Type 2 diabetes (T2D) is a major global health problem often caused by the inability of pancreatic islets to compensate for the high insulin demand due to apoptosis. However, the complex mechanisms underlying the activation of apoptosis and its counter process, anti-apoptosis, during T2D remain unclear. In this study, we employed bioinformatics and systems biology approaches to understand the anti-apoptosis-associated gene expression and the biological network in the pancreatic islets of T2D mice. First, gene expression data from four peripheral tissues (islets, liver, muscle and adipose) were used to identify differentially expressed genes (DEGs) in T2D compared to non-T2D mouse strains. Our comparative analysis revealed that Gm2036 is upregulated across all four tissues in T2D and is functionally associated with increased cytosolic Ca2+ levels, which may alter the signal transduction pathways controlling metabolic processes. Next, our study focused on islets and performed functional enrichment analysis, which revealed that upregulated genes are significantly associated with sucrose and fructose metabolic processes, as well as negative regulation of neuron apoptosis. Using the Ingenuity Pathway Analysis (IPA) tool of QIAGEN, gene regulatory networks and their biological effects were analyzed, which revealed that glucose is associated with the underlying change in gene expression in the islets of T2D; and an activated gene regulatory network—containing upregulated CCK, ATF3, JUNB, NR4A1, GAST and downregulated DPP4—is possibly inhibiting apoptosis of islets and β-cells in T2D. Our computational-based study has identified a putative regulatory network that may facilitate the survival of pancreatic islets in T2D; however, further validation in a larger sample size is needed. Our results provide valuable insights into the underlying mechanisms of T2D and may offer potential targets for developing more efficacious treatments.
Citation: Firoz Ahmed. Deciphering the gene regulatory network associated with anti-apoptosis in the pancreatic islets of type 2 diabetes mice using computational approaches[J]. AIMS Bioengineering, 2023, 10(2): 111-140. doi: 10.3934/bioeng.2023009
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Abstract
Type 2 diabetes (T2D) is a major global health problem often caused by the inability of pancreatic islets to compensate for the high insulin demand due to apoptosis. However, the complex mechanisms underlying the activation of apoptosis and its counter process, anti-apoptosis, during T2D remain unclear. In this study, we employed bioinformatics and systems biology approaches to understand the anti-apoptosis-associated gene expression and the biological network in the pancreatic islets of T2D mice. First, gene expression data from four peripheral tissues (islets, liver, muscle and adipose) were used to identify differentially expressed genes (DEGs) in T2D compared to non-T2D mouse strains. Our comparative analysis revealed that Gm2036 is upregulated across all four tissues in T2D and is functionally associated with increased cytosolic Ca2+ levels, which may alter the signal transduction pathways controlling metabolic processes. Next, our study focused on islets and performed functional enrichment analysis, which revealed that upregulated genes are significantly associated with sucrose and fructose metabolic processes, as well as negative regulation of neuron apoptosis. Using the Ingenuity Pathway Analysis (IPA) tool of QIAGEN, gene regulatory networks and their biological effects were analyzed, which revealed that glucose is associated with the underlying change in gene expression in the islets of T2D; and an activated gene regulatory network—containing upregulated CCK, ATF3, JUNB, NR4A1, GAST and downregulated DPP4—is possibly inhibiting apoptosis of islets and β-cells in T2D. Our computational-based study has identified a putative regulatory network that may facilitate the survival of pancreatic islets in T2D; however, further validation in a larger sample size is needed. Our results provide valuable insights into the underlying mechanisms of T2D and may offer potential targets for developing more efficacious treatments.
1.
