Hindawi Computational and Mathematical Methods in Medicine Volume 2017, Article ID 7837109, 9 pages https://doi.org/10.1155/2017/7837109
Research Article Kalman Filtering for Genetic Regulatory Networks with Missing Values Qiongbin Lin,1 Qiuhua Liu,1 Tianyue Lai,1 and Wu Wang1,2 1
College of Electrical Engineering and Automation, Fuzhou University, Fuzhou, Fujian 350116, China Fujian Key Lab of Medical Instrument and Pharmaceutical Technology, Fuzhou, Fujian 350116, China
2
Correspondence should be addressed to Qiongbin Lin;
[email protected] Received 17 March 2017; Accepted 8 June 2017; Published 26 July 2017 Academic Editor: Konstantin Blyuss Copyright ยฉ 2017 Qiongbin Lin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The filter problem with missing value for genetic regulation networks (GRNs) is addressed, in which the noises exist in both the state dynamics and measurement equations; furthermore, the correlation between process noise and measurement noise is also taken into consideration. In order to deal with the filter problem, a class of discrete-time GRNs with missing value, noise correlation, and time delays is established. Then a new observation model is proposed to decrease the adverse effect caused by the missing value and to decouple the correlation between process noise and measurement noise in theory. Finally, a Kalman filtering is used to estimate the states of GRNs. Meanwhile, a typical example is provided to verify the effectiveness of the proposed method, and it turns out to be the case that the concentrations of mRNA and protein could be estimated accurately.
1. Introduction According to the genetic central dogma, a specific protein can be generated by a complex gene expression process (including transcription process, translation process, and other interaction process) among DNAs, RNAs, and gene products [1, 2]. To guide the gene expression correctly, each stage of the gene expression should be regulated. The regulation functions for each stage form genetic regulatory networks (GRNs). Cleary, gene expression levels can be determined by GRNs. For this, a lot of GRNs models have been built to track the concentration of mRNA and protein, like Boolean model [3, 4], Bayesian model [5โ7], differential equation model [8โ11], and statespace model [12, 13]. However, due to the uncertainties of the system, time-varying delays [14โ16] and data missing [17, 18] in real gene expression process, the measurements obtained from the sensor are usually contaminated by noise and cannot represent the true values well. Thus, a lot of filtering methods are proposed to reveal the true values. In studying the stability of genetic regulatory networks, noise disturbances are one of the main factors that cannot be ignored, and it is mainly composed of process noise and measurement noise. In order to restrain these noise
disturbances, many filtering methods like ๐ปโ filter [19] and Kalman filter [20] are proposed to obtain stable GRNs. Although process noise and measurement noise were usually taken into consideration, the correlation between process noise and measurement noise always is ignored in these methods, so it does not have the generality from this point of view. In this paper, in order to make the filtering method more representative, the correlation between process noise and measurement noise would be taken into consideration; meanwhile, the correlation will also be decoupled in theory. Generally, gene expression levels (the concentration of mRNA and protein) can be measured by the DNA microarray technology, but there are many reasons which can cause value miss like dust or scratch on the slide, inappropriate thresholds in preprocessing, insufficient resolution of the microarray, experimental errors during the laboratory processes, or image corruption [18]. So, the measured value for gene expression levels would contain a certain degree of distortion that would cause concentration value deviating from real concentration. To overcome this drawbacks, the setvalues filtering for GRNs with missing value was proposed in [17, 21]; although this method has dealt with the specific well, it did not give a detailed explanation about missing
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Computational and Mathematical Methods in Medicine Table 1: The parameter descriptions of system (1).
Parameter ๐(๐) ๐(๐) ๐ด(๐) ๐ถ(๐) ๐ต(๐) ๐ท(๐) ๐
Description The concentrations of mRNA The concentrations of protein The degradation rates of mRNA The degradation rates of protein The coupling coefficient of the genetic networks The translation rate The bounded constant which denotes the dimensionless transcriptional rate [21]
value in a detailed mathematical formula, so, in this paper, the observation model with missing value will be given; meanwhile, a Kalman filtering will also be designed to obtain stable GRNs with missing value. In this paper, an estimation problem for a class of discretetime GRNs model with time-varying delays, missing values, and correlation of noise is considered. The rest of the paper is organized as follows. In Section 2, a discrete model of genetic regulation networks is introduced; we also built observation model with missing value to give a detailed explanation about it in mathematical formula; meanwhile, the correlation between process noise and measurement noise is decoupled in theory. In Section 3, a Kalman filtering is designed to estimate the real concentrations of GRNs; meanwhile, the stability of Kalman filtering is analyzed. In the Section 4, a typical example is provided to illustrate the effectiveness of the proposed method.
