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7 views10 pagesThe impulses are one of the sources of fluctuations which lead to the sharp changes in the biochemical systems such as the changes in epidemic and population models. These effects have been comprehensively studied under deterministic models, whereas, have not been analyzed in stochastic models. Hereby, in this study, we implement these effects in two exact stochastic simulation algorithms, namely, the direct method and the first reaction method under different dimensional systems and impulses scenarios. In the application, we use real systems and apply impulses to the biologically meaningful proteins. Then, we evaluate the performances of both exact methods in terms of computational demand via distinct criteria.

Jul 26, 2016

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The impulses are one of the sources of fluctuations which lead to the sharp changes in the biochemical systems such as the changes in epidemic and population models. These effects have been comprehensively studied under deterministic models, whereas, have not been analyzed in stochastic models. Hereby, in this study, we implement these effects in two exact stochastic simulation algorithms, namely, the direct method and the first reaction method under different dimensional systems and impulses scenarios. In the application, we use real systems and apply impulses to the biologically meaningful proteins. Then, we evaluate the performances of both exact methods in terms of computational demand via distinct criteria.

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The impulses are one of the sources of fluctuations which lead to the sharp changes in the biochemical systems such as the changes in epidemic and population models. These effects have been comprehensively studied under deterministic models, whereas, have not been analyzed in stochastic models. Hereby, in this study, we implement these effects in two exact stochastic simulation algorithms, namely, the direct method and the first reaction method under different dimensional systems and impulses scenarios. In the application, we use real systems and apply impulses to the biologically meaningful proteins. Then, we evaluate the performances of both exact methods in terms of computational demand via distinct criteria.

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Impulsive Scenarios

Mge Yazc1, Vilda Purutuolu2, Derya Altntan3

1,2

Department of Statistics, Middle East Technical Universtiy, Turkey

3

Department of Mathematics, Seluk University, Turkey

mugergul15@gmail.com

ABSTRACT

The impulses are one of the sources of fluctuations

which lead to the sharp changes in the biochemical

systems such as the changes in epidemic and

population models. These effects have been

comprehensively studied under deterministic

models, whereas, have not been analyzed in

stochastic models. Hereby, in this study, we

implement these effects in two exact stochastic

simulation algorithms, namely, the direct method

and the first reaction method under different

dimensional systems and impulses scenarios. In the

application, we use real systems and apply impulses

to the biologically meaningful proteins. Then, we

evaluate the performances of both exact methods in

terms of computational demand via distinct criteria.

KEYWORDS

Stochastic simulation, biochemical systems,

impulses, direct method, first reaction method.

1 INTRODUCTION

The biochemical modeling is the mathematical

way to explain the dynamics of biological

systems such as the interaction of proteins and

molecules (Wilkinson, 2006). But, the

vivo/vitro analyses of the biological systems

can be expensive and limited. In this situation,

we can perform the simulation methods under

realistic assumptions so that we can visualize

the behavior of the real biological system

artificially.

Each biological event can be represented by a

reaction. Thus, the biochemical reaction is a

can be presented by a mathematical expression,

as shown below.

(1)

where ma and mb are called the stoichiometric

coefficient of the reactant A and the product B,

respectively. Furthermore, k is the rate constant

of the reaction which is dependent on the

temperature and the volume of the

environment.

Hereby, in this study, we aim to compare the

performance of the stochastic simulation

algorithms of the biological systems and to

evaluate their performances under abrupt

changes. In real systems, such abrupt changes

are called as impulses and in biological

networks, these changes are used to present the

cancer, diabetes or similar diseases whose

attacks

are

observed

suddenly

and

stochastically (Jonge, 2014).

Therefore, in the application, we choose distinct

dimensional real systems. In the calculation, we

apply the Lotka Volterra model as the toy

example. Then, we simulate the PKC pathway

and LysisLysogeny model as moderate networks.

