Inferring Nonstationary Gene Networks from Temporal Gene Expression Data
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Harvard Medical School Massachusetts Institute of Technology
Inferring Nonstationary Gene Networks from Temporal Gene Expression Data
Hsun-Hsien Chang1, Jonathan J. Smith2, Marco F. Ramoni1
1Children’s Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School 2Department of Mathematics, Massachusetts Institute of Technology
IEEE Workshop on Signal Processing SystemsOctober 7, 2010
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Harvard Medical School Massachusetts Institute of Technology
Background
• Genetic information flows from DNA to RNA through transcription.
• Modern microarray technologies are able to assess expression of 50K genes in parallel.
• Gene expression is the measure of RNA abundance in cells, revealing the gene activities.
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Harvard Medical School Massachusetts Institute of Technology
Clinical Applications
• Thanks to cost down, more samples can be collected in a single study. A new clinical application:– Monitor time-series gene expression in response to drugs,
treatments, vaccines, virus infection, etc.
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Multiple patients in distinct biological
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Harvard Medical School Massachusetts Institute of Technology
Time-Series Gene Expression Analysis• Since genes interact each other in cells, an intriguing
analysis is to infer gene networks:– Detailed models (e.g., differential equations).
– Abstract models (e.g., Boolean networks).
– Probabilistic graphical models (e.g., dynamic Bayesian networks).
• Do not require densely sampled data. • Model expression levels by random variables to
handle noisy expression measurements and biological variability.
• Utilize the inferred networks to make prediction.
gene on gene off
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Harvard Medical School Massachusetts Institute of Technology
Data Representation by Bayesian Networks• Bayesian networks are directed acyclic graphs where:
– The network model can serve as a prediction tool.
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– Example: variables X and Y at time T modulate variable Z at time T+1.
• Dynamic Bayesian networks with arcs indicating temporal dependency.
– Nodes correspond to random variables (i.e., expressions of genes, clinical variables).
– Directed arcs encode conditional probabilities of the target (child) nodes on the source (parent) nodes.
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Harvard Medical School Massachusetts Institute of Technology
Network Inference Engine
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data at time T+1 depends only on the preceding time T.
• For a variable at a time T+1, search which set of variables at time T has the highest likelihood of modulating its value at T+1.
• Step-wise search algorithm.
Clinical variable
Genes
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Harvard Medical School Massachusetts Institute of Technology
Inference of Whole Dynamic Gene Network
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• Infer a transition network between every pair of times.
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Harvard Medical School Massachusetts Institute of Technology
Parallelize Learning Individual Transition Nets
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Harvard Medical School Massachusetts Institute of Technology
Parallelize Parent Searching of Individual Variables
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Harvard Medical School Massachusetts Institute of Technology
Step-by-Step Prediction
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Harvard Medical School Massachusetts Institute of Technology
Forecasting by Initial Data
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Harvard Medical School Massachusetts Institute of Technology
Clinical Study: HIV Viral Load Tracking• Global AIDS epidemic is one of the greatest threats to
human health, causing 2 million deaths every year.• Viral load (i.e., virus density in blood) is:
– associated with clinical outcomes. – an indicator of which treatment physicians should provide.
• If there is a tool to predict/forecast viral load trajectory, physicians could foresee how patients progress to AIDS and could allocate the best treatments upfront.
Enroll 1 2 4 12 24
viral load
...gene expre.
• Data: Fourteen (12 Africans, 2 Americans) untreated adult patients during acute infection.
