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Seminar Wageningen Centre for Systems Biology (WCSB)
Dec. 9, 2014
Natal van Riel
Eindhoven University of Technology, the Netherlands
Dept. of Biomedical Engineering,
Systems Biology and Metabolic Diseases
@nvanriel
Systems Biology of Disease Progression
2http://www.youtube.com/watch?v=x54ysJDS7i8
/ biomedical engineering PAGE 310-12-2014
/ biomedical engineering PAGE 410-12-2014
Liver X Receptor
Novel cholesterol lowering medication
• Liver X Receptor (LXR, nuclear receptor),
induce transcription of multiple genes
modulating metabolism of fatty acids,
triglycerides, and
lipoproteins
• LXR agonists stimulate cellular cholesterol
efflux from peripheral tissues (including
macrophages)
• LXR as target for anti-atherosclerotic
therapy?
/ biomedical engineering PAGE 510-12-2014
Preclinical study of pharmaceutical
intervention
• control, treated with T0901317 for 1, 2, 4, 7, 14, and 21 days
/ biomedical engineering PAGE 610-12-2014
0 10 200
100
200Hepatic TG
Time [days]
[um
ol/g]
0 10 200
1
2
3Hepatic CE
Time [days]
[um
ol/g]
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2
4
6Hepatic FC
Time [days]
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ol/g]
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50
100Hepatic TG
Time [days]
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ol]
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1
1.5Hepatic CE
Time [days]
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ol]
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2
4Hepatic FC
Time [days]
[um
ol]
0 10 200
1000
2000
3000Plasma CE
Time [days]
[um
ol/L]
0 10 200
1000
2000
3000HDL-CE
Time [days]
[um
ol/L]
0 10 200
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1000
1500Plasma TG
Time [days]
[um
ol/L]
0 10 206
8
10
12VLDL clearance
Time [days]
[-]
0 10 20100
200
300
400ratio TG/CE
Time [days]
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15VLDL diameter
Time [days]
[nm
]
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2
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Time [days]
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ol/h]
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3Hepatic mass
Time [days]
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m]
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0.2
0.4DNL
Time [days]
[-]
Grefhorst et al. Atherosclerosis, 2012, 222: 382– 389
Liver section of mice
treated 4 days with LXR
agonist T0901317
Oil-Red-O staining for
neutral fat
hepatic steatosis
/ biomedical engineering PAGE 710-12-2014
WHY/ HOW?
BENEFIT WITHOUT
SIDE -EFFECT?
measuringmodelling
/ biomedical engineering PAGE 810-12-2014
/ biomedical engineering PAGE 910-12-2014
Physiology of lipid and lipoprotein metabolism
• Coarse-grained when possible,
detailed when necessary
/ biomedical engineering PAGE 1010-12-2014
Computational modeling
/ biomedical engineering PAGE 1110-12-2014
• 1.0 Tiemann et al, 2011 BMC Syst Biol
• 2.0 Tiemann et al, 2013 PLOS Comput Biol
• 3.0 Tiemann et al, 2015 PLOS ONE
Tiemann 2.0
/ biomedical engineering PAGE 1210-12-2014
1. Fluxes
-VLDL-TG production
-Hepatic HDL cholesterol uptake
-Hepatic cholesterol synthesis
-Biliary cholesterol excretion
-Biliary bile acid excretion
-Fecal cholesterol excretion
-Fecal bile acid excretion
-Transintestinal cholesterol excretion
-Beta-oxidation (available but not included yet)
-Hepatic FFA uptake (available but not included yet)
-VLDL catabolism/clearance from the plasma
2. Metabolite concentrations
-Hepatic FC
-Hepatic CE
-Hepatic TG
-Plasma FFA
-Plasma TG
-Plasma total cholesterol
-HDL cholesterol
-Hepatic fractional DNL (de novo triglycerides)
-Nascent VLDL particle diameter
Uncertainty
• Data uncertainty
• Parameter uncertainty
• Prediction uncertainty
/ biomedical engineering PAGE 1312/10/2014
Computational
modelParameter space
Solution / prediction
space
forward
Data space
inverse
Vanlier et al, Bioinformatics. 2012; 28(8):1130-5
Vanlier et al, Math Biosci. 2013; 246(2):305-14
‘Connecting’ the longitudinal data
in time, and with each other
/ biomedical engineering PAGE 1410-12-2014
• Data: mice, 3
weeks (black bars
and white dots)
differences in
data accuracy
• Model: (the darker
the more likely)
differences in
uncertainties
• Calculating unobserved quantities
• Does LXR agonist improve lipid/lipoprotein profile?