Finally, we use the sole JAK-STAT pathway

and the combination of JAK-STAT and PKC

pathways as a single and large system. In the

simulation, we perform the direct and the first

reaction algorithms which are the two wellknown exact stochastic simulation algorithms.

In both methods, the assumption is that the

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Proceedings of The Third International Conference on Data Mining, Internet Computing, and Big Data, Konya, Turkey 2016

system, mix well in a constant volume and

under a constant temperature. Accordingly, in

the organization of the study, we introduce the

underlying simulation algorithms and the

impulses in Section 2. Then, we present the

measurement criteria and the findings of the

implementations in Section 3. Finally, we

conclude the study and discuss the future work

in Section 4.

large networks as the calculation takes long

time.

The Gillespie algorithm is known as the

discrete event simulation. For a system with r

reactions and n species, its procedure can be

listed as follows.

i.

constants c1, c2,.,cr and the molecular

numbers for each species x1, x2,., xn

are initialized.

ii.

computed for each reaction (i=1,,r)

and the total hazard is calculated via

h0(x,c)=

.

iii.

reaction, is generated from the

exponential density with a rate h0, i.e.,

Exp(h0(x,c)).

iv.

mathematical

distribution

with

probabilities hi(x,ci)/h0(x,c) under the

assumption that the reactions are

independent of each other.

v.

x:=x+S(j) and t:=t+t, respectively. Here

S(j)(j=1,,n) indicates the jth column of

the stoichiometry matrix and t denotes

the new time interval used in the update

of the current time t. In the

stoichiometry matrix, the rows show the

reaction and the columns denote the

number of species. This matrix has rn

dimension for a system with r reactions

and n species.

vi.

time of the simulation T, i.e., t<T, then,

the algorithm is repeated from step (ii)

until t T.

2 METHODS

2.1 Stochastic Simulation Algorithms

The gene regulation is generally modeled by

differential equations (DE). Although this

deterministic model is the most widely used

approach and can successfully explain the

steady-state behavior of the system under

discrete time and states, it cannot describe the

randomness of the system as seen in the

transcription and the translation of the proteins.

Thus, the stochastic model is the only choice to

present this randomness in a mathematical way

(Bower and Bolouri, 2001; Purutuolu, 2010).

There are five main exact stochastic simulation

algorithms which enable to generate the actual

randomness in the model. These are the direct

method (Wilkinson, 2006), also called Gillespie

method, the first reaction method (Gillespie

1992; Turner, 2005), the next reaction method

(Gibson and Bruck, 2000; Turner, 2004), also

named as the Gibson-Bruck algorithm, the

optimal direct method (Cao, 2004) and the

sorting direct method (McCollum and Peterson,

2006).

2.1.1 Direct Method

The direct algorithm, also called as the

Gillespie method, is the fastest simulator in the

calculation of time, especially, for small

systems (Wilkinson, 2006, Gillespie, 1977;

Turner, 2004). However, its application is hard

in heterogeneous situation and is not

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Proceedings of The Third International Conference on Data Mining, Internet Computing, and Big Data, Konya, Turkey 2016

The first reaction method is a simulation

method which is suggested to decrease the

computational time of the Gillespie algorithm

for large systems (Gillespie, 1992; Turner,

2004).

The steps of this algorithm for a system with r

reactions and n species are presented as below.

i.

numbers of molecules for species

x1,,xn and the total time of the

simulation T are initialized for the

system at time t=0.

ii.

(i=1,,r) is calculated.

iii.

(i=1,,r) is computed from the

exponential distribution with a rate

hi(x,ci), i.e, ti~Exp(hi(x,ci)).

iv.

interval for the next reaction which is

generated from the multinominal

distribution with probabilities hi/h0 as

taken in the Gillespie algorithm,

h0=

.

v.

t are updated via t:=t+tj and x:=x+S(j) in

which S(j) denotes the jth row of the

stoichiometry matrix.

vi.

algorithm is repeated until t T.