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Harvard Medical School Massachusetts Institute of Technology
Dynamic Gene Network of HIV Viral Load
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Harvard Medical School Massachusetts Institute of Technology
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Harvard Medical School Massachusetts Institute of Technology
Accuracy of HIV Viral Load Tracking
Fitted Validation (Accuracy)
Cross Validation (Robustness)
Dynamic Gene Network 97.8% 95.8%Viral Load Auto-Regression 90.1% 89.5%
• Prediction accuracy:
• Forecasting accuracy:Fitted Validation
(Accuracy)Cross Validation
(Robustness)Dynamic Gene Network 92.9% 91.8%
Viral Load Auto-Regression 88.7% 87.0%
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Harvard Medical School Massachusetts Institute of Technology
30 Genes Dynamically Interact with Viral LoadAMY1A: amylase, alpha 1a; salivary OTOF: otoferlin
TNFAIP6 : tumor necrosis factor, alpha-induced protein 6
KIR2DL3: killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3
NBPF14: neuroblastoma breakpoint family, member 14 OSBP2: oxysterol binding protein 2
IRF7: interferon regulatory factor 7 CFD: complement factor d (adipsin)
HLA-DQA1: major histocompatibility complex, class ii, dq alpha 1
HLA-DRB1: major histocompatibility complex, class ii, dr beta 1
RPS23: ribosomal protein s23 GPR56: g protein-coupled receptor 56
IFI44L: interferon-induced protein 44-like CCL23: chemokine (c-c motif) ligand 23
KLRC2: killer cell lectin-like receptor subfamily c, member 2
ITIF3: interferon-induced protein with tetratricopeptide repeats 3
SOS1: son of sevenless homolog 1 (drosophila) G1P2: interferon, alpha-inducible protein (clone ifi-15k)
LOC652775: similar to ig kappa chain v-v region l7 precursor
CCL3L1: chemokine (c-c motif) ligand 3-like 1
MBP: myelin basic protein S100P: s100 calcium binding protein p
IFITM3: interferon induced transmembrane protein 3 (1-8u)
MX1: myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse)
HERC5: hect domain and rld 5 NME4: non-metastatic cells 4, protein expressed in
HLA-DQB1: major histocompatibility complex, class ii, dq beta 1
LOC653157: similar to iduronate 2-sulfatase precursor (alpha-l-iduronate sulfate sulfatase) (idursulfase)
LOC643313: similar to hypothetical protein loc284701 RSAD2: radical s-adenosyl methionine domain containing 2
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Harvard Medical School Massachusetts Institute of Technology
Conclusions
• A Bayesian network framework to infer dynamic gene networks from time-series gene expression microarrays:– Does not require densely sampled microarray data.– Able to handle noise and handle biological variability.– Temporal dependency is captured by first-order Markov
process.– The optimal network model is achieved by parallelized search
algorithm. • Application to HIV viral load tracking shows how our
method can be used in clinical studies:– Our network model tracks viral load trajectories with higher
accuracy than viral load auto-regressive model.– Our model provides candidate gene targets for drug/vaccine
development.
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Harvard Medical School Massachusetts Institute of Technology
Acknowledgements
Supported by Center for HIV/AIDS Vaccine Immunology (CHAVI) # U19 AI067854-06:
•National Institute of Allergy and Infectious Diseases (NIAID)•National Institutes of Health (NIH)•Division of AIDS (DAIDS)•U.S. Department of Health and Human Services (HHS)
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Harvard Medical School Massachusetts Institute of Technology
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Stationary Network Inference
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• All networks between pairs of times are identical.
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Harvard Medical School Massachusetts Institute of Technology
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Harvard Medical School Massachusetts Institute of Technology
Pathway: Immune Response (16/30 genes, p<10-6)AMY1A: amylase, alpha 1a; salivary OTOF: otoferlin
TNFAIP6 : tumor necrosis factor, alpha-induced protein 6
KIR2DL3: killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3
NBPF14: neuroblastoma breakpoint family, member 14 OSBP2: oxysterol binding protein 2
IRF7: interferon regulatory factor 7 CFD: complement factor d (adipsin)
HLA-DQA1: major histocompatibility complex, class ii, dq alpha 1
HLA-DRB1: major histocompatibility complex, class ii, dr beta 1
RPS23: ribosomal protein s23 GPR56: g protein-coupled receptor 56
IFI44L: interferon-induced protein 44-like CCL23: chemokine (c-c motif) ligand 23
KLRC2: killer cell lectin-like receptor subfamily c, member 2
ITIF3: interferon-induced protein with tetratricopeptide repeats 3
SOS1: son of sevenless homolog 1 (drosophila) G1P2: interferon, alpha-inducible protein (clone ifi-15k)
