Molecular Classification of Biological...

Molecular Classification of Biological Phenotypes

Esfandiar Haghverdi

School of Informatics

November 13, 2008

Esfandiar Haghverdi Molecular Classification of Biological Phenotypes

Outline

I Introduction

I Class Comparison

I Class Discovery

I Class Prediction

I Example

I Biological states and state modulation

I Chemical Genomics

I Toxicogenomics

I Software Tools

I Ideas

Introduction

I Welcome to Genomics Data Mining (GDM) working group.

I Meetings will be bi-weekly starting today.I Extract meaningful information about the system being

studied from gene expression data.I The work is motivated by recent progress in cancer genomics.I This overview is by no means comprehensive.I There is no one-size-fits-all solution for the analysis and

interpretation of genome wide data.I Many analysis options are available at all phases of analysis.I An understanding of both biology and the computational

methods is essential.I Complex mathematical methods do not necessarily perform

better than simpler ones.I Prepackaged analysis tools are not a good substitute for

collaboration with computational/statistical scientists oncomplex problems.

Introduction

I Welcome to Genomics Data Mining (GDM) working group.I Meetings will be bi-weekly starting today.

I Extract meaningful information about the system beingstudied from gene expression data.

I The work is motivated by recent progress in cancer genomics.I This overview is by no means comprehensive.I There is no one-size-fits-all solution for the analysis and

Introduction

I Welcome to Genomics Data Mining (GDM) working group.I Meetings will be bi-weekly starting today.I Extract meaningful information about the system being

studied from gene expression data.

I The work is motivated by recent progress in cancer genomics.I This overview is by no means comprehensive.I There is no one-size-fits-all solution for the analysis and

Introduction

studied from gene expression data.I The work is motivated by recent progress in cancer genomics.

I This overview is by no means comprehensive.I There is no one-size-fits-all solution for the analysis and

Introduction

studied from gene expression data.I The work is motivated by recent progress in cancer genomics.I This overview is by no means comprehensive.

I There is no one-size-fits-all solution for the analysis andinterpretation of genome wide data.

I Many analysis options are available at all phases of analysis.I An understanding of both biology and the computational

Introduction

interpretation of genome wide data.

I Many analysis options are available at all phases of analysis.I An understanding of both biology and the computational

Introduction

interpretation of genome wide data.I Many analysis options are available at all phases of analysis.

I An understanding of both biology and the computationalmethods is essential.

I Complex mathematical methods do not necessarily performbetter than simpler ones.

I Prepackaged analysis tools are not a good substitute forcollaboration with computational/statistical scientists oncomplex problems.

Introduction

methods is essential.

I Complex mathematical methods do not necessarily performbetter than simpler ones.

Introduction

better than simpler ones.

Introduction

Central Ideas

I Gene expression signatures: One can rationally distill a list ofgenes from an unbiased global scan of gene-expressionchanges observed across a carefully selected sample set.

I Biological states can be characterized by gene expressionsignatures.

I We can use gene expression signatures as surrogates forbiological states.

Central Ideas

Central Papers

I Gene expression signatures: Molecular Classification ofCancer, T.R. Golub et al., Science 286, 531, 1999.

I GSEA: Gene Set Enrichment Analysis, A. Subramanian et al.,PNAS, 102, 2005.

I GE-HTS: Gene Expression-based High-throughput Screening,K. Stegmaier et al., Nature genetics 36, 257, 2004.

I Connectivity Map: The Connectivity Map, J. Lamb et al.,Science 313, 1929, 2006.

Central Papers

Class Comparison

I Goal: Identify differentially expressed genes.

I Methods:I Calculate a test statistic (t-test, ANOVA F statistic,

non-parametric rank-based,. . .)I Determine the significance of the observed value for test

statistic.I Normality, equal variance, multiple testing, FWER vs FDR

I Issues:I Two or more experimental conditionsI Conditions may be independent or related (time series)I Many different combinations of experimental variablesI Replication, to estimate variability, to identify biologically

reproducible changesI How to incorporate estimates of variation (model-based

methods)

Class Comparison

I Goal: Identify differentially expressed genes.I Methods:

I Calculate a test statistic (t-test, ANOVA F statistic,non-parametric rank-based,. . .)

I Determine the significance of the observed value for teststatistic.

I Normality, equal variance, multiple testing, FWER vs FDR

methods)

Class Comparison

I Goal: Identify differentially expressed genes.I Methods:

I Calculate a test statistic (t-test, ANOVA F statistic,non-parametric rank-based,. . .)

I Determine the significance of the observed value for teststatistic.