Gillespie and the first reaction algorithms are

similar to each other. But the latter does not use

the total hazard in the update of the next

reaction time. Hence, it can produce longer

demand than the Gillespie method.

2.2 Impulses

The natural activity is generally dynamic and

can have sudden changes which are called as

the impulses. The shocks, natural disasters and

vaccinations are some examples of the

impulses. Hereby, these dynamic changes can

happen into two different ways, namely,

deterministically and stochastically. If the

concentration of species in the system is low

and the stochastic fluctuations have a

significant effect on the system, the stochastic

impulses are used to describe the sudden

changes in the model.

The deterministic impulses are simply based on

the ordinary differential equations (ODE) and

the random behavior is ignored in this

approach. In order to define the time of

impulses, the hybrid strategies are used. The

hybrid methods basically split the species and

the reactions as continuous and discrete groups.

The former describes the fast reactions and

associated species and the latter represents

relatively slow reactions and related species.

On the other hand, the time of impulses in the

deterministic approach is called as the jump

times that are found by the discrete groups of

reactions in the implementation of the hybrid

methods (Bower and Bolouri, 2001).

The simple ODE system can be summarized as

shown in Equation 2.

dx (t )

f ( x(t ))

dt

(2)

vector at time t>0 when the system is defined

by the n number of species and the r number of

reactions as used beforehand. Accordingly, the

deterministic impulsive model is based on this

general ODE modeling with a jump function,

84

Proceedings of The Third International Conference on Data Mining, Internet Computing, and Big Data, Konya, Turkey 2016

Equations 3 and 4 for a given initialization of

the system via the (t0, x0) (x0=x01,.,x0n). Here,

t0 and x0 refer to the initial time and the

associated initial state, respectively.

(3)

(4)

In Equation 4,

denotes the impulsive

function at time

. When the impulse

occurs at time

, the state vector x(t) =

x(t;t0,x0) is transferred to the new position x(t)

= x(t;

) where

is the new x(t)

point for

).

On the other side, the stochastic impulses are

based on the chemical master equations with

impulses at fixed or varying times. Hereby, the

time of impulses can be generated under

different scenarios. For instance, it can be

produced as a continuous function, threshold

function or a fixed value from a Poisson

distribution. For the continuous function, the

impulse can occur at time t=

, where x is

the r-dimensional vector of x. For the threshold

function, the time of jumps depends on a

threshold defined by xT. Here, x(t) and xT

denote the current time and the state of the total

time T where t: x(t) xT. Finally, in the last

case, the time of jumps is determined from a

random value from a Poisson distribution

(Altntan et al., 2010). In this study, we merely

deal with the first two scenarios.

has many reactions such as j = 1,2,r. So, the

average search depth, SD, indicates the average

number of operations in the firing of a reaction

as shown below.

SD=

(5)

occurs during the simulation and j stands for

the time of the occurrence of the jth reaction.

Average weighted degree: The average

weighted degree, WD, calculates the average

degree in the firing of each reaction. Here, the

degree implies how many reactions are affected

by the firing of a reaction. Thereby, WD is

computed as follows.

WD=

(6)

describes the number of firing times of the jth

reaction as presented in the expression of SD.

Central processing unit: The central

processing unit, CPU, is the necessary unit to

understand and to translate the program codes.

Therefore, it is also known as the computer

time of a calculation.

3.2 Description of Systems

3 APPLICATION

3.1 Measurement Criteria

In order to assess the performance of different

simulation methods in terms of the

computational demand, certain measures are

suggested. Among alternatives, the most widely

used ones can be listed as the average search

depth, the average weighted degree and the

central processing unit.