Introduction
The inference of the stress-strength parameter R=P(Y<X) is an interesting topic in reliability analysis. The stress Y and the strength X are considered to be random variables. Let X represents the barrier's fire resistance, and Y represents the severity of the fire to which the barrier is exposed. If a unit's strength exceeds the stress applied to it, it works in the simplest stress-strength paradigm. Several authors have studied the reliability estimate of a single component stress-strength version using various lifetime distributions for the stress-strength random variate. The reliability and estimation of X and Y have been investigated under various distributional assumptions. There is a large literature on estimating R for various stress-strength distributions under various situations. For more examples see: Ghitany et al. [1], Chen and Cheng [2], Rezaei et al. [3] and Sharma [4], where the inference of reliability was performed using complete data as examples. The estimation of R under various filtering schemes was established by Genç [5], Krishna et al. [6] and Babayi and Khorram [7]. The inference for R based on upper or lower record data was introduced by Nadar and Kızılaslan [8], Tripathi et al.[9] and Asgharzadeh et al. [10]. Under ranked set sampling data, Akgül and Şenoğlu [11], Akgül et al. [12,13] and Safariyan et al. [14] investigated the R estimator. Al-Babtain et al. [15] introduced R estimation of stress-strength model for power-modified Lindley distribution. Sabry et al. [16] obtained stress-strength model and reliability estimation for extension of the exponential distribution. Yousef and Almetwally [17] obtained multi stress-strength R based on progressive first failure for Kumaraswamy model. Rezaei et al. [18] discussed estimation of P[Y<X] for generalized Pareto distribution. Kundu and Gupta [19] estimated P[Y<X] for Weibull distributions. Jose [20] discussed Estimation of stress-strength reliability using discrete phase type distribution. Almetwally et al. [21] discussed optimal plan of multi-stress-strength reliability Bayesian and non-Bayesian methods for the alpha power exponential model using progressive first failure. Kotz et al. [22], added a significant literature on the topic up to the year 2003, it can be consulted for more information. In all the previous studies there was a single component in the model, while in our proposed paper we are considering a multi-component system.
A multi-component system refers to a system with more than one component. This system, which is made up of k independent and identical strength components, operates if s(1≤s≤k) or more of the components operate at the same time. The system is subjected to stress Y in its operating environment. The component's strengths, or the minimal stress required to create failure, are random variables with a distribution function that is independent and identically distributed. The s-out-of-k: G system corresponds to this model. The s-out-of-k system is used in a variety of industrial and military systems.
In a multi-component system with k components, each component has independent and identically distributed (iid) random strengths X1,X2,...,Xk and each component is stressed randomly Y. The system would survive if and only if the strengths were greater than the stresses by at least s out of k,(1≤s≤k). Let Y,X1,X2,...,Xk be independent random variables, with G(y) being the continuous cumulative density function (cdf) of Y and F(x) being the common continuous cdf of X1,X2,...,Xk. Bhattacharyya and Johnson [23] introduced the reliability in a multi-component stress-strength (MSS) model, which is given by
Although complete sample cases have been used to derive statistical inference on multi-component stress-strength models in the reliability literature, this subject has received little attention under censored data, particularly progressive Type-II censored sample. The following sources are closely relevant to the structure of our research.
Kohansal [24] recently discussed estimating dependability in a multi-component stress-strength model, where data are observed using progressive Type-II censoring for the Kumaraswamy distribution. For the general class of inverse exponentiated distributions, Kizilaslan [25] studied the classical and Bayesian estimate of reliability in a multi-component stress-strength model based on complete data. Gunasekera [26] evaluated the reliability of a multi-component system using progressively Type-II censored sample with uniformly random removals. When the common parameter is known, the author obtains different interval inferences. Estimation is evaluated in the cases in which the common parameter is either known or unknown. Gunasekera [26] performed inference for known common parameter cases. In the Bayesian situation, we develop a uniformly-minimum-variance-unbiased estimator and use the Tierney-Kadane approximation technique. It should be noted that Gunasekera [26] did not consider the case of an unknown common parameter.
Progressive Type-II censoring is commonly used in life-testing trials to analyze data under time and cost restrictions. Type-I and Type-II are the two most common censoring techniques. When using Type-I censoring, a test is almost finished at a specific time, however when using Type-II censoring, the test is finished after a certain amount of failure times have been logged. These censoring systems prevent live units from being removed between studies. The following is a description of the progressive Type II censoring scheme. On the life test, the experimenter first arranges N independent and identical units. When the first failure occurs, say at t(1),r1 units are eliminated at random from the remaining N−1 surviving units. When the second failure occurs at t(2),r2 units are eliminated at random from the remaining N−r1−2 surviving units. When the nth failure occurs at time tn, the experiment ends, and the rn=N−n−∑n−1i=1ri surviving units are eliminated from the test. For various uses of this censoring in lifespan analysis, see Balakrishnan and Aggarwala [27] and Balakrishnan and Cramer [28]. For some useful implications on this censoring scheme, see Raqab and Madi [29], Wu et al. [30] and Rastogi and Tripathi [31].