Clearly, a discrete-time model of genetic regulatory networks (GRNs) can be described as follows [21โ23]:
๐ (๐ + 1) = ๐ถ (๐) ๐ (๐) + ๐ท (๐) ๐ (๐ โ ๐) ,
(1)
๐ (๐) โ ๐ (๐) โ ๐โ .
(2)
Thus, system (1) can be rewritten as
๐ (๐ + 1) = ๐ถ (๐) ๐ (๐) + ๐ท (๐) ๐ (๐ โ ๐) .
๐ (๐ + 1) = ๐ถ (๐) ๐ (๐) + ๐ท (๐) ๐ (๐ โ ๐) . In practice, the actual GRNs might be influenced by the dynamic reaction of the networks, time delays, and molecular noise. Based on system (4), discrete-time GRNs with observation equation and noises are considered: ฬ (๐) ๐ (๐) + ๐ตฬ (๐) ๐ (๐ โ ๐) ๐ (๐ + 1) = ๐ด + ๐น (๐) ๐ค (๐) ,
(5)
โ (๐) = ๐ธ (๐) ๐ (๐) + V (๐) , ๐
where ๐(๐) โ [๐(๐)๐ ๐(๐)๐ ] , โ(๐) โ R๐ is the sampled output, V(๐) is the external noise, ๐ค(๐) is the process noise, ๐น(๐) is the noise driven matrix, and ๐ธ(๐) is the observation matrix. In addition, ๐ด (๐) 0 ฬ (๐) โ [ ๐ด ], 0 ๐ถ (๐) ๐๐ ๓ตจ๓ตจ๓ตจ๓ตจ 0 ๐ต (๐) ๓ตจ ๐ตฬ (๐) โ [ ๐๐ ๓ตจ๓ตจ๓ตจ๐=๐โ ] . 0 [๐ท๐ ]
(6)
๐
๐ฅ (๐) โ [๐๐ (๐) ๐๐ (๐ โ 1) โ
โ
โ
๐๐ (๐ โ ๐)] .
(8)
๐ง (๐) = ๐ป (๐) ๐ฅ (๐) + V (๐) ,
where ๐ค(๐) and V(๐) are white, zero-mean, correlated noises; furthermore, [ [ [ [ ฮฆ (๐) = [ [ [ [ [
ฬ (๐) 0 โ
โ
โ
0 ๐ตฬ (๐) ๐ด ๐ผ๐
0 โ
โ
โ
0
0
๐ผ๐ โ
โ
โ
0
.. .
.. . . d ..
] 0 ] ] 0 ] ] ] .. ] ] . ]
[ 0
0 โ
โ
โ
๐ผ๐
0 ](๐ร๐)ร(๐ร๐) ๐
(3)
(7)
Using the new state variable (7) gives
๐ค (๐) = [๐ค๐ (๐) 0 โ
โ
โ
0](๐ร๐)ร1 ,
๐ (๐ + 1) = ๐ด (๐) ๐ (๐) + ๐ต (๐) [๐ (๐ (๐ โ ๐)) โ ๐ (๐โ )] ,
๐๐ ๓ตจ๓ตจ๓ตจ๓ตจ ๐ (๐ โ ๐) , ๓ตจ ๐๐ ๓ตจ๓ตจ๓ตจ๐=๐โ (4)
๐ฅ (๐ + 1) = ฮฆ (๐) ๐ฅ (๐) + ฮ (๐) ๐ค (๐) ,
where the descriptions of systemโs parameters are shown in Table 1. In addition, ๐(โ
) โ R is a monotonic function in Hill form, which represents the feedback regulation of the protein. Here, ๐๐ (๐ฅ) = (๐ฅ/๐ฝ๐ )๐ป๐ /(1 + (๐ฅ/๐ฝ๐ )๐ป๐ ), where ๐ป๐ is the Hill coefficient and ๐ฝ๐ is positive constant. Let ๐โ and ๐โ denote the equilibrium points of system (1); define ๐ (๐) โ ๐ (๐) โ ๐โ ,
๐ (๐ + 1) = ๐ด (๐) ๐ (๐) + ๐ต (๐)
Then, in order to solve the time-delay of the system (5), a new state vector is defined as follows:
2. Problem Formulation
๐ (๐ + 1) = ๐ด (๐) ๐ (๐) + ๐ต (๐) ๐ (๐ (๐ โ ๐)) + ๐,
Based on the first-order Taylor expansion, ๐(๐(๐ โ ๐)) โ ๐(๐โ ) = (๐๐/๐๐)|๐=๐โ ๐(๐โ๐), system (3) can be expressed as
V (๐) = V (๐) , ฮ (๐) = diag (๐น (๐) 0 โ
โ
โ
0)(๐ร๐)ร(๐ร๐) .