stochastic simulation algorithms, we select

different dimensional systems, namely, small,

moderately large and realistically large

networks. For the toy system, we choose the

Lotka-Volterra model (Wilkinson, 2006). This

system is based on the relation of preys and

predators. On the other hand, for the

moderately large system, we select the reaction

list of the PKC pathway. This system stands for

85

transduction pathway, related to the significant

neural functions, especially, for the memory

and the learning process. Moreover, it has

importance at neuronal functions such as the

synaptic long-term potentiation (LTP) and the

depression (LTD) (Manninen et al., 2006). On

the other hand, as the moderate system, we also

use the Lysis-Lysogency (LL) model (Arkin et

al., 1998). Indeed, the lysogenic cycle implies

the reproduction of viral issues and the lytic

means that the cell integrity is distorted. The

mechanism of the lytic system is initiated with

the transcription and the translation. Generally,

this system has low concentrations of species

and slow reaction rates. Furthermore, we also

apply the JAK-STAT pathway (Maiwald et al.,

2010) under the realistic complexity. This

network is one of the major signaling pathways

controlling the immune system based on the

regulation of interferons. The interferons

(IFNs) are the proteins synthesized by host

cells in the reply to pathogens like viruses or

bacteria and are used for the bridge between

cells to activate defenses of the immune system

against pathogens. Finally, we investigate the

convergence of JAK-STAT and PKC pathways

to observe the response of the methods for large

systems. In the activation, the reaction of the

STAT1 and GATA4 proteins trigger the

underlying convergence. The vasoactive

hormone, called AII, changes the transcription

of the gene. AII reacts with AT1R and AT1R

modifies the biological effects of AII. AT1R is

generally used for the treatment of the

cardiovascular disease. In fact, some STAT

molecules are activated by AII. Hereby, the link

of these two pathways are based on AT1R and

AII activations (Wang, 2005).

3.3 Results

The LV, LL, PKC and JAK-STAT systems are

investigated for the time t= 5, 20 and 50 for

both the direct and the first reaction methods. In

simulations, the initial number of molecules is

taken as 100 arbitrarily for each system.

about the initial number of molecules of each

gene. Whereas, the reaction rates of each

system are set to their biologically validated

values in the associated literature about every

system. The list of reactions and the proteins in

the system are described in details in the study

of Wilkinson (2006) for the LV pathway, in the

study of Schaechter and Benowitz (1993) for

the PKC pathway in the study of Arkin et al.,

(1998) for the LL pathway and in the study of

Maiwald et al., (2010) for the JAK-STAT

pathway.

of the PKC-cytosolic, Substance PKC.Ca2+ and

PKC.DAG.AA of the PKC system via Direct Method

(DR) and First Reaction Method (FR) for the time 20

when the system has no impulse.

number of substances for the PKC system with

t=20 as illustration. From the results, it is

observed that the outputs of both the direct and

the first reaction methods are almost the same

apart from the fluctuations due to the

stochasticity of the systems.

Then, we investigate the impulsive effects in all

the systems by using these two methods for

short and long runs. In order to observe

underlying effects, we consider two different

86

to detect the effect of the changes in the number

of molecules at a decreasing direction. Hereby,

if the number of the biologically meaningful

substance becomes greater than 60 in

simulations, we decrease it 20 units. On the

other side, in Scenario 2, we consider to

decrease the number of this substance at 20

units if it exceeds 60 molecules in the

simulations. For the PKC and JAK-STAT

systems, the impulses are put on STAT2c and

ISGF-3c_CP substances, respectively, as they

control whole activations in these pathways.

the number of the Receptor IFNAR1, STAT2c and ISGF3c_CP of JAK-STAT system via Direct Method (DR)

and First Reaction Method (FR) for the fixed time 20

when the system has the impulsive effect.

the number of Receptor IFNAR1, STAT2c and ISGF3c_CP of JAK-STAT Model for Direct Method (DR) and

First Reaction Method (FR) for the fixed time 20,

respectively, when the system has the impulsive effect.

changes in activations for Receptor IFNAR1,

STAT2c and ISGF-3c_CP proteins in the JAKSTAT pathways under impulses as examples.

