a versatile platform for multilevel modeling of ... · metabolism. vol. 285 n jiang, rd cox, jm...

A Versatile Platform for Multilevel Modeling

of Physiological Systems

Yoshiyuki Asai, PhD

1The screen versions of these slides have full details of copyright and acknowledgements

1

Yoshiyuki Asai, PhD

Group Leader of Open Biology Unit

Okinawa Institute of Science and Technology

Okinawa, Japan

A Versatile Platform

for Multilevel Modeling


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Multilevel modeling and simulation for predictive medicine

Objective

20mV

0mV

-40mV

-80mV

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Concept of multi-level modeling

Time

Blo

od

Co

nce

ntr

atio

n

Circulation

Drug-Protein

interaction

Cellular-level

electrophysiology

Organ-level

electro-kinematic

physiologyMedication

SBML

PHML

CellML



Yoshiyuki Asai, PhD


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Strategies for the physiome project

• The Physiome Project is the concerted effort to define the physiome,

through databasing of observations and analyses,

and through the development of integrated, descriptive,

logical, and quantitative modeling.

• The early goals of the Physiome Project involve developing strategies

and methods for putting information together.

1. To develop comprehensive methods for acquisition and databasing

of very large sets of information on all aspects of biology.

2. To construct descriptive and quantitative models that integrate

the available knowledge so as to determine the inadequacies,

inconsistencies, and insecurities in that knowledge.

3. To organize collaborations at the national and international levels

to target particular areas of integrative biology.

Bassingthwaighte, Annal Biomed Eng, 2000

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• Mathematical models play a key role for describing/databasing

"physiological functions“.

Φ(x, λ)=0

Large-scale,

quantitative models

Understanding

and applications

Database

Physiome database and mathematical modeling

Functions of Living

Organisms

MathModels

PhysiomeDatabase

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Variety of techniques

for modeling and simulation

Diffusion

Inside Outside

Pump

Agent Based System

Algebraic Equations

Partial Differential Equations

• Variety of model expressions

• Variety of solving methods

Ordinary Differential Equations



Yoshiyuki Asai, PhD


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PhysioDesigner, PHML, simulator and databases

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Modeling

Concentrate on

modeling apart from

numerical algorithms

Parallel computation

is supported by simulator

Description

• Meta-information

Article, Model creator,

Description of model entities

• Modularity

Modules & Edges

Open

• Easy reproduction of results

• Validation of correctness

• Easy share & reuse

‒ Collaborative model building

‒ Large scale, multi-level modeling

PhysioDesigner

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PhysioDesigner.org



Yoshiyuki Asai, PhD


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Principle idea of PhysioDesigner

• Multiple scales and levels of physiological structures and functions

can be explicitly expressed in models based on Modularity.

‒ Each physiological entity in a model is represented as a module.

‒ A model is an aggregate of “module”s linked by “edge”s.

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Module and physical-quantity

Edge

(Structural, Logical)

InputPort OutputPort

Module A

Edge

(Functional)

Physical-Quantity

DATA from FILE

Morphological Data

Drive

inhibit

constituteInclude

VIext

CS

V

Module B

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PHML

Requirements

It must be able to:

• Express hierarchy of biophysical functions

and structures.

• Describe dynamics of biophysical functions.

‒ Ordinary / Partial differential equations, agent based system, boundary conditions, etc.

• Describe structures related to biophysical functions.

‒ Surface information, Volume information.

• Describe meta-information of the model and physiology.

• XML-based model descriptive specification

‒ PHML is designed for describing multilevel

hierarchical structure and functional network.

‒ PHML has some compatibility with CellML,

and is developing cooperative frameworks

with SBML.



Yoshiyuki Asai, PhD


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Structure of mathematical expressions

in a model

Simple example: Hodgkin-Huxley model in ODEs

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Hodgkin Huxley Model

Membrane

Ionic Currents

Channel

Gate Variables

Conductance

Structure of mathematical expressions

in a model (2)

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Reuse of modules

Replacement of a channel model



Yoshiyuki Asai, PhD


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SBML-PHML hybrid modeling

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What is SBML?