, (9)
Computational and Mathematical Methods in Medicine
3
As for the measurements model with missing value, it can be expressed as that measurement values lost at a certain probability, so, the measurements model with missing value can be described as follows [24]: ๐ฆ (๐) = ๐ (๐) ๐ง (๐) + (1 โ ๐ (๐)) ๐ฆ (๐ โ 1) ,
(10)
where ๐ฆ(๐) is received by the estimator, the initial state ๐ฅ(0) is independent of ๐(๐), ๐ค(๐), and V(๐) and satisfies the fact that E[๐ฅ(0)] = ๐0 , E[(๐ฅ(0) โ ๐)(๐ฅ(0) โ ๐)๐ ] = ๐0 , and ๐(๐) โ R obey the Bernoulli distribution, and it is uncorrelated with other random variables. There are two basic properties about ๐(๐): Prob {๐ (๐) = 1} = E {๐ (๐)} fl ๐ผ (๐) , Prob {๐ (๐) = 0} = 1 โ E {๐ (๐)} fl 1 โ ๐ผ (๐) ,
ฬ (๐) ๐ (๐) + ๐ (๐) V (๐) , ๐ฆ (๐) = ๐ป
๐๐ (๐) = E [
๐ค (๐) ๐ค๐ (๐) ๐ค (๐) V๐ (๐)
]
V (๐) ๐ค๐ (๐) V (๐) ๐ค๐ (๐)
๐๐ค (๐) ๐1 (๐) ], =[ ๐ ๐1 (๐) ๐V (๐) ๐ค (๐) ๐ ๐ค (๐) V๐ (๐) ๐ (๐) = E [ ] V (๐) = E [ ] V (๐) V (๐) V๐ (๐) =[
(15)
๐1๐ (๐)
] ๐V (๐)
(11)
where 0 โค ๐ผ(๐) โค 1. If ๐ผ(๐) = 0, it means the measurements value is lost at ๐, and there is no missing value with ๐ผ(๐) = 1. More properties about the distribution of ๐(๐) are showed in [24]. Then, substituting the observation equation of system (8) into (10), thus, a discrete-time model of GRNs with the observation equation with missing value is established as follows: ฬ (๐) ๐ (๐ก) + ฮฬ (๐) ๐ (๐) , ๐ (๐ + 1) = ฮฆ
where
(12)
and where ๐1 = ๐ค(๐)V๐ (๐). ฬ ฬ ฬ can be To simplify the calculation, ฮฆ(๐), ฮ(๐), and ๐ป(๐) broken down into some simple separations as follows: ฮฆ (๐) 0 ฬ (๐) = [ ฮฆ ] ๐ (๐) ๐ป (๐) (1 โ ๐ (๐)) ๐ผ๐ ฮฆ (๐) 0 =[ ] ๐ผ (๐) ๐ป (๐) (1 โ ๐ผ (๐)) ๐ผ๐ + (๐ (๐) โ ๐ผ (๐)) [
0
0
๐ป (๐ก) โ๐ผ๐
]
โ ฮฆ0 (๐) + (๐ (๐) โ ๐ผ (๐)) ฮฆ1 (๐) ,
where
ฮ (๐) 0 ฮฬ (๐) = [ ] 0 ๐ (๐) ๐ผ๐
๐ฅ (๐)
๐ (๐) = [ ], ๐ฆ (๐ โ 1) ๐ (๐) = [
๐ค (๐ก) V (๐ก)
ฮ (๐) 0 0 0 =[ ] + (๐ (๐) โ ๐ผ (๐)) [ ] 0 ๐ผ (๐) ๐ผ๐ 0 ๐ผ๐
],
ฮฆ (๐)
0
ฬ (๐) = [ ฮฆ ], ๐ (๐) ๐ป (๐) (1 โ ๐ (๐)) ๐ผ๐ ฮฬ (๐) = [
(16)
ฮ (๐)
0
0
๐ (๐) ๐ผ๐
(13)
+ (๐ (๐) โ ๐ผ (๐)) [๐ป (๐ก) โ๐ผ๐ ]
ฬ (๐) = [๐ (๐) ๐ป (๐) (1 โ ๐ (๐)) ๐ผ๐ ] . ๐ป
โ ๐ป0 (๐) + (๐ (๐) โ ๐ผ (๐)) ๐ป1 (๐) .