In this study, we attempt to estimate Rs,k when the underlying distribution is the power Lomax distribution (POLO). According to Rady et al. [32], the power Lomax POLO distribution is obtained by the power transformation X=Y1β, where the random variable X has pdf in Eq (1.2). The pdf of the POLO distribution is defined by
f(x)=αβλxβ−1(1+xβλ)−α−1.
(1.2)
The corresponding cumulative distribution function (CDF) and survival function of POLO distribution are given by
F(x)=1−(1+xβλ)−α
(1.3)
and
S(x)=(1+xβλ)−α,
(1.4)
where α and β are shape parameters and λis a scale parameter.
Due to physical constraints in these sectors, such as limited power supply, maintenance resources, and/or system design life, we suggest the POLO distribution for modeling reliability and life-testing data sets. The survival function studies the possibility of breakdowns of organisms, technical units, and other systems failing beyond a certain point in time. The hazard rate is used to measure a unit's lifetime over the duration of its lifetime distribution. The hazard rate (HRF) is a significant criterion for determining lifetime distributions since it measures the probability of failing or dying based on the age attained.
When both stress and strength follow the POLO distribution, the major goal of this study is to estimate Rs,k using both classical and Bayesian techniques. This paper studies the feasibility of estimating Rs,k by using maximum likelihood under progressive Type-II censoring and constructing an asymptotic confidence interval when all the parameters are unknown, these are discussed in Section 1. In Section 2, the maximum product of spacing methodology is used to obtain the explicit estimator of Rs,k. Section 3 includes the construction of boot-p and boot-t confidence intervals. In Section 4, the Bayes estimates are determined under a squared error loss function (SELF) and a linear-exponential loss function (LINEX) using gamma informative priors. The Markov-Chain Monte-Carlo (MCMC) method is obtained for Bayesian computation. Also, the Bayesian credible and HPD credible intervals are constructed. A simulation study and real data set are analyzed in Sections 5 and 6 respectively. Finally, conclusion is presented in Section 7.
2.
Estimation of Rs,k when α is unknown
Let X1,X2,...,Xk and Y be an iid random samples taken from the general class of power Lomax POLO(α1,β,λ) and POLO(α2,β,λ) distributions, respectively, with a common shape parameter βand scale parameter λ. Under this setup, the reliability Rs,k is as follows
since B(.,.) is the standard Beta function and k and i are integers.
2.1. Maximum likelihood estimation of Rs,k
To achieve the desired MLE of Rs,k, the MLEs of α1,α2,β and λ are evaluated assuming the progressive Type-II censoring scheme. Suppose N systems are employed in a life-testing experiment, with a progressive Type-II censored sample {Xi1,Xi2,...,Xik}, i=1,2,…,n is generated from the general class of power Lomax POLO(α1,β,λ), where the progressive censoring scheme is {K,k,r1,…,rk}. Consider a progressively censored sample {Y1,Y2,...,Yn} obtained from another broad class of power Lomax POLO(α2,β,λ) using the censoring scheme {N,n,S1,…,Sn}.
Then likelihood function of α1,α2,β and λ is obtained as
The parameters α1 and α2 MLEs are derived from the solutions of Eqs (1.6) and (1.7), respectively:
ˆα1=nkn∑i=1k∑j=1(rj+1)ln[1+xβijλ]
(2.10)
and
ˆα2=nn∑i=1(Si+1)ln[1+yβiλ].
(2.11)
By incorporating ˆα1 and ˆα2 into Eq (1.2), the MLE of Rs,k becomes
ˆRs,k=k∑i=s(ki)ˆα2ˆα1B(ˆα2ˆα1+i,k−i+1).
(2.12)
2.2. Asymptotic confidence intervals
We use the asymptotic distribution of MLE ˆRs,k to construct an asymptotic confidence interval for the multicomponent reliability Rs,k, also need to observe an asymptotic distribution of ˆθ=(ˆα1,ˆα2,ˆβ,ˆλ). In this regard, let E[I(θ)] denote the expected Fisher-information matrix, where
for more details one may refer to Rao [33] It should be noticed that we obtain Rs,k and its derivatives for (s,k)=(1,3) and (2,4), independently to avoid the difficulty in deriving Rs,k.
Therefore, 100(1−γ)% confidence interval of Rs,k is constructed as given below
ˆRs,k±zγ/2√ˆV(ˆRs,k),
where zγ/2 denotes the upper γ/2th quantile of the standard normal distribution and ˆV(ˆRs,k) is the MLE of V(Rs,k) which is obtained by replacing (α1,α2,β,λ) in V(Rs,k) by their corresponding MLEs.