I Normality, equal variance, multiple testing, FWER vs FDR

methods)

Class Comparison

Opportunities:Time-series analysis:

I Regulatory pathway inference

I Yeast cell cycle (Fourier transform, . . .)

I Model organism (e.g., Drosophila, Daphnia) development

I Analysis of samples (cells) exposed to different doses of thesame drug

I Analysis of expression patterns from related bacterial strains

Class Discovery

I Goal: Identify meaningful patterns in the data, (aka.Unsupervised learning.)

I Methods:

I Dimensionality reduction methods: Most of the variation indata can be explained by a smaller number of transformedvariables.

I For example: SVD, PCA, MDS, . . ..

I Clustering: Data can be grouped into groups of similar pointsbased on some similarity measure.

I Aggregation methods (e.g., HC)I Partitioning or centroid methods (for example, k-means, SOM

or Kohonen maps)I Model-based methods (e.g., fitting into some mixture model)I Optimization techniques (within class, between class)

Class Discovery

I Methods:

I Dimensionality reduction methods: Most of the variation indata can be explained by a smaller number of transformedvariables.

Class Discovery

I Methods:I Dimensionality reduction methods: Most of the variation in

data can be explained by a smaller number of transformedvariables.

Class Discovery

Class Discovery cont’d

Issues:

I It is unbiased, no a priori assumption.

I The structure may not be of clinical or biological interest.

I Should be viewed as a first step in more detailed analysis.

I There is no single best way to evaluate a clustering method ora cluster.

I How to evaluate clustering methods?

I There is no single best clustering method for a data set.

I Some desirable properties maybe: Stability (reliability),predictive power, reduction power, ...

I How to choose the number of clusters (Gordon, repeatedsampling, gap statistic, ...)

Issues:

Opportunities:

I Stochastic clustering (e.g., NMF)

I Techniques from statistical physics (e.g., DeterministicAnnealing)

I Spectral methods (e.g., Diffusion maps on graphs)

I Geometric methods (e.g., Diffusion maps on manifolds)

I Information theoretic methods

I Statistical theory of clustering (Cf. comparing clusteringmethods)

Opportunities:

Class Discovery Methodology

Expression Dataset

Scaling, Filtering and Normalization

Select Number of Classes

Cluster Data

Validation of Putative Classes

Discovered Classes

Class Prediction

I Goal: Design an accurate classifier (predictor) under theguidance of a supervisor, (aka. Supervised learning problem.)E.g., predicting cancer (sub)types, clinical outcomes, etc.

I Methods:I Linear and quadratic discriminant analysisI Weighted votingI Shrunken centroidsI k-NNI Neural netsI SVMI Decision tree classifiersI Naive BayesI Bagging and boosting (combining classifiers)

Class Prediction

I Goal: Design an accurate classifier (predictor) under theguidance of a supervisor, (aka. Supervised learning problem.)E.g., predicting cancer (sub)types, clinical outcomes, etc.

I Methods:I Linear and quadratic discriminant analysisI Weighted votingI Shrunken centroidsI k-NNI Neural netsI SVMI Decision tree classifiersI Naive BayesI Bagging and boosting (combining classifiers)

Class Prediction, cont’d

Issues:

I features >> samples

I Overfitting (modeling the training data too exactly)

I High level of noiseI Which method to choose?

I Careful with comparisonsI Some trends emerge (e.g, Diagonal LD does better than

Fisher’s LD, k-NN performs better after gene filtering,combined methods do better, simpler methods do better, ...)

Issues:

I High level of noise

I Which method to choose?

Issues:

I Careful with comparisons

I Some trends emerge (e.g, Diagonal LD does better thanFisher’s LD, k-NN performs better after gene filtering,combined methods do better, simpler methods do better, ...)

Issues:

Class Prediction cont’d

Opportunities:

I Theory for method and classifier comparison

I Combining knowledge from different methods

I Incorporating knowledge from complementary sources

I Boosting the power and rigor of analysis

I Subpattern discovery, Califano et al. 99

Opportunities:

Marker Selection Methodology

Gene ExpressionDataset

Known Classes(Phenotype)

Compute Gene−Class Correlationsand sort genes accordingly

(Feature Selection)

More Experiments

(Validation)Computational

Analysis

Visualization and

Biological Study of MarkersBuild Supervised Classifier

Predictive Model

Class Prediction Methodology

Evaluate Predictor on

Independent Test Set

Test Classifier by Cross−Validation

Build Classifier(Training)

Compute Gene−Class Correlationsand sort Genes Accordingly

(Feature Selection)

Expression Data Known or Discovered Classes

Example (Golub et al. 1999)

ALL vs AML (The Biology of Cancer, R. Weinberg)

Compare to this!!