Let ๐๐ค (๐) denote the autocovariance matrix of ๐ค(๐), ๐V (๐) denote the autocovariance matrix of V(๐), and ๐(๐) denote the cross-covariance matrix of ๐ค(๐) and V(๐). For (12), there is some statistical information:
V (๐) โผ N (0, ๐V (๐)) ,
ฬ (๐) = [๐ (๐) ๐ป (๐) (1 โ ๐ (๐)) ๐ผ๐ ] ๐ป = [๐ผ (๐) ๐ป (๐) (1 โ ๐ผ (๐)) ๐ผ๐ ]
],
๐ (๐) โผ N (0, ๐๐ (๐)) ,
โ ฮ0 (๐) + (๐ (๐) โ ๐ผ (๐)) ฮ1 (๐) ,
(14)
Since the process noises of this system are correlated with the observation noises, to decouple the relevance about ฬ ๐ค(๐) and V(๐), according to system (12), ๐ฆ(๐ก) โ ๐ป(๐)๐(๐) โ ๐(๐)V(๐) = 0; obviously, ฬ (๐) ๐ (๐) โ ๐ (๐) V (๐)) = 0 ๐ฝ (๐) (๐ฆ (๐ก) โ ๐ป
(17)
4
Computational and Mathematical Methods in Medicine
and then adding (17) to the state equation of (12), we have ฬ (๐) ๐ (๐) + ฮฬ (๐) ๐ (๐) ๐ (๐ + 1) = ฮฆ ฬ (๐) ๐ (๐) โ ๐ (๐) V (๐)) + ๐ฝ (๐) (๐ฆ (๐ก) โ ๐ป ฬ (๐) โ ๐ฝ (๐) ๐ป ฬ (๐)) ๐ (๐) + ๐ฝ (๐) ๐ฆ (๐) = (ฮฆ
(18)
ฬ (๐ + 1 | ๐) = ฮฆ ฬ (๐) ๐ ฬ (๐ | ๐) ๐
+ ฮฬ (๐) ๐ (๐) โ ๐ฝ (๐) ๐ (๐) V (๐) , ๐ร๐
where ๐ฝ(๐) โ ๐
process noises
the filtering error ๐ is calculated, and then the Kalman gain ๐พ can be obtained by minimizing the covariance matrix of the filtering error ๐; at last, the recursion of the filtering error ๐ is calculated; thus, the design of Kalman filtering is completed. According to system (12) and (18), the state prediction equation can be calculated as
ฬ (๐) ๐ ฬ (๐ | ๐)] + ๐ฝ (๐) [๐ฆ (๐) โ ๐ป
. Clearly, the last two terms in (18) are the
(23)
and the measurement update equation is
ฬ (๐) โ ๐ฝ (๐) ๐ป ฬ (๐) , ฮฆ (๐) = ฮฆ โ
๐ (๐) = ฮฬ (๐) ๐ (๐) โ ๐ฝ (๐) ๐ (๐) V (๐) . โ
(19)
E [๐โ (๐) V๐ (๐)] = ฮ0 (๐) ๐1 (๐) โ ๐ผ (๐) ๐ฝ (๐) ๐V (๐) . (20) Let E[๐โ (๐)V๐ (๐)] = 0, and then ๐ฝ(๐) is (21)
Clearly, if ๐ฝ(๐) is chosen as (21), ๐โ (๐) and V(๐) are uncorrelated. Secondly, we discuss ๐โ (๐),
ฬ (๐ + 1 | ๐ + 1) ๐ ฬ (๐ + 1 | ๐) =๐
(25)
+ ๐พ (๐ + 1) [๐ฆ (๐ + 1) โ ๐ฆฬ (๐ + 1)] , where ๐พ(๐ + 1) denotes the Kalman gain. Then, the posterior estimation error can be computed as follows: ฬ (๐ + 1 | ๐ + 1) ๐ (๐ + 1 | ๐ + 1) = ๐ (๐ + 1) โ ๐ ฬ (๐ + 1 | ๐) โ ๐พ (๐ + 1) = ๐ (๐ + 1) โ ๐ ฬ (๐ + 1) ๐ (๐ + 1) + ๐ (๐ + 1) V (๐ + 1) โ
[๐ป
E [๐โ (๐)] = ฮฬ (๐) E [๐ (๐)] โ ๐ผ (๐) ๐ฝ (๐) E [V (๐)]
ฬ (๐ + 1) ๐ ฬ (๐ + 1 | ๐)] = [๐ผ โ๐ป
= 0, ๐
(24)
So, the optimal state estimation is
Since Kalman filtering requires that the process noise and the measurement noise must be white uncorrelated Gaussian noise, then consider the correlation between process noise and measurement noise firstly:
๐ฝ (๐) = ๐ผโ1 (๐) ฮ0 (๐) ๐1 (๐) ๐Vโ1 .
