examples (38 train, 34 test), about 7,000 genes

well-studied (CAMDA-2000), good test example

ALL AML

Visually similar, but genetically very different


Gene subset selection: one X-validation

Error Avg for 10-fold X-val

0%5%

10%15%20%25%30%

1 2 3 4 5 10 20 30 40

Genes per Class

Single Cross-Validation run


Gene subset selection: multiple cross-validation runs

For ALL/AML data, 10 genes per class had the lowest error: (<1%)

Point in the centeris the average error from 10 cross-validation runs

Bars indicate 1 st. devabove and below


ALL/AML: Results on the test dataGenes selected and model trained on Train set

ONLY!

Best Net with 10 top genes per class (20 overall) was applied to the test data (34 samples):

33 correct predictions (97% accuracy),

1 error on sample 66

Actual Class AML, Net prediction: ALL

other methods consistently misclassify sample 66 -- misclassified by a pathologist?


Pediatric Brain Tumour Data

92 samples, 5 classes (MED, EPD, JPA, EPD, MGL, RHB) from U. of Chicago Children’s Hospital

Outer cross-validation with gene selection inside the loop

Ranking by absolute T-test value (selects top positive and negative genes)

Select best genes by adjusted error for each class

Bagging of 100 neural nets


Selecting Best Gene Set

Minimizing Combined Error for all classes is not optimal

Average, high and low error rate for all classes


Error rates for each class

Error rate

Genes per Class


Evaluating One Network

9%EPD24%RHB

8.3%*ALL*19%JPA

17%MGL2.1% MED

Error rateClass

Averaged over 100 Networks:


Bagging 100 Networks

Note: suspected error on one sample (labeled as MED but consistently classified as RHB)

8.3%19%9%24%17%2.1%

Individual Error Rate

91%0 EPD76%11% RHB

92%3% (2)**ALL*81%0JPA

83%10% MGL98%2% (0)*MED

Bag Avg Conf

Bag Error rate

Class


AF1q: New Marker for Medulloblastoma? AF1Q ALL1-fused gene from chromosome 1q

transmembrane protein

Related to leukemia (3 PUBMED entries) but not to Medulloblastoma


Future directions for Microarray AnalysisAlgorithms optimized for small samples

Integration with other data

biological networks

medical text

protein data

Cost-sensitive classification algorithms

error cost depends on outcome (don’t want to miss treatable cancer), treatment side effects, etc.


Acknowledgements

Eric Bremer, Children’s Hospital (Chicago) & Northwestern U.

Greg Cooper, U. Pittsburgh

Tom Khabaza, SPSS

Sridhar Ramaswamy, MIT/Whitehead Institute

Pablo Tamayo, MIT/Whitehead Institute


Thank you

Further resources on Data Mining: www.KDnuggets.com

Microarrays:

www.KDnuggets.com/websites/microarray.html

Contact:

Gregory Piatetsky-Shapiro: www.kdnuggets.com/gps.html

Documents

Introduction