From the plots, we see the considerable effects

of impulses in the selected proteins. On the

other hand, similar to previous findings, there is

no biological differences in both simulation

algorithms. On the other side, when we

compare the tabulated values for all systems as

given in Table 1, we observe that the impulses

cause sharp increases in the computational

demand for small systems in terms of the local

time and CPU. Furthermore, the impulses under

Scenario 1 (increase in the number of

molecules) have less WD and higher SD than

impulses under Scenario 2 (decrease in the

number of molecules) and the values of WD

and SD under no impulses are roughly equal to

the average of the systems scores of both

impulses. Finally, there is no significant

difference between the results of both

algorithms for all time periods as seen in Table

1.

On the other hand, if we compare the findings

of the moderate systems as presented in Tables

2-4, we detect that there is no unique case

where the results of impulses produce higher

scores within the impulsive scenarios and

between the scenario with/without impulses.

For instance, the values of SD and WD are

higher under the impulses of Scenario 1

regarding the corresponding entries of Scenario

2 and both SD and WD are smallest when there

is no impulse for the PKC pathway as given in

Table 3. On the contrary, SD without impulses

is the highest compared to both sorts of

87

the entries of SD and WD within the scores of

impulsive scenarios for the JAK-STAT

pathway as shown in Table 4. Moreover, we

observe that the outputs of the direct method

are better in all cases for the PKC pathway,

whereas, it is not seen any particular improved

performance of the direct method for the JAKSTAT pathway.

Finally, from the results of the large system as

presented in Table 5, both SD and WD are

higher when there is no impulse in the system.

Furthermore, CPU and local time increase

significantly under impulses as found in all

previous findings. But the main gain of the first

reaction method over the direct one in the

computational demand can be better observed

when the system becomes larger and the

duration of the simulation is taken longer. In

this study, all the codes for both algorithms and

their impulsive versions are originally

developed in R by the authors and we do not

use any particular CRAN package developed

for the simulations such as smfsb or

GillespieSSA. Hence, we observe that the direct

method typically has less CPU and uses less

local time in the calculation with respect to the

results of the first reaction method for small and

moderate systems with/without impulses, and

this conclusion is still valid if the system is

large, but the time of the simulation is longer.

On the other side, the first reaction method over

performs when the system is complex and the

duration of the simulation is longer. This result

is invariant from the firing of the impulses as

well as their types, i.e., scenarios. Lastly, if we

compare the outputs of without impulses versus

with impulses, it is observed that the values of

CPU and local time are always bigger under the

impulsive effects for all dimensions and

computational time. Whereas, SD and WD

values are affected by the types of impulses and

there is no unique conclusion in these criteria

with respect to the findings of without impulses

under distinct dimensions and large systems, as

well as different simulation times.

4 CONCLUSION

In this study, we have dealt with the stochastic

simulation of the biochemical systems by

performing two major algorithms in this field.

These are the direct and the first reaction

methods. They are exact algorithms in the sense

that they are based on the chemical master

equation. Here, we have evaluated them under

different dimensional systems and impulsive

scenarios.

From the results, we have observed that there is

no significant difference between the direct and

the first reaction methods in most of the

pathways and simulation times. But a slight

difference is seen when the system gets

complicated. Moreover, we have detected that

the effect of impulses can be observable for

large systems and can be hardly seen under

small or moderate dimensional systems.

Furthermore, if the impulses are put on the

initial species which can trigger whole

activation of the systems, such as the growth

factor or external stimulus, the activations of all

remaining species alter too as expected and the

impulses become visible in the outputs of the

simulations. On the other hand, if the

underlying effects, either in increasing or

decreasing direction in the number of

molecules, are frequently fired, they cannot be

observed clearly. Whereas, such effects have

always caused an increase in CPU and local

time as expected and these differences become

visible while the systems have complex

structures, i.e., higher dimensions.