ฬ (๐ + 1) ๐ ฬ (๐ + 1 | ๐) . ๐ฆฬ (๐ + 1) = ๐ป
๐
E [๐โ (๐) ๐โ (๐ก)] = cov [๐โ (๐) , ๐โ (๐ก)]
(26)
โ ๐พ (๐ + 1) ๐ป0 (๐ + 1)] ๐ (๐ + 1 | ๐) โ (๐ (๐ + 1) โ ๐ผ (๐ + 1)) ๐พ (๐ + 1) ๐ป1 (๐ + 1) ๐ (๐ + 1 | ๐) โ ๐ (๐
= var [๐โ (๐)] ๐ฟ๐๐ก ,
+ 1) ๐พ (๐ + 1) V (๐ + 1)
var [๐โ (๐)] = ๐โ = ฮ0 ๐๐ค ฮ0๐ โ ๐ผ (๐) ฮ0 ๐ (๐) ๐ฝ๐ (๐)
(22)
+ ๐ผ (๐) (1 โ ๐ผ (๐)) ฮ1 (๐) ๐๐ค ฮ1๐ (๐) ๐
โ ๐ผ (๐) (1 โ ๐ผ (๐)) ฮ1 (๐) ๐ (๐) ๐ฝ (๐) โ ๐ผ (๐) ๐ฝ (๐) ๐๐ (๐) ฮ0๐ (๐) ๐
and the covariance matrix of estimation error can be described as ๐ (๐ + 1 | ๐ + 1) = E [๐ (๐ + 1 | ๐ + 1) ๐๐ (๐ + 1 | ๐ + 1)] . Substituting (26) into (27) gives
๐
โ ๐ผ (๐) (1 โ ๐ผ (๐)) ๐ฝ (๐) ๐
(๐) ฮ1๐ (๐)
๐
+ ๐ผ (๐) ๐ฝ (๐) ๐V ๐ฝ (๐) so if ๐ฝ(๐) = ๐ผโ1 (๐)ฮ0 (๐)๐1 (๐)๐Vโ1 , ๐โ (๐) is a white, zeromean noise.
๐ (๐ + 1 | ๐ + 1) = E [๐ (๐ + 1 | ๐ + 1) ๐๐ (๐ + 1 | ๐ + 1)] = [๐ผ โ ๐พ (๐ + 1) ๐ป0 (๐ + 1)] ๐ (๐ + 1 | ๐) ๐
3. Main Results In this section, the Kalman filtering is designed for obtaining the minimum variance estimation. Firstly, the expression of
โ
[๐ผ โ ๐พ (๐ + 1) ๐ป0 (๐ + 1)] + ๐ผ (๐ + 1) โ
(1 โ ๐ผ (๐ + 1)) ๐พ (๐ + 1) ๐ป1 (๐ + 1) ๐ (๐ + 1 | ๐) โ
๐ป1๐ (๐ + 1) + ๐ผ (๐ + 1) ๐พ (๐ + 1) ๐V ๐พ๐ (๐ + 1)
(27)
Computational and Mathematical Methods in Medicine
5
= ๐ (๐ + 1 | ๐) โ ๐พ (๐ + 1) ๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐)
Furthermore, ๐พ (๐ + 1) = ๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1) [๐ป0 (๐ + 1)
๐
โ ๐ (๐ + 1 | ๐) [๐พ (๐ + 1) ๐ป0 (๐ + 1)] + ๐พ (๐ + 1) โ
[๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1)] + ๐ผ (๐)
โ
๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1) + ๐ผ (๐) (1 โ ๐ผ (๐))
โ
(1 โ ๐ผ (๐)) ๐ป1 (๐ + 1) ๐ (๐ + 1) ๐ป1๐ (๐ + 1)
โ
๐ป1 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป1๐ (๐ + 1) + ๐ผ (๐ + 1)
+ ๐ผ (๐ + 1) ๐V (๐ + 1) ๐พ๐ (๐ + 1) .
โ
๐V (๐ + 1)] ,
โ1
(28)
๐ (๐ + 1 | ๐ + 1) = ๐ (๐ + 1 | ๐) โ ๐ (๐ + 1 | ๐) ๐ป0๐ (๐
Then, ๐ฟ is designed to minimize ๐(๐ + 1/๐ + 1), and
+ 1) [๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1) + ๐ผ (๐)
๐ฟ = ๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1)
โ
(1 โ ๐ผ (๐)) ๐ป1 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป1๐ (๐ + 1)
โ
[๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1) + ๐ผ (๐) (1 โ ๐ผ (๐)) ๐ป1 (๐ + 1) ๐ (๐ + 1) ๐ป1๐ (๐ + 1)
โ1
+ ๐ผ (๐ + 1) ๐V (๐ + 1)] ๐ป0 (๐ + 1) ๐๐ (๐ + 1 | ๐) .
