Identifiability of biological systems

Afonso Guerra Assuno Senra Paula Freire Susana Barbosa

Identifiability of a biological system

A biological system is a group of biomolecules that together perform a certain task. High throughput technologies generates great amount of data unknown underlying systems. Data quality observed with noise A system can be described by a set of mass action equations. For simplicity: 0th , 1st , 2nd order

Identification problem
Equation structure search (model the system- set of ODEs) Experimental design (inputs - initial concentrations) Parameter fitting (optimization problem- minimum least squares) Statistical analysis

Equation structure

Ilustrating: A C B D

Hypergraph
Equation system represented by a directed hypergraph Each edge can involve more than two nodes Nodes Molecules Edges Reactions Real world restrictions apply

Project Plan
1. Generate GMA for a set of components 2. Choose systems of increasing complexity and simulate dynamic trajectories 3. Parameter inference
Perfect observations and complete knowledge of equation structure No knowledge of equation structure With noise: observations and time Partial knowledge of the equation system

1. Apply evolutionary model

Experimental Design
Simulation of dinamic trajectories
A priori estimates for parameters Initial conditions Algorithm to numerically solve ODEs

0.8

0.6

Conc

0.4

0.2

50

100

150

200

time

Curve fitting
Sampling : CHALLENGE in instationary systems
Simultaneous sampling Sequential sampling Parameterized sampling
Equidistant Exponential

Parameter fitting
Widely applied: local search algorithm requires a good guess! Estimate parameters one by one each new step use the previous estimate 1-dimensional problem

Curve fitting
1. No noise and complete knowledge Mean least squares distance (MLS) 2. No noise and No knowledge of equation structure Equation Structure Search - Greedy recursive algorithm i. Zeros on the rigth side of the equation set ii. Add a term of the form kx,y [X][Y] or kx[X] iii. Predefine a set of realistic reactions (0.001 < f < 0.05) n components (n+1)n2/2+n2 possibilities

Evolutionary Model
Evolution of one model into another Two models: A and B
Full knowledge of B PA=PB+ X , X ~ N (0,t) Stochastic process: Brownian Motion

Questions
Stiff equations Nonlinear systems of ODEs no global optimization guaranteed- stuck in local minima How sufficient and accurate is the data? How reliable are the models? What are the computational challenges?

Thank you for your attention!

Open Discussion