3.
Maximum product of spacing estimation
Ng et al. [34] presented the MPS approach. MPS technique determines the parameter values that makes the observed data as uniform as possible, with respect to a given quantitative measure of uniformity and based on a progressively Type-II censored sample
S=n+1∏i=1(F(ti;θ)−F(ti−1;θ))n+1∏i=1(1−F(ti;θ))Ri.
(3.1)
Cheng and Amin [35] defined as the geometric mean of the spacing as
such that ∑Di=1, depending on MPS method that was introduced by Cheng and Amin [36] and progressive Type-II censored scheme that was discussed by Balakrishnan and Aggarwala [27] and Ng et al. [37]. For more application of MPS on complete samples see Abu El Azm et al. [38], Sabry et al. [39] and Singh et al. [40].
We partially differentiate Eq (2.3) with respect to the parameters α1,α2,β and λ, then equate them to zero to obtain the normal equations for the unknown parameters. The estimators for α1,α2,β and λ can be found by solving the equations below.
The Eqs (2.4)–(2.7), on the other hand, must be solved numerically using a nonlinear optimization approach. By incorporating ˆα1(MPS) and ˆα2(MPS) into Eq (2.2), the MPS estimator of Rs,k becomes
According to point estimation, a parametric bootstrap interval informs us a lot about the population values of the quantity of our interest. Furthermore, CIs based on asymptotic results clearly make errors for small sample size. To determine the bootstrap CIs of α1,α2,β and λ, two parametric bootstrap methods are explained. The percentile bootstrap (Boot-p) CIs, introduced by Efron [41], and the CIs known as the bootstrap-t (Boot-t), which was presented by Hall [42]. Boot-t was developed using a studentized 'pivot' and it requires a variance estimator for the MLE of α1,α2,β, and λ.
4.1. Parametric Boot-p
Step 1: Generate a bootstrap sample of size nk, {x∗i1,x∗i2,...,x∗ik}from {xi1,xi2,...,xik},i=1,2,...,n,and generate a bootstrap sample of size n, {y∗1,y∗2,...,y∗n} from {y1,y2,...,yn}. Compute the bootstrap estimate of Rs,k, say ˆR∗s,k, using Eq (1.2).
Step 2: Repeat Step 1, NBoot times.
Step 3: Let G1(z)=P(ˆR∗s,k≤z) be the cumulative distribution function of ˆR∗s,k. Define ˆR∗s,k(boot−p)=G−11(z) for given z. The approximate bootstrap-p 100(1−γ)% CI of ˆRs,k, is given by
[ˆR∗s,k(boot−p)(γ2),ˆR∗s,k(boot−p)(1−γ2)].
(4.1)
4.2. Parametric Boot-t
Step 1: From the samples {xi1,xi2,...,xik},i=1,2,...,n and {y1,y2,...,yn},then compute ˆRs,k.
Step 2: The same as the parametric Boot-p in Step 1.
Step 3: Compute the T∗ statistic defined as
T∗=(ˆR∗s,k−ˆRs,k)√^V(ˆR∗s,k),
where V(ˆR∗s,k)can compute as in Eq (1.15).
Step 4: Repeat Steps 1–3, NBoottimes.
Step 5: Let G2(z)=P(T∗≤z) be the cumulative distribution function of T∗ for given z. Define ˆR∗s,k(boot−t)=ˆRs,k+G−12(z)√^σ2(ˆR∗s,k). Then, the approximate bootstrap-t 100(1−γ)% CI of Rs,k, is given by
[ˆR∗s,k(boot−t)(γ2),ˆR∗s,k(boot−t)(1−γ2)].
(4.2)
5.
Bayes estimation
In this section, Bayesian estimates are obtained for the parameters that are assumed to be random, and the uncertainties in the parameters are described by a joint prior distribution, which has been developed before the collected failure data. The Bayesian approach is highly useful in reliability analysis because it may incorporate previous knowledge into the analysis. Bayesian estimates of the unknown parameters α1,α2,β and λ, as well as some lifetime parameter Rs,k under the SELF and LINEX loss function are developed. It is assumed here that the parameters α1,α2,β and λ are independent and follow the gamma prior distributions,
where all the hyperparameters aiand bi,i=1,2,3,4 are assumed to be known non negative numbers. To determine the elicit hyper-parameters of the independent joint prior (5.1), we can use ML estimates and variance-covariance matrix of MLE method. By equating mean and variance of gamma priors, the estimated of hyper-parameters can be written as
where, L is the number of iteration and Ω is a vector of parameters.
