predictive sub-typing of subjects retrospective and prospective studies exploration of...
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![Page 1: Predictive sub-typing of subjects Retrospective and prospective studies Exploration of clinico-genomic data Identify relevant gene expression patterns](https://reader038.vdocuments.us/reader038/viewer/2022103022/56649d545503460f94a306dc/html5/thumbnails/1.jpg)
• Predictive sub-typing of subjects
• Retrospective and prospective studies
• Exploration of clinico-genomic data
• Identify relevant gene expression patterns
Issues in Bayesian Tree Modeling of Clinical and Gene
Expression Data
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Current Areas of Application
Breast Cancer
lymph node status
disease recurrence
Ovarian Cancer
tumor location
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Lymph Node Involvement Is a Key Breast Cancer Risk Factor
But -- lymph node dissection also carriesmorbidity and inaccuracy
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Identifying Metagenes Associated With Lymph Node Status
Tumor Sample
Gen
e
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Metagenes/ Expression Signatures
• Dimension reduction: Signal improvement
• Clustering• Singular value decomposition• Empirical or model-based factor
analysis• Characterize patterns in data
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Gene Clustering
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Gene Clustering (cont’d)
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Factor extraction (SVD)
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Differential Gene Expression
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Differential Gene Expression (Threshold 1)
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Differential Gene Expression (Threshold 2)
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Differential Gene Expression (Threshold 3)
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Nonlinear Expression
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Nonlinear Expression (Threshold 1)
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Nonlinear Expression (Threshold 2)
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Lymph Node Metastasis Metagenes
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Ovarian Tumor Site Genes
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Statistical Tree Models for Clinico-Genomic Prediction
• Regression trees: Non-linear, interactions
• Recursive partitioning • Retrospective studies• Many trees: Model uncertainty• Predictions average across trees
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Binary Outcomes Retrospective Sampling
)|1(Pr 1 ppxxY
LN +LN +
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Binary Outcomes: Prospective Inference from Retrospective
Model)τ,...,xτ|x(Yπ kk 111Pr
10Pr 111 , yy), |Yτ(x a y
10,|Pr 11222 , yy), Yx(x a y
0201
1211
0Pr
1Pr
1 ,,
,,
aa
aa
)(Y
)(Y
π
π
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Binary Outcomes: Retrospective Model
• Model conditionals for predictors
• Nonparametric Bayes: Dirichlet model
• Modeling in x space – joint structure• Implies Beta priors on
y)Yτ,...,xτ|xF(x 1k1kk ,11
iya
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Growing Binary Trees
Node split:• Each candidate predictor:threshold pair• 2x2 table: 2 Bernoulli’s, fixed columns
(Y=0/1)• Assess and select split, or stop• Conservative Bayesian tests
Multiple trees:• Multiple splits at any node
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Inference with Many Binary Trees
Within-tree inference & prediction: • Sequences of beta posteriors for • Simulate: Impute Pr(Y=1|leaf)
Multiple trees:• Likelihood across trees• Average predictions across trees • Model (predictor:threshold)s
uncertainty• “Smoothing” classification boundaries
iya
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Binary Outcome: Lymph Node Metastasis
Tumor Sample
Gen
e
Predictive trees:
• Nonparametric Bayes’
• Metagene expression
• Retrospective sampling
Lancet 2003 (Huang, West et Lancet 2003 (Huang, West et al)al)
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Predicting Lymph Node Status With Metagenes
LN+ LN-
Pro
babi
lity
of L
N+
Out-of-sample cross validation
Sample
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Forests of Clinico-Genomic Trees
Select from potential clinical and genomic predictor variables
multiple trees
variable combination – co-occurrence
multiple subtypes
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… With Metagenes and Clinical Predictors
LN+ LN-
Pro
babi
lity
of L
N+
Out-of-sample cross validation
Sample
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Lymph Node Clinico-Genomic Predictors
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Predicting Ovarian Tumor Site
Omentum Ovary
Pro
babi
lity
of O
men
tum
Out-of-sample cross validation
Sample
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Gene Identification
• Implicated metagenes – gene subsets
• Genes correlated with key metagenes
Breast Cancer – nodal metastasis:• Interferon pathway/inducible gene subset
• Interferons mediate anti-tumor response
Evidence of dysfunction of normal anti-tumor response?
Ovarian Cancer – tumor site:• Growth regulatory pathway/inducible gene subset
Evidence of dysfunction of normal cell growth?
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Ongoing Research
• Stochastic search (sequential,annealing)
• Representation of tree ‘forest’• Metagene definition/ creation• Cluster implementation of tree models
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Computational & Applied Genomics Program
Joseph Nevins Mike WestErich Huang Ed IversenHolly Dressman
Duke University
Koo Foundation-Sun Yat Sen Cancer Center
Andrew Huang, Skye Cheng, Mei-Hua Tsou
http://www.isds.duke.edu/~jennifer/
Department of Obstetrics and Gynecology
John LancasterAndrew Berchuck
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Growing Binary Trees (2x2)
kk tx
kk tx
0Y 1Y
1N
0N00n 01n
10n 11n
N
)Yτ,x,τ|xP(x 1k1kkk 0,11
)1,,,|( 11 YxxxP 1k1kkk
?