(29)
ฬ According to (18) and (25), the estimation error ๐(๐+1/๐) can be obtained
โ1
+ ๐ผ (๐ + 1) ๐V (๐ + 1)] ๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐) ;
ฬ (๐ + 1 | ๐) = ๐ (๐ + 1) โ ๐ ฬ (๐ + 1 | ๐) ๐
thus, ๐(๐ + 1/๐ + 1) can be rewritten as
ฬ (๐) ๐ (๐) โ ๐ฝ (๐) ๐ป ฬ (๐) ๐ (๐) + ๐ฝ (๐) ๐ฆ (๐) =ฮฆ
๐ (๐ + 1 | ๐ + 1) = ๐ (๐ + 1 | ๐ + 1) โ ๐ฟ + ๐ฟ = ๐ (๐ + 1 | ๐) โ ๐ (๐ + 1 |
๐) ๐ป0๐ (๐
(33)
ฬ (๐) ๐ ฬ (๐ | ๐) + ๐โ โ ฮฆ
+ 1) [๐ป0 (๐ + 1)
โ
๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1) + ๐ผ (๐) (1 โ ๐ผ (๐)) โ
๐ป1 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป1๐ (๐ + 1) + ๐ผ (๐ + 1)
ฬ (๐) = [ฮฆ0 (๐) โ ๐ฝ (๐) ๐ป0 (๐)] ๐
โ1
ฬ (๐ + 1 | ๐) ๐ ฬ๐ (๐ + 1 | ๐)] ๐ (๐ + 1 | ๐) = E [๐ = [ฮฆ0 (๐) โ ๐ฝ (๐) ๐ป0 (๐)] ๐ (๐ | ๐)
where
๐
โ
[ฮฆ0 (๐) โ ๐ฝ (๐) ๐ป0 (๐)] + (๐ (๐) โ ๐ผ (๐))
๐ด = ๐ (๐ + 1) ๐ป0๐ (๐) ,
๐
โ
[ฮฆ1 (๐) โ ๐ฝ (๐) ๐ป1 (๐)] + ๐โ .
โ ๐ผ (๐)) ๐ป1 (๐ + 1) ๐ (๐ + 1) ๐ป1๐ (๐ + 1) + ๐ผ (๐ + 1) (31)
๐ถ = ๐พ (๐ + 1) [๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1) + ๐ผ (๐) (1 โ ๐ผ (๐)) ๐ป1 (๐ + 1) ๐ (๐ + 1 | ๐)
The linear optimal filtering, (23), (25), (33), and (35), is uniformly asymptotically stable when the linear discretetime-varying stochastic system (12) is uniformly controllable and observable [24].
4. Numerical Example
โ
๐ป1๐ (๐ + 1) + ๐ผ (๐ + 1) ๐V (๐ + 1)] . Let ๐ด = ๐ถ; the covariance matrix of estimation error is minimized. Thus ๐ (๐ + 1) ๐ป0๐ (๐) = ๐พ (๐ + 1) [๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐)
โ
๐ (๐ + 1 | ๐) ๐ป1๐ (๐ + 1) + ๐ผ (๐ + 1) ๐V (๐ + 1)] .