As a future work, we consider to investigate the

effect of bifurcations in the stochastic modeling

and in these algorithms. Because the impulses

can cause unstable positions for the systems

and the bifurcation is detected under such

instabilities. Finally, we think to extend this

study for the approximate stochastic simulation

algorithms under various conditions of

88

2.68

2.69

2.72

2.64

2.66

2.75

First Reaction

Method

Without Impulse

2.07

13511.13

1485.81

First

Reaction

Method

Local Time

SD

WD

t=5

16.20

352.26

5.49

2.78

t=20

6677.65

29867.95

5.68

2.99

t=50

8806532.30

2935560.26

457.51

231.66

t=5

22.88

388.73

5.64

2.78

t=20

11153.05

45008.64

6.70

2.99

t=50

9899785.86

6675700.8

546.5

242.8

2.76

13517.28

1486.68

2.33

2.63

4132.7

30.52

t=50

Direct

Method

CPU

2.20

2.04

11798.44

1441.96

26.42

t=20

3922.02

2.58

2.36

1483.75

13278.22

2.73

2.22

1.95

12095.05

1445.47

22.24

t=5

3651.37

2.38

2.57

1475.25

12961.56

2.55

2.39

2.06

12280.33

1447.36

28.89

t=50

4127.22

2.62

2.33

1485.81

13511.13

2.79

2.20

2.04

11789.94

1440.7

24.69

t=20

3916.6

2.59

2.35

1482.68

13274.68

2.72

2.23

1.97

12089.78

1444.55

20.98

t=5

3648.11

2.37

2.55

1474.64

12959.4

2.59

2.39

SD

Local Time

CPU

SD

Local

Time

CPU

LV

Path

way

CPU

Local

Time

SD

WD

Without Impulse

for the Direct and the First Reaction methods.

LL Pathway

WD

WD

pathway for the Direct and the First Reaction Methods

Direct Method

in the leap condition.

89

170.35

478.39

1221

t=5

First Reaction

t=20

Method

t=50

24.22

22.34

23.01

23.76

8329.5

9107.82

t=5 1286.39

First Reaction

t=20 1444.1

Method

22.06

SD

8245.74

Local

Time

23.24

1259.2

9.28

9.53

10.24

9.29

9.39

Without Impulse

6299.52

3026.31

1471.29

4730.27

2526.77

10.21

SD

Direct

Method

t=5

851.9

t=50

CPU

323.88

1348.92

Local

Time

Without Impulse

7.11

7.17

7.18

7.03

7.18

7.18

WD

5.70

5.75

5.91

5.72

5.73

5.87

WD

184537.8

185542.4

187302.8

184121.8

185175.6

187167.2

Local Time

10.46

10.50

10.97

10.47

10.47

10.85

SD

Local

Time

SD

2262.23

2028.8

1884.21

21.50

97368.3

23.27

96482.65 22.48

95327.5

CPU

WD

5.85

5.86

5.96

5.85

5.87

5.94

7.00

7.12

7.15

6.99

7.17

7.11

WD

3282.69

3511.34

3848.27

3151.68

3405.7

3807.95

CPU

Local

Time

190665

188761

9.19

9.38

9.94

SD

5.75

5.80

5.87

WD

9.75

9.98

5.76

5.81

Local

Time

SD

CPU

7.25

7.18

7.18

7.28

7.22

7.18

WD

4877.44 191787.9

4201.15 189185.1

4536.39

4073.76

3894.72 187801.2

CPU

and the First Reaction methods.

JAK-STAT

Pathway

133.55

CPU

t=5

PKC Pathway

Direct and the First Reaction methods.

90

and PKC systems for the Direct and the First Reaction

methods.

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Chemistry, 28, 165178.

[15]

for Systems Biology, Chapman and Hall Press/ CRC

Press.

ACKNOWLEDGEMENT

The authors would like to thank the AGEP

project of the Middle East Technical University

(Project no: BAP-08-11-2014-007) for their

support.

REFERENCES

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simulation algorithms (Under review).

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(1998). Stochastic kinetic analysis of developmental

pathway bifurcation in phage -nfected escherichia

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