Normal kidney vs Renal cell carcinoma.

Example cont’d

I Sample: 38 bone marrow samples (27 ALL, 11 AML).6817 genes

I Test statistic: SNR = µ1−µ2σ1+σ2

to determine gene-classcorrelation

I Significance test: Permutation test (nhood analysis)

I Signature: 50 informative genes are selected

I Prediction: Given a new sample each informative gene casts aweighted vote, the votes are then summed to determine thewinning class and to define the 0 < PS < 1 (predictionstrength) which needs to be above 0.3 for each decisive vote.

I Validity of the predictor: Cross-validation and trying on testdata.

Example cont’d

In symbols ...

Suppose we have n samples.

I Gene vector: v(g) = (e1, · · · , en),

I Class vector: c = (c1, · · · , cn): ci = 1 if i ∈ AML, and 0 ifi ∈ ALL.

I Gene-Class Correlation:P(g , c) = (µ1(g)− µ2(g))/(σ1(g) + σ2(g)) for each gene g .

I Nhood: N1(c , r) = {g |P(g , c) = r}I Permutation test: compare with N1(c

∗, r), for 400permutations.

I Number of informative genes is a free parameter, chosen to be50: 25 top-most and 25 bottom-most.

I Robustness to noiseI Ease of applicability.

In symbols ...

I Nhood: N1(c , r) = {g |P(g , c) = r}

I Permutation test: compare with N1(c∗, r), for 400

permutations.

In symbols ...

I Robustness to noise

I Ease of applicability.

In symbols ...

In symbols cont’d

Predictor Design:

I vg = ag (xg − bg ) where ag = P(g , c),bg = [µ1(g) + µ2(g)]/2,

I xg normalized log expression level of gene g in sample x

I vg ≥ 0 means g votes for class 1 (AML) and vg < 0 means gvotes for class 2 (ALL).

I V1 =∑

g∈IG vg for vg ≥ 0, and

I V2 =∑

g∈IG |vg | for vg < 0.

I PS = (Vwin − Vlose)/(Vwin + Vlose)

I V1 > V2 with PS > 0.3 means x ∈ AML, if PS ≤ 0.3 thenuncertain.

In symbols cont’d

Predictor Design:

I V1 =∑

I V2 =∑

In symbols cont’d

Predictor Design:

I V1 =∑

I V2 =∑

In symbols cont’d

Predictor Design:

I V1 =∑

I V2 =∑

In symbols cont’d

Predictor Design:

I V1 =∑

I V2 =∑

In symbols cont’d

Predictor Design:

I V1 =∑

I V2 =∑

In symbols cont’d

Predictor Design:

I V1 =∑

I V2 =∑

In symbols, cont’d

I Cross-validation: 36 were assigned classes (with 100%)accuracy and 2 were uncertain. Median PS = 0.77

I Test data (34 samples): 24 bone marrow and 10 peripheralblood samples, 20 ALL, 14 AML.Result: 29 predicted with 100% accuracy and 5 uncertain.Median PS = 0.73.

In symbols, cont’d

I Cross-validation: 36 were assigned classes (with 100%)accuracy and 2 were uncertain. Median PS = 0.77

I Test data (34 samples): 24 bone marrow and 10 peripheralblood samples, 20 ALL, 14 AML.Result: 29 predicted with 100% accuracy and 5 uncertain.Median PS = 0.73.

Example cont’d, clustering

I View each sample as a 6817-dimensional vector and clustersamples.

I 2-SOM on 38 samples:A1: 24 ALL, 1 AML and A2: 10 AML, 3 ALL.

I View each sample as a 6817-dimensional vector and clustersamples.

I 2-SOM on 38 samples:A1: 24 ALL, 1 AML and A2: 10 AML, 3 ALL.

I 4-SOM on the same samples:B1: 10 AML, B2: 8 T-ALL, 1 B-ALLB3: 5 B-ALL, B4: 13 B-ALL, 1 AML.

ALL B−Cell

ALL T−Cell

B1 B2 B3 B4

I How to evaluate clusters to see if they represent truebiological structure?

I Idea: true structure implies more accurate predictor.

I So design predictors based on clustering classes: leads tomerging B3 and B4.

Enrichment Analysis

I Goal: Look at (Gene Set)-Class correlation instead ofGene-Class correlation.

I Motivation:I Mootha 03: No single gene is significantly differentially

expressed, yet sets of genes might express differentially.I Subramanian 05: 1. Robustness to different sites, and 2.