Combining the likelihood function in Eq (1.4) with the priors in Eq (4.1), resulted with the posterior distribution of the parameters α1,α2,β and λ indicated by π∗(α1,α2,β,λ∣x_,y_), which can be expressed as
A commonly used loss function is the SELF, which is a symmetrical loss function that assigns equal losses to overestimation and underestimation. If ϕ is the parameter to be estimated by an estimator ˆϕ, then the square error loss function is defined as:
L(ϕ,ˆϕ)=(ˆϕ−ϕ)2.
Therefore, the Bayes estimate of any function of α1,α2,β and λ, say g(α1,α2,β,λ) under the SELF can be obtained as
Varian [43] considered the LINEX loss function L(△) for a parameter ϕ is given by
L(△)=(ec△−c△−1),c≠0,△=ˆϕ−ϕ,
(5.4)
This loss function is suitable for situations where overestimation of is more costly than its underestimation. Zellner [44]. discussed Bayesian estimation and prediction using LINEX loss. Hence, under LINEX loss function in Eq (4.3), the Bayes estimate of a function g(α1,α2,β,λ) is
The multiple integrals in Eqs (4.3) and (4.6) can not be obtained analytically. Thus, the MCMC technique can be used to generate samples from the joint posterior density function in Eq (4.2). In order to be able to implement the MCMC technique, we consider the Gibbs within the Metropolis-Hasting samplers procedure. The Metropolis-Hasting and Gibbs sampling are two useful MCMC methods that have been widely used in statistics.
The joint posterior density function of α1,α2,β and λ is obtained as follows:
Under the SELF and LINEX loss function, the Bayesian estimation of Rs,k is the mean of the posterior function in Eq (4.7), which can be written as shown below
The integral given in Eq (4.8) is obviously impossible to be calculated analytically. As a result, the Bayesian estimator of Rs,k, specifically the Gibbs sampling methods, is obtained using this approach. The next subsection get across the specifics of these strategies.
5.1. Gibbs sampling
The Gibbs sampling method is employed, which is a sub type of Monte-Carlo Markov Chain (MCMC) method, to create the Bayesian estimate of Rs,k and the related credible interval. The idea behind this method is to use posterior conditional density functions to generate posterior samples of parameters of interest. The posterior density function of the parameters of interest is produced by Eq (4.7). The posterior conditional density functions of α1,α2,β and λ can be expressed as follows using this equation:
The conditional density function of α1,α2,β and λ cannot be obtained in the form of the well-known density functions, as shown by Eqs (4.9)–(4.12). In this case, we can utilize the Metropolis-Hasting (MH) technique, developed by Metropolis et al. [45], to create random-samples from the posterior density of α1,α2,β and λ using a normal proposal distribution.
The steps of Gibbs sampling are described as follows:
(1) Start with initial guess (α(0)1,α(0)2,β(0),λ(0)).
(2) Set l=1.
(3) Using the following M-H algorithm, generate α(l)1,α(l)2,β(l) and λ(l) from
π∗1(α(l)1∣α(l−1)2,β(l−1),λ(l−1),x_,y_), π∗2(α(l)2∣α(l)1,β(l−1),λ(l−1),x_,y_),π∗3(β(l)∣α(l)1,α(l)2,λ(l−1),x_,y_) and π∗4(λ(l)∣α(l)1,α(l)2,β(l),x_,y_) with the normal proposal distributions
(ii) Generate a u1, u2,u3and u4 from a uniform (0,1) distribution.
(iii) If u1<ηα1, accept the proposal and set α(l)1=α∗1, else set α(l)1=α(l−1)1.
(iv) If u2<ηα2, accept the proposal and set α(l)2=α∗2, else set α(l)2=α(l−1)2.
(iiv) If u3<ηβ, accept the proposal and set β(l)=β∗, else set β(l)=β(l−1).
(v) If u4<ηλ, accept the proposal and set λ(l)=λ∗, else set λ(l)=λ(l−1).
(5) Compute R(l)s,k at (α(l)1,α(l)2,β(l),λ(l)).