• SBML is a language developed for describing

mainly intracellular phenomena

such as signal transmission

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SBML-PHML hybridization

• Include a whole SBML model

in an PHML module

SB

ML

Module

K

SBML

s

k

r

S

The value of physical-

quantity in PHML is used

by species in SBML

Physical-quantity

in PHML refers the value

of species in SBML

PHML

SetGet

• Values of species and parameters

of SBML are available in the simulation

via physical-quantities of PHML

PH

ML



Yoshiyuki Asai, PhD


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SBML network in PHML

• Information of a SBML model

can be transferred by edges of PHML

• Information of a PHML model

can be utilized in a SBML model

M

U

V

SBMLm

v

u

K

SBML

v

k

r

V

Physical-quantity

referring SBML

can go out via a port

M

UV

PHML

PHMLPHML module

wrapping a SBML model

can be located

in a tree structure

of an PHML model

• Using edges, SBML models can be

connected to each other indirectly

• It is possible to create a hierarchical

SBML model

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ADP ATP

TCA

ATP

ATP

NADH

FADH2

Ca2+

Na+

Insulin

Granule

KATP KATP

pyruvateGlycolysis

glucose

GLUT2

Ca2+

PHML

Example: pancreatic beta cellLE Fridlyand, N Tamarina,

LH Philipson (2003)

Modeling of Ca2+ flux

in pancreatic beta-cells:

role of the plasma

membrane and

intracellular stores.

American journal

of physiology.

Endocrinology and

metabolism. vol. 285

N Jiang, RD Cox, JM Hancock. (2007) A kinetic core

model of the glucose-stimulated insulin secretion network

of pancreatic beta cells. Mamm Genome. 18(6-7): 508-20SBML

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Example: pancreatic beta cell (2)

ATP

Cytoplasm



Yoshiyuki Asai, PhD


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Template and instance framework

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Template and instance for large-scale modeling

• Example: Cell assembly connected to each other

For persistent network

• Static instances

‒ Editable in GUI canvas

For variable network

• Dynamic instances

‒ Define rules to create

and destroy instances

e.g. neural network

e.g. skin cells

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Modeling with template and instance

Template

Instances



Yoshiyuki Asai, PhD


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Use case: neural network

using template/instance

Create one neuron model at first as a Template

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Create many instances to form multiple layer neural network

Use case: neural network

using template/instance (2)

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Integration of time series data

and morphology



Yoshiyuki Asai, PhD


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Time-series data integration to a module

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Physical-quantity assigned to time-series data

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Modeling with morphology



Yoshiyuki Asai, PhD


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Image processing for integrating morphology

Electrical

conductivity

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Manipulation on medical images

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Integrating morphology with PDEs:

EEG example

PDE: Poisson equation

I

-I

Current

dipole

V : Potential

Im : Current source density

I : Current

σ ： Conductivity tensor

ω : Angular frequency

ODE: current source

Simulation region

Time step = 1e-3sec

Collaboration with Prof. Yoko Yamaguchi (RIKEN)

Combination

of PDE and ODE

and multi-time step



Yoshiyuki Asai, PhD


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Simulation

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Simulation (2)

• Simulator Flint

– Supports SBML as well as PHML

– Supports parallel computation

• Export to FreeFEM format

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Flint

+

+ Time series

integration



Yoshiyuki Asai, PhD


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Parameter scan

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Flint K3

Simulation Servers

are on each cloud or HPC

• Run parallel computations

• Store simulation results

Interface Server is somewhere in the internet

• Receives simulation requests from users

• Sends jobs to simulation servers distributed

on clouds or HPCs

• Garuda alliance

member applications

can send simulation

jobs to Flint K3

via Garuda APIs.

• There is a web interface

of Flint K3 to submit

requests as well.

• NII cloud

• Amazon cloud

• Google cloud

• etcM

http://flintk3.org

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Flint K3 (2) http://flintk3.org



Yoshiyuki Asai, PhD


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Flint K3 with SNS or other services

Submit simulation jobs

Report simulation progress

Simulation data / Figs

Figs of simulation

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Visualization

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Visualization by PhysioVisualizer



Yoshiyuki Asai, PhD


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Visualization of model in 3D morphology space

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Databases

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Physiome.jp

• In 2007 Physiome.jp

is established by global

COE “insilico medicine

oriented world

wide platform”.

• In 2013, fully renovated

• Various tools other

than PhysioDesigner

are distributed

in this site.



Yoshiyuki Asai, PhD


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PH database at Physiome.jp

• In 2007 Physiome.jp

is established by global

COE “insilico medicine

oriented world

wide platform”.

• In 2013, fully renovated

• Various tools other

than PhysioDesigner

are distributed

in this site.

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Inter-operation among applications

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Garuda

http://www.garuda-alliance.org/



Yoshiyuki Asai, PhD


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Linkage among applications

Model creator/Analyzer

Text mining / Model database

Simulator

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SBML-PHML hybrid modeling

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Summary

http://physiodesigner.org



Yoshiyuki Asai, PhD


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a versatile platform for multilevel modeling of ... · metabolism. vol. 285 n jiang, rd cox, jm...

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