Integrating biological knowledge.

I Methods:

I GSEA (A. Subramanian, PNAS 2005). Lung adenocarcinomawith good/poor outcome. |SB ∩ SM | = 12 and|SB ∩ SM ∩ SS | = 1 whereas SB in M was NES = 1.9,p < 0.001 and SM in B was NES=2.13, p < 0.001.

I Tibshirani and EfronI R. Gentleman (Bioconductor)I Module maps, a refinement of GSEA, gene set minimization

(Segal et al. Nature Genetics, 04,05)

Enrichment Analysis

I Methods:

I GSEA (A. Subramanian, PNAS 2005). Lung adenocarcinomawith good/poor outcome. |SB ∩ SM | = 12 and|SB ∩ SM ∩ SS | = 1 whereas SB in M was NES = 1.9,p < 0.001 and SM in B was NES=2.13, p < 0.001.

Enrichment Analysis

I Methods:I GSEA (A. Subramanian, PNAS 2005). Lung adenocarcinoma

with good/poor outcome. |SB ∩ SM | = 12 and|SB ∩ SM ∩ SS | = 1 whereas SB in M was NES = 1.9,p < 0.001 and SM in B was NES=2.13, p < 0.001.

Enrichment Analysis

I Methods:I GSEA (A. Subramanian, PNAS 2005). Lung adenocarcinoma

with good/poor outcome. |SB ∩ SM | = 12 and|SB ∩ SM ∩ SS | = 1 whereas SB in M was NES = 1.9,p < 0.001 and SM in B was NES=2.13, p < 0.001.

EA cont’d

Opportunities:

I Using BLAST theory to enhance the predictive power.

I Random walks on networks.

EA cont’d

Opportunities:

I Using BLAST theory to enhance the predictive power.

I Random walks on networks.

Chemical Genomics

I Generating large collections of small molecules and using themto modulate cellular states.

I One approach is to screen different compounds that inducestate modulations, using signatures for the states.

I GE-HTS (Stegmaier et al., Nature Genetics, 2004) 1,739compounds are screened for AML/neutrophil andAML/monocyte terminal cell differentiation.

I Connectivity Map (J. Lamb et al., Science 06):

disease – gene – drug.

Chemical Genomics

CG, cont’d

Issues:

I Necessary modifications when dealing with moreheterogeneous situations, e.g., BC vs Leukemia.

I Choice of cell type

I Measurement time

I Concentration and treatment duration

I Analytical methods for detecting relevant signals

CG, cont’d

Issues:

I Measurement time

CG, cont’d

Issues:

I Measurement time

CG, cont’d

Issues:

I Measurement time

CG, cont’d

Issues:

I Measurement time

Toxicogenomics

I Identification of potential human and environmental toxicants,and their putative mechanisms of action, through the use ofgenomics resources.

I Gene expression is altered during toxicity.

I Challenge: Given a set of experimental conditions, define thecharacteristic and specific pattern of gene expression elicitedby a given toxicant. (Toxicant signatures!)

I Given a model organism:Known toxicants → signatures → database → determine theaction mechanism of an unknown toxicant.

I Connectivity Map: gene – toxicant

Toxicogenomics

TG, cont’d

Issues:

I Proper definition of signature similarity

I Model system selection

I Dose selection

I Measurement time (Time series analysis?)

I Other factors: age, diet, etc

TG, cont’d

Issues:

I Dose selection

TG, cont’d

Issues:

I Dose selection

TG, cont’d

Issues:

I Dose selection

TG, cont’d

Issues:

I Dose selection

I Bioconductor

I BRB ArrayTools (NCI, Richard Simon)

I GenePattern, includes GeneCluster (Broad Institute)

I Connectivity Map (Broad Institute)

I Benchmark data sets

I Local implementations with interface to the tools above

I Bioconductor

Some ideas ...

I Technical improvements at different levels

I Integrating biological knowledge into the mathematicalmodels (after Random Markov Fields)

I New mathematical tools

I Using signatures to infer signalling pathways

I Using signatures to improve clustering algorithms

I Technology transfer from: Time-series analysis of financialdata, VLDB, Theoretical Neuroscience

Some ideas ...

Ideas, cont’d

I New biologically relevant and important questions:

I Daphnia based toxicogenomics

I Daphnia based ecogenomics

I Signatures in developmental stages of model organisms

I Time series analysis of environmental effects

I Other genomic signatures: DNA methylation patterns,microRNA profiles, metabolite profiles, ...

Ideas, cont’d

Molecular Classification of Biological...

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