(6) Set l=l+1.
(7) Repeat Steps (3)–(6), N times and obtain α(l)1,α(l)2,β(l),λ(l)and R(l)s,k,l=1,2,...N.
(8) To compute the CRs of α1,α2,β, λ and Rs,k, ψ(l)k,k=1,2,3,4,5,(ψ1,ψ2,ψ3,ψ4,ψ5)=(α1,α2,β,λ,Rs,k) as ψ(1)k<ψ(2)k...<ψ(N)k, then the 100(1−γ)%CRIs of ψk is
(ψk(Nγ/2),ψk(N(1−γ/2))).
The first M simulated variants are discarded in order to ensure convergence and remove the affection of initial value selection. Then the selected samples are ψ(i)k,j=M+1,...N, for sufficiently large N.
Based on the SELF, the approximate Bayes estimates of ψk is given by
ˆψk=1N−MN∑j=M+1ψ(j),k=1,2,3,4,5,
the approximate Bayes estimates forψk, under LINEX loss function, from Eq (4.6) is
ˆψk=−1clog[1N−MN∑j=M+1e−cψ(j)],k=1,2,3,4,5.
6.
Simulation
In this section random samples are generated from POLO distribution using the R-coding. The simulation experiment is carried out to determine the reliability coefficient and compare the suggested methods.
6.1. Simulation study
The performance of the parameters and Rs,k is compared using different sample sizes based on Monte Carlo simulation, where k = 5, and s = 2, 3, and 4. A total of 5, 000 random samples of size are n1=10,n2=15,n3=15,n4=10,n5=12 created from the stress and strength populations and the sample size of censored sample are chosen as (m1=7,m2=10,m3=10,m4=8,m5=9), and (m1=9,m2=13,m3=13,m4=9,m5=11). This section examines some empirical data derived from Monte-Carlo simulations to see how the proposed methods perform with different sample sizes. For (aj,bj);j=,...,4, we may use the estimate and variance-covariance matrix of the MLE approach to elicit hyper-parameters of the independent joint prior. The estimated hyper-parameters are calculated by equating the mean and variance of gamma priors. For the random variables generating, the values of the parameters α1,α2,λ, and β are chosen as follows:
Tables 1–6 show the simulation results of MLEs, MPS, Bayesian estimates, and interval estimations of Rs,k. All of the results are calculated using a total of 5000 simulated samples. The simulation methods are compared using the criteria of parameters estimation, the comparison is performed by calculating the Bias, the mean of square error (MSE), the length of asymptotic and bootstrap confidence intervals (L.CI) and coverage probability (CP) for each estimation method. In simulation results Tables 1–3, for each sample-size mi, scheme (S), and estimator, the first four values represent the average bias and MSE of the parameters model, and the next three values represent the estimated risk for the corresponding stress-strength reliability when k=5 and s=2,3,4, respectively. In simulation results for CI Tables 4–6, for each sample size mi, and scheme (S), in MLE, and MPS estimators, the first four values represent the average length of asymptotic CI (L.CI), CP, Boot-p (BP), and Boot-t (BT) of the parameters model, and the next three values represent the average length of delta CI of risk for the corresponding Rs,k when k=5 and s=2,3,4, respectively. While, in Bayesian estimation, the average length of credible CI (L.CI) of the parameters model and risk for the corresponding stress-strength reliability when k=5 and s=2,3,4, respectively.
Table 1.
Bias, MSE for MLE, MPS and Bayesian when α1=1.3,λ=1.2,α2=2,β=1.5.
Numerical simulations, on the other hand, make it impossible to see in a basic sense how estimated dangers decrease with sample size. For probability, product spacing, and Bayesian estimates, we see this trend. In terms of estimated risks, the Bayesian estimates of Rs;k perform significantly better than the MLE and MPS. We notice that the Bayesian estimate's predicted risks under the LINEX loss are often lower than those under the SELF. The Bayes estimates and their estimated risks are sometimes near to each other based on calculated findings. The average length of HPD intervals is found to be shorter than that of asymptotic confidence intervals. When the sample size is increased, the lengths of both intervals shrink. But, the bootstrap CI has the shortest length of CI.
7.