Flux Distribution Analysis
/ biomedical engineering PAGE 1512/10/2014
white lines enclose the central
67% of the densities
Analysis: HDL cholesterol
/ biomedical engineering PAGE 1610-12-2014
Analysis: increased excretion of cholesterol
Observation: increased concentration of HDL
(the good cholesterol)
• SR-B1
• Protein expression/ activity:
Experimental testing of model prediction
• HDL excretion and uptake flux
are increased
• Transcription:
/ biomedical engineering PAGE 1710-12-2014
Transcription of cholesterol efflux transporters
Tiemann et al., PLOS Comput Biol 2013
SR-B1 protein content is decreased in
hepatic membranes
Srb1 mRNA
expression not
changed
model: decreased
hepatic capacity to
clear cholesterol
Summary first part
• Metabolism and metabolic modeling as ‘foundation’
• Combining data and modelling
• Improved understanding
• Testable predictions
• Importance of fluxes (both data and model)
/ biomedical engineering PAGE 1810-12-2014
Translation
FP7-HEALTH Systems medicine: Applying systems biology
approaches for understanding multifactorial human diseases
and their co-morbidities
Preclinical testing of interventions in mouse models of age and age-related diseases
/ biomedical engineering PAGE 1910-12-2014
http://www.cost.eu/COST_Actions/bmbs/Actions/BM1402
AGE
/ biomedical engineering PAGE 2010-12-2014
Human Metabolic Phenotyping
Metabolic challenge test – Metabolic flexibility
• Cross-sectional (comparing phenotypes)
• Different time-scale
/ biomedical engineering PAGE 2110-12-2014
Krug et al, 2012 FASEB J. 26(6): 2607-19 Tiemann et al, 2011 BMC Syst. Biol.
• Metabolic challenge test
• Metabolic flexibility
Longitudinal - Treatment in time
/ biomedical engineering PAGE 2210-12-2014
The computational method: ADAPT
• ADAPT: Analysis of Dynamic Adaptations in Parameter Trajectories
/ biomedical engineering PAGE 2310-12-2014
? ? ?
/ biomedical engineering PAGE 2410-12-2014
ADAPT
• Dynamic system
• Maximum Likelihood Estimation
/ biomedical engineering PAGE 2510-12-2014
Van Riel et al. (2013) Interface Focus, 3(2): 20120084
Introducing time-dependent parameters
Dividing the simulation of the system in Nt steps of Dt time period
/ biomedical engineering PAGE 2610-12-2014
Modelling phenotype transition (1)
27
treatment
disease progression
longitudinal discrete data: different phenotypes
Parameter estimation (1)
28
steady state model
Parameter estimation (2)
29
steady state model
iteratively calibrate model to data: estimate parameters over time
minimize difference between data and model simulation
Parameter estimation (2)
30
steady state model
iteratively calibrate model to data: estimate parameters over time
Parameter estimation (2)
31
steady state model
iteratively calibrate model to data: estimate parameters over time
Modelling phenotype transition (3)
longitudinal discrete data: different phenotypes
estimate continuous data: ensemble of cubic smooth spline
incorporate uncertainty in data: multiple describing functions
/ biomedical engineering PAGE 3210-12-2014
Propagation of Uncertainty
• ADAPT accounts for uncertainty in the data
/ biomedical engineering PAGE 3310-12-2014
Gaussian distribution
Sampling replicates from error model
( , )d d NVanlier et al. Math Biosci. 2013 Mar 25
Vanlier et al. Bioinformatics. 2012, 28(8):1130-5
Propagation of Uncertainty
• ADAPT accounts for uncertainty in the model
/ biomedical engineering PAGE 3410-12-2014
Estimated parameter trajectories
/ biomedical engineering PAGE 3512/10/2014
physiologically
unrealistic
Regularization of parameter trajectories
• Identifying minimal adaptations that are necessary to describe
the change in phenotype
/ biomedical engineering PAGE 3610-12-2014
changing a parameter is costly
Regularization of parameter trajectories
• Determine adequate regularization strength
/ biomedical engineering PAGE 3710-12-2014
ADAPT – time-varying parameters
/ biomedical engineering PAGE 3810-12-2014
ADAPT
/ biomedical engineering PAGE 3910-12-2014
ADAPT toolbox
• Model simulation
• MEX files - CVode
• Parameter estimation
• ADAPT
• Parallel
/ biomedical engineering PAGE 4010-12-2014
Acknowledgements
• Peter Hilbers
• Christian Tiemann
• Joep Vanlier
• Yvonne Rozendaal
• Fianne Sips
• Bert Groen
• Jan Albert Kuivenhoven
• Maaike Oosterveer
• Brenda Hijmans
• Yared Paalvast
• Yanan Wang
• Partrick Rensen
• Ko Willems-van Dijk
/ biomedical engineering PAGE 4110-12-2014