LOC652775: similar to ig kappa chain v-v region l7 precursor
CCL3L1: chemokine (c-c motif) ligand 3-like 1
MBP: myelin basic protein S100P: s100 calcium binding protein p
IFITM3: interferon induced transmembrane protein 3 (1-8u)
MX1: myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse)
HERC5: hect domain and rld 5 NME4: non-metastatic cells 4, protein expressed in
HLA-DQB1: major histocompatibility complex, class ii, dq beta 1
LOC653157: similar to iduronate 2-sulfatase precursor (alpha-l-iduronate sulfate sulfatase) (idursulfase)
LOC643313: similar to hypothetical protein loc284701 RSAD2: radical s-adenosyl methionine domain containing 2
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Harvard Medical School Massachusetts Institute of Technology
major histocompatibility complex, class ii, dr beta 1 otoferlin
tumor necrosis factor, alpha-induced protein 6 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3
neuroblastoma breakpoint family, member 14 oxysterol binding protein 2
interferon regulatory factor 7 complement factor d (adipsin)
major histocompatibility complex, class ii, dq alpha 1 amylase, alpha 1a; salivary
ribosomal protein s23 g protein-coupled receptor 56
killer cell lectin-like receptor subfamily c, member 2 chemokine (c-c motif) ligand 23
interferon-induced protein 44-like interferon-induced protein with tetratricopeptide repeats 3
son of sevenless homolog 1 (drosophila) interferon, alpha-inducible protein (clone ifi-15k)
similar to ig kappa chain v-v region l7 precursor chemokine (c-c motif) ligand 3-like 1
myelin basic protein s100 calcium binding protein p
interferon induced transmembrane protein 3 (1-8u) myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse)
hect domain and rld 5 non-metastatic cells 4, protein expressed in
major histocompatibility complex, class ii, dq beta 1 similar to iduronate 2-sulfatase precursor (alpha-l-iduronate sulfate sulfatase) (idursulfase)
similar to hypothetical protein loc284701 radical s-adenosyl methionine domain containing 2
Pathway: Antiviral Defense (8/30 genes, p<10-3)
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Harvard Medical School Massachusetts Institute of Technology
major histocompatibility complex, class ii, dr beta 1 otoferlin
tumor necrosis factor, alpha-induced protein 6 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3
neuroblastoma breakpoint family, member 14 oxysterol binding protein 2
interferon regulatory factor 7 complement factor d (adipsin)
major histocompatibility complex, class ii, dq alpha 1 amylase, alpha 1a; salivary
ribosomal protein s23 g protein-coupled receptor 56
killer cell lectin-like receptor subfamily c, member 2 chemokine (c-c motif) ligand 23
interferon-induced protein 44-like interferon-induced protein with tetratricopeptide repeats 3
son of sevenless homolog 1 (drosophila) interferon, alpha-inducible protein (clone ifi-15k)
similar to ig kappa chain v-v region l7 precursor chemokine (c-c motif) ligand 3-like 1
myelin basic protein s100 calcium binding protein p
interferon induced transmembrane protein 3 (1-8u) myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse)
hect domain and rld 5 non-metastatic cells 4, protein expressed in
major histocompatibility complex, class ii, dq beta 1 similar to iduronate 2-sulfatase precursor (alpha-l-iduronate sulfate sulfatase) (idursulfase)
similar to hypothetical protein loc284701 radical s-adenosyl methionine domain containing 2
Pathway: Inflammatory Response (5/30 genes, p<0.05)
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Harvard Medical School Massachusetts Institute of Technology
major histocompatibility complex, class ii, dr beta 1 otoferlin
tumor necrosis factor, alpha-induced protein 6 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3
neuroblastoma breakpoint family, member 14 oxysterol binding protein 2
interferon regulatory factor 7 complement factor d (adipsin)
major histocompatibility complex, class ii, dq alpha 1 amylase, alpha 1a; salivary
ribosomal protein s23 g protein-coupled receptor 56
killer cell lectin-like receptor subfamily c, member 2 chemokine (c-c motif) ligand 23
interferon-induced protein 44-like interferon-induced protein with tetratricopeptide repeats 3
son of sevenless homolog 1 (drosophila) interferon, alpha-inducible protein (clone ifi-15k)
similar to ig kappa chain v-v region l7 precursor chemokine (c-c motif) ligand 3-like 1
myelin basic protein s100 calcium binding protein p
interferon induced transmembrane protein 3 (1-8u) myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse)
hect domain and rld 5 non-metastatic cells 4, protein expressed in
major histocompatibility complex, class ii, dq beta 1 similar to iduronate 2-sulfatase precursor (alpha-l-iduronate sulfate sulfatase) (idursulfase)
similar to hypothetical protein loc284701 radical s-adenosyl methionine domain containing 2
Interferon Family Dominates
3 pathways; 2 pathways; 1 pathway