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Research article Special Issues

Hopf bifurcation in a CTL-inclusive HIV-1 infection model with two time delays

  • In this paper, we investigate a delayed HIV-1 infection model with immune response. Though a logistic growth is incorporated in the growth of the target cells, our focus is on the effect of delays on the infection dynamics. We first study the existence of steady states, which depends on the basic reproduction number R0. When R01, there is only the infection-free steady state, which is globally asymptotically stable if R0<1. When R0>1, besides the unstable infection-free steady state, there is a unique infected steady state. We then study the local stability of the infected steady state and local Hopf bifurcation at it. The theoretical analysis indicates that the dynamics scenario is complicated. For example, there can be three sequences of critical values, stability switches and double Hopf bifurcation can occur. Some of the theoretical results are also illustrated with numerical simulations.

    Citation: Juan Wang, Chunyang Qin, Yuming Chen, Xia Wang. Hopf bifurcation in a CTL-inclusive HIV-1 infection model with two time delays[J]. Mathematical Biosciences and Engineering, 2019, 16(4): 2587-2612. doi: 10.3934/mbe.2019130

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  • In this paper, we investigate a delayed HIV-1 infection model with immune response. Though a logistic growth is incorporated in the growth of the target cells, our focus is on the effect of delays on the infection dynamics. We first study the existence of steady states, which depends on the basic reproduction number R0. When R01, there is only the infection-free steady state, which is globally asymptotically stable if R0<1. When R0>1, besides the unstable infection-free steady state, there is a unique infected steady state. We then study the local stability of the infected steady state and local Hopf bifurcation at it. The theoretical analysis indicates that the dynamics scenario is complicated. For example, there can be three sequences of critical values, stability switches and double Hopf bifurcation can occur. Some of the theoretical results are also illustrated with numerical simulations.


    For a continuous risk outcome 0<y<1, a model with a random effect has potentially a wide application in portfolio risk management, especially, for stress testing [1,2,7,16,19], capital allocation, conditional expected shortfall estimation [3,11,17].

    Given fixed effects x=(x1,x2,,xk), two widely used regression models to estimate the expected value E(y|x) are: the fraction response model [10] and Beta regression model [4,6,8]. There are cases, however, where tail behaviours or severity levels of the risk outcome are relevant. In those cases, a regression model may no longer fit in for the requirements. In addition, a fraction response model of the form E(y|x)=Φ(a0+a1x1++akxk) may not be adequate when data exhibits significant heteroscedasticity, where Φ is a map from R1 to the open interval (0,1).

    In this paper, we assume that the risk outcome y is driven by a model:

    y=Φ(a0+a1x1++akxk+bs), (1.1)

    where s is a random continuous variable following a known distribution, independent of fixed effects (x1,x2,,xk). Parameters a0,a1,,ak are constant, while parameter b can be chosen to be dependent on (x1,x2,,xk) when required, for example, for addressing data heteroscedasticity.

    Given random effect model (1.1), the expected value E(y|x) can be deduced accordingly. It is given by the integral ΩΦ(a0+a1x1++akxk+bs)f(s)ds over the domain Ω of s, where f is the probability density of s. Given the routine QUAD implemented in SAS and Python, this integral can be evaluated as quickly as other function calls. Relative error tolerance for QUAD is 1.49e-8 in Python and is 1e-7 in SAS. But one can rescale the default tolerance to a desired level when necessary. This leads to an alternative regression tool to the fraction response model and Beta regression model.

    We introduce a family of interval distributions based on variable transformations. Probability densities for these distributions are provided (Proposition 2.1). Parameters of model (1.1) can then be estimated by maximum likelihood approaches assuming an interval distribution. In some cases, these parameters get an analytical solution without the needs for a model fitting (Proposition 4.1). We call a model with a random effect, where parameters are estimated by maximum likelihood assuming an interval distribution, an interval distribution model.

    In its simplest form, the interval distribution model y=Φ(a+bs), where a and b, are constant, can be used to model the loss rate as a random distribution for a homogeneous portfolio. Let yα and sα denote the α -quantiles for y and s at level α, 0<α<1. Then yα=Φ(a+bsα). The conditional expected shortfall for loss rate y, at level α, can then be estimated as the integral 11α[sα,+)Φ(a+bs)f(s)ds, where f is the density of s. Meanwhile, a stress testing loss estimate, derived from a model on a specific scenario, can be compared in loss rate to severity yα(=Φ(a+bsα)), to position its level of severity. A loss estimate may not have reached the desired, for example, 99% level yet, if it is far below y0.99, and far below the maximum historical loss rate. In which case, further recalibrations for the model may be required.

    The paper is organized as follows: in section 2, we introduce a family of interval distributions. A measure for tail fatness is defined. In section 3, we show examples of interval distributions and investigate their tail behaviours. We propose in section 4 an algorithm for estimating the parameters in model (1.1).

    Interval distributions introduced in this section are defined for a risk outcome over a finite open interval (c0,c1), where c0< c1 are finite numbers. These interval distributions can potentially be used for modeling a risk outcome over an arbitrary finite interval, including interval (0, 1), by maximum likelihood approaches.