(35)
โ
[ฮฆ1 (๐) โ ๐ฝ (๐) ๐ป1 (๐)] ๐ (๐ | ๐)
๐ต = ๐ป0 (๐ + 1) ๐ (๐ + 1 | ๐) ๐ป0๐ (๐ + 1) + ๐ผ (๐) (1
โ
๐ป0๐ (๐ + 1) + ๐ผ (๐) (1 โ ๐ผ (๐)) ๐ป1 (๐ + 1)
+ ๐โ ; thus
โ
๐ตโ1 (๐ด โ ๐ถ)๐ ,
โ
๐V (๐ + 1) ,
ฬ (๐) + (๐ (๐) โ ๐ผ (๐)) [ฮฆ1 (๐) โ ๐ฝ (๐) ๐ป1 (๐)] ๐
(30)
โ
๐V (๐ + 1)] ๐ป0 (๐ + 1) ๐๐ (๐ + 1 | ๐) + (๐ด โ ๐ถ)
(34)
(32)
In this section, an example will be provided to show the effectiveness of the proposed method. In Escherichia coli [25], the dynamics of the networks have been experimentally studied, and the model of 3-gene repressilator is given as follows: ๐ผ๐ , ๐ฬ ๐ = โ๐๐ + 1 + ๐๐๐ป (36) ฬ ๐๐ = โ๐ฝ๐ ๐๐ + ๐พ๐ ๐๐ ,
6
Computational and Mathematical Methods in Medicine
where ๐๐ denotes the concentrations of three mRNA and ๐๐ denotes the concentrations of three repressor-proteins, ๐ผ๐ is the feedback regulation coefficient, ๐ฝ๐ denotes the ratio of the protein decay rate to the mRNA, and ๐ป is the Hill coefficient, ๐ = lacl, tetR, cl; ๐ = cl, lacl, tetR. The discrete-time GRNs model based on the method in [26] can be obtained as
1.2
1+
๐ผ๐ ๐ป ๐๐ (๐
โ ๐)
, (37)
1 mRNA concentration
๐๐ (๐ + 1) = ๐โโ ๐๐ (๐) + (1 โ ๐โโ )
1.1
0.9 0.8 0.7 0.6 0.5 0.4
๐๐ (๐ + 1) = ๐โ๐ฝ๐ โ ๐๐ (๐) + (1 โ ๐โ๐พ๐ โ ) ๐๐ (๐ โ ๐) .
0.3
Let โ = 1, the Hill coefficient ๐ป = 2, the time-delay ๐ = 1, ๐(๐ฅ) = ๐ฅ2 /(1 + ๐ฅ2 ), and the other parameters are taken as follows:
0.2
0
10
15 Time t
20
25
30
M๏ผฆ๏ผ๏ผ๏ผฆ M๏ผฎ๏ผ๏ผฎ๏ผ M๏ผ๏ผฆ
๐ผ1 = 1.2656, ๐ผ2 = 0.6328,
Figure 1: The concentration of mRNA with ๐ค(๐ก) = 0.
๐ผ3 = 1.4238,
0.7
๐ฝ1 = ๐ฝ2 = ๐ฝ3 = 0.6703,
(38)
๐พ1 = 0.6, ๐พ3 = 0.5, ๐น = diag (0.2, 0.3, 0.2, 0.3, 0.2, 0.4) . So, the parameters of system (4) can be obtained: [ ๐ด=[
0.3679
0
0
0
0.3679
0
[
0
0
0 [โ๐ผ ๐ต = (1 โ ๐ ) [ 2 โโ
[ 0 ๐ฝ1 0 0 [0 ๐ฝ 0] ๐ถ=[ ], 2
0.5 0.4 0.3 0.2 0.1
] ],
0
0.3679] 0
0.6 Protein concentration
๐พ2 = 0.4,
[0
5
โ๐ผ1
0
0 ] ],
โ๐ผ3
0 ]
0
5
10
15 Time t
20
25
30
N๏ผ๏ผฆ N๏ผฆ๏ผ๏ผ๏ผฆ N๏ผฎ๏ผ๏ผฎ๏ผ
(39)
0 ๐ฝ3 ]
๐พ1 0 0 [0 ๐พ 0] ๐ท=[ ]. 2 [ 0 0 ๐พ3 ] According to system (3), we can get that the mRNA and proteins will adjust each other; they will also degrade along with the time, so the GRNs would tend to be equilibrium if there are no noise disturbances, and the unique equilibrium can be checked easily when ๐ค(๐ก) = 0; thus, the systemโs states ๐(๐) and ๐(๐) with ๐ค(๐ก) = 0 are shown in Figures 1 and 2.
Figure 2: The concentration of protein with ๐ค(๐ก) = 0.
From Figures 1 and 2, we can get that the states of the GRNs stay at a point stably, so the equilibrium can be calculated; that is, ๐โ = (0.6695, 0.3444, 0.8833) , ๐โ = (0.4016, 0.1378, 0.4416) .
(40)
Now, check the states of system (37) under the excitation of external disturbances; let the initial states be ๐ (โ1) = [0.8695, 0.4444, 0.6833]๐ , ๐ (0) = [0.7695, 0.3444, 0.7833]๐ ,
Computational and Mathematical Methods in Medicine
7 1.1 1.05 1 The concentration of M๏ผ๏ผฆ
The concentration of M๏ผฆ๏ผ๏ผ๏ผฆ
0.85 0.8 0.75 0.7
0.95 0.9 0.85 0.8 0.75 0.7
0.65
0.65 0.6
0
5
10
15 Time t
20
25
0.6
30
0
The estimate of M๏ผฆ๏ผ๏ผ๏ผฆ The equilibrium state of M๏ผฆ๏ผ๏ผ๏ผฆ (0.6695)
5
10
15 Time t
20
25
30
The estimate of M๏ผ๏ผฆ The equilibrium state of M๏ผ๏ผฆ (0.8833)
Figure 3: The trajectory of concentration of ๐lacl (missing rate 10%).
Figure 5: The trajectory of concentration of ๐cl (missing rate 10%). 0.6 0.55
0.5
The concentration of N๏ผ๏ผฆ
The concentration of M๏ผฎ๏ผ๏ผฎ๏ผ
0.55
0.45 0.4 0.35 0.3
0.45 0.4 0.35
0.25 0.2
0.5
0
5
10
15 Time t
20
25
30
The estimate of M๏ผฎ๏ผ๏ผฎ๏ผ The equilibrium state of M๏ผฎ๏ผ๏ผฎ๏ผ (0.3444)
0.3
0
5
10
15 Time t
20
25
30
The estimate of N๏ผ๏ผฆ The equilibrium state of N๏ผ๏ผฆ (0.4016)
Figure 4: The trajectory of concentration of ๐tetR (missing rate 10%).
๐ (โ1) = [0.5016, 0.0378, 0.7416]๐ , ๐ (0) = [0.4016, 0.2378, 0.6416]๐ , (41) and ๐๐ค = 12, ๐V = 36, and E[๐ค๐ V๐๐ ] = 1.2 (where ๐ = 1, 2, . . . , ๐, ๐ = 1, 2, . . . , ๐); the estimate values of the concentration of mRNA and proteins are shown in Figures 3โ8. According to Figures 3โ8, the blue lines show the estimate values of mRNAs and protein, and the green lines illustrate the equilibrium of GRNs; we can get that the concentration of mRNAs and protein tends to the equilibrium well under the excitation of external disturbances, so, the Kalman filtering
Figure 6: The trajectory of concentration of ๐cl (missing rate 10%).
designed in this paper is effective for the GRNs with missing value and noise correlation. In order to test out the influence of the missing rate, the experiments with four missing rates of 10%, 20%, 30%, and 50% are carried out. In addition, the normalized root mean squared error (NRMSE) [27] is used to indicate the influence level of the missing rate, and the NRMSE is defined as NRMSE = โ
2
mean (๐ฅฬ๐ โ ๐ฅ๐ ) . mean ๐ฅ๐2
(42)
So, the NRMSE are shown in Table 2. Compared with the NRMSE obtained by set-membership filtering given in [17], in spite of the missing rate increases from 10% to 30%, the NRMSE listed in Table 2 increases
8
Computational and Mathematical Methods in Medicine 0.4
Table 2: The average values of NRMSE.
The concentration of N๏ผฆ๏ผ๏ผ๏ผฆ
0.35
Method
0.3
10% 20% 30% 50%
0.25 0.2
Kalman 0.5389 0.5785 0.5800 0.6824
Method Set-membership [17] 0.4125 0.7074 โ 0.8792
0.15 0.1 0.05 0
0
5
10
15 Time t
20
25
30
The estimate of N๏ผฆ๏ผ๏ผ๏ผฆ The equilibrium state of N๏ผฆ๏ผ๏ผ๏ผฆ (0.1378)
Figure 7: The trajectory of concentration of ๐lacl (missing rate 10%).
process noise and measurement noise is decoupled in theory. Finally, a Kalman filtering is designed to obtain stable GRNs; meanwhile, the simulation result shows that the method proposed in this paper is effective for the GRNs with missing value, and compared with the set-membership filtering, the Kalman filtering has a better performance when the missing rate stays at a high level.
Conflicts of Interest The authors declare that they have no conflicts of interest.
References
The concentration of N๏ผฎ๏ผ๏ผฎ๏ผ
0.8 0.7 0.6 0.5 0.4 0.3 0.2
0
5
10
15 Time t
20
25
30
The estimate of N๏ผฎ๏ผ๏ผฎ๏ผ The equilibrium state of N๏ผฎ๏ผ๏ผฎ๏ผ (0.4416)
Figure 8: The trajectory of concentration of ๐tetR (missing rate 10%).
slightly; however, the NRMSE increases greatly with the increasing of the missing rate in [17]. Moreover, at the low level of missing rate, the set-membership filtering has a better performance, but at the high level of missing rate, the method proposed in this paper is more appropriate than the setmembership filtering, and the cut-off point roughly equals 14.66%. Thus, it shows that the proposed method is more effective for the filtering problem for GRNs.
5. Conclusion In this paper, a discrete model of genetic regulation networks is introduced; we also built an observation model with missing value to give a detailed explanation about it in mathematical formula; meanwhile, the correlation between
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