Application of real data
For demonstration purposes, the analysis of a pair of real data sets is shown. The idea is to figure out how we can create conditions in which there is a lot of droughts. We assert that there will be no excessive drought if the water capacity of a reservoir in an area in August for at least two years out of the next five years is more than the amount of water achieved in December of 2019. It's also feasible that in this case, rather than entire samples from both groups, one sees censored samples. To achieve this purpose, we used the monthly water capacity of the Shasta reservoir in California, as well as the months of August and December from 1975 to 2016. http://cdec.water.ca.gov/cgi-progs/queryMonthly/SHA contains the data. Some writers have previously used these data, including Nadar and Kizilaslan [46], and Kızılaslan and Nadar [47].
In the whole data case, assuming k = 5 and s = 2, Y1 represents December 1975 capacity while X11,...,X15 represents August capacities from 1976 to 1980. Also, Y2 represents December 1981 capacity, while X21,...,X25 represents August capabilities from 1982 to 1986. n = 7 data for Y are acquired by continuing this approach till 2016. The corrected data are listed in Table 7.
To begin, we make sure that the POLO distribution can be utilized to examine the data set in Table 7. We get the MLEs of unknown parameters in Table 8. The Kolmogorov-Smirnov distance (KSD) values are also reported, along with the appropriate p-values. We can see from this table that the POLO distribution fits the data pretty well. For the data sets X and Y, the empirical cdf distribution, estimated pdf with histogram plot, and the PP-plot are given in Figures 1–3, respectively. In Figure 4, we plot the empirical cdf distribution, estimated pdf with histogram plot, and the PP-plot for X=(x1,x2,x3,x4,x5). These figures confirmed that the data have been fitted for POLO distribution.
Two distinct progressively censored samples are produced from the previous data sets for illustration purposes. In Table 9, the MLEs, MPS, and the Bayesian estimation of unknown parameters for the model have been obtained for this scheme. In Table 10, the estimation of reliability in a multi-component stress-strength model have been obtained. Figure 5 shows the trace and density plots for all parameters in the MCMC trace. Also it shows the trace and density plots for all parameters in an MCMC trace. The posterior density of MCMC results for each parameter is shown, which demonstrates a symmetric normal distribution that is identical to the proposed distribution. The convergence of the MCMC results is confirmed in Figure 5.
Table 9.
MLE, MPS, and Bayesian estimation with different loss functions.
When the two schemes are compared using Bayesian and non-Bayesian, it is found that estimators in scheme 1 have lower standard errors than estimators in scheme 2. Also, it is found that estimators in scheme 1 have high reliability than estimators in scheme 2 and the whole scheme.
8.
Conclusions
The study discusses the multi-component stress-strength model. The reliability has been investigated where both the stress and strength variables follow the POLO distribution. To calculate the multi-component stress-strength reliability Rs;k, we apply both classical and Bayesian methods. We compute the Bayesian estimates of parameters and Rs;k under symmetric and asymmetric loss functions by using the MH algorithm. We compute the classical estimates as MLE ad MPS of the parameter of the model and Rs;k by using the Newton-Raphson (NR) and Markov Chain Monte Carlo algorithms. Based on the simulation analysis, we observe that the predicted risks of the proposed Rs;k estimators show good behavior when the sample size increases. In general, as the sample size increases, the average length of the intervals decreases, therefor The average length of higher posterior density intervals is found to be shorter than that of asymptotic confidence intervals. Based on tabulated numerical results we find that the predicted risks of Bayesian estimation are often lower than the risks of the classical approaches. For illustrating the applicability of the multi-component stress strength model under POLO distribution we have examined a real life data taken from the monthly water capacity of the Shasta reservoir in California, and by using Kolmogorov-Smirnov distance (KSD)and its corresponding p-values we conclude that the above model fit the data very well. This study can further be extended by using different censoring schemes and different lifetime models.
Acknowledgments
This work was supported by the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia (Project No. GRANT421), King Faisal University (KFU), Al Ahsa, Saudi Arabia. The Authors, therefore, acknowledge technical and financial support of the Deanship of Scientific Research at KFU.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was funded by the Deanship of Scientific Research (DSR), University of Jeddah, Jeddah, under grant No. (UJ-20-025-DR). The author, therefore, acknowledges with thanks the DSR, University of Jeddah, for its technical and financial support. The author also thanks his previous affiliated institute, the Center for Genomics and Systems Biology (CGSB) of New York University, for providing technical support, including access to the QIAGEN IPA web-based software application.
Conflict of interest
The author declares no conflict of interest.
