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c c c
= + = + =
c c c
2
,
,
,
( )
( , ) ( ( ) ( ) )
i i j i l
k i
j
i j
i
k
l
i
i
l
J
H j l s k s
s
r k
k
k e e
u u u
c
c
= =
c c
c
Hessian matrix
Correlation matrix
( )
c
M correlation S =
Understanding correlations
cost functions w.r.t. (k
28
, k
36
) and (k
9
, k
28
).
Sensitivity coefficients for NF-kB
n
.
K
28
and k
36
are correlated
Global sensitivity analysis: Morris method
One-factor-at-a-time (OAT) screening method
Global design: covers the entire space over which the
factors may vary
Based on elementary effect (EE). Through a pre-defined
sampling strategy, a number (r) of EEs are gained for each
factor.
Two sensitivity measures: (mean), (standard deviation)
Max D. Morris, Dept. of Statistics, Iowa State University
large : high overall influence
(irrelevant input)
large : input is involved with
other inputs or whose effect is
nonlinear
sensitivity ranking - plane
Sensitive parameters of NF-kB model
k28, k29, k36, k38
k52, k61
k9, k62 k19, k42
Global sensitive Local sensitive
k29: IkBo mRNA degradation
k36: constituitive IkBo translation
k28: IkBo inducible mRNA synthesis
k38: IkBo
n
nuclear import
k52: IKKIkBo-NF-kB association
k61: IKK signal onset slow adaptation
k9: IKKIkBo-NF-kB
catalytic
k62: IKKIkBo catalyst
k19: NF-kB nuclear
import
k42: constitutive IkB|
translation
IKK, NF-kB, IkBo
Improved data fitting via estimation
of sensitive parameters
(a) Hoffmann et al., Science (2002)
(b) Jin, Yue et al., ACC2007
The fitting result of NF-kB
n
in the IkBo-NF-kB model
Optimal experimental design
Basic measure of optimality:
Aim: maximise the identification information while minimizing the
number of experiments
What to design?
Initial state values: x
0
Which states to observe: C
Input/excitation signal: u(k)
Sampling time/rate
Fisher Information Matrix
1 T
FIM S Q S
=
Cramer-Rao theory
2 1
i
FIM
u
o
>
lower bound for the variance of unbiased
identifiable parameters
A-optimal
D-optimal
E-optimal
Modified E-optimal design
Optimal experimental design
maxdet( ) FIM
min
max ( ) FIM
1
min trace( ) FIM
Commonly used design principles:
min cond( ) FIM
u
1
u
2
1.96 , 1.96
i i
i i
u u
u o u o
(
+
95% confidence interval
The smaller the joint confidence intervals are, the
more information is contained in the measurements
Measurement set selection
Estimated parameters:
19 29 31 36
38 42 52 61
, , , ,
, , ,
k k k k
k k k k
x
12
(IKKIkB|-NF-kB), x
21
(IkBc
n
-NF-kB
n
), x
13
(IKKIkBc) , x
19
(IkB|
n
- NF-kB
n
)
Forward selection with modified E-optimal design
Step input amplitude
95% confidence intervals when :-
IKK=0.01M (r) modified E-optimal
design
IKK=0.06M (b) E-optimal design
Robust experimental design
Aim: design the experiment which should valid for a range of
parameter values
1
1 1
, ,
, 1, 0,
, ,
m
m
i i
i m
x x
i e e
e e
=
= = >
`
)
0
1
( , )
(nominal)
m
T T
i
i i i i
i
f x
FIM
=
c
= =
c
u
u
evv v
u
( )
1
1
(with uncertainty)
( , , )
m
T
i i i i
i
m
FIM
blkdiag
=
= A
A A s
e vv