Author contributions
F.A. is the PI who conceived the idea and designed the project, collected and analyzed the data, interpreted the results, wrote and revised the manuscript.
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Firoz Ahmed. Deciphering the gene regulatory network associated with anti-apoptosis in the pancreatic islets of type 2 diabetes mice using computational approaches[J]. AIMS Bioengineering, 2023, 10(2): 111-140. doi: 10.3934/bioeng.2023009
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Figure 1. (A) Principal component analysis of Affymetrix microarray data of T2D and control mice. The figure showed the first three PCA data (PC1, PC2, and PC3) and revealed that the gene expression patterns of each tissue with T2D and control are relatively distinct. Venn diagram depicting the numbers of genes (B) upregulated and (C) downregulated across different tissues of T2D compared to their controls
Figure 2. Enrichment analysis of DEGs in islets of T2D compared to the control. (A) Association of upregulated genes with various diseases using DisGeNET. (B) Association of downregulated genes with various diseases using DisGeNET. In A and B, each disease is represented with a p-value and its corresponding -log10(p-value). (C) Association of DEGs with canonical pathways using IPA. The top of the figure lists the number of genes/proteins present in the IPA dataset for each canonical pathway. The left side of the figure shows the overlap ratio percentage, which is calculated by dividing the number of genes/molecules in the DEGs by the total number of genes/molecules in the canonical pathway. The right side of the figure shows the significance of the overlap ratio percentage in -log10(p-value). The value of -log10(p-value) > 1.30 indicates a statistically significant p-value < 0.05. The upregulated genes are represented in red, while the downregulated genes are represented in green
Figure 3. Causal networks and their master regulators reflecting DEGs in the islets of T2D generated by the IPA tool. The figure depicts three causal networks: (A) activation of Glucose; (B) inhibition of GW3965, (C) inhibition of PPARa-RXRa. The nodes and edges represent genes and gene relationships, respectively. The intensity of the node color indicates the degree of upregulation (red) and downregulation (green) of genes in T2D compared to the control. A direct connection between two nodes is indicated with a solid line, while an indirect connection is indicated with a dotted line. Node shapes indicate the types of genes: ellipse for transcription regulator, rhombus for enzyme, trapezoid for transporters, square for cytokines, double circles for complex/groups and the circle represents others
Figure 4. Regulatory networks demonstrating downstream effect on islets in T2D, generated by the IPA tool. (A) Decrease of insulin resistance and increase of quantity of insulin in blood. (B) Inhibition of apoptosis. The intensity of the node color indicates the degree of upregulation (red) and downregulation (green) genes in T2D compared to the control. The pointed arrowhead indicates activating relationships, while the blunt arrowhead indicates inhibitory interaction. The blue inhibition edge indicates that the downstream node activity is predicted to be decreased if the upstream node is activated. The blue activation edge indicates that the downstream node activity is predicted to be decreased if the upstream node is inhibited. The orange activation edge indicates that the downstream node activity is predicted to be increased if the upstream node is activated. The orange inhibition edge indicates that the downstream node activity is predicted to be increased if the upstream node is inhibited. The edge color is yellow if the findings underlying the relationship are inconsistent with the state of the downstream node
Figure 5. Mechanistic networks of apoptosis in islets of T2D and their potential upregulators generated by the IPA tool. (A) Five upstream regulators of target molecules in our dataset. (B) One upstream regulator of target molecules in our dataset. The intensity of the node color indicates the degree of upregulation (red) and downregulation (green) of genes in T2D compared to the control. The pointed arrowhead indicates activating relationships, while the blunt arrowhead indicates inhibitory interaction. The blue inhibition edge indicates that the downstream node activity is predicted to be decreased if the upstream node is activated. The blue activation edge indicates that the downstream node activity is predicted to be decreased if the upstream node is inhibited. The orange activation edge indicates that the downstream node activity is predicted to be increased if the upstream node is activated. The orange inhibition edge indicates that the downstream node activity is predicted to be increased if the upstream node is inhibited. The edge color is yellow if the findings underlying the relationship are inconsistent with the state of the downstream node
Figure 6. Evidence of DPP4 in T2D using the Open Targets Platform. The color gradient in the heatmap displays the association score between evidence and diseases. Diseases with an overall association score of more than 0.50 were shown, while the white cells indicated a lack of association data. The heatmap was created using pheatmap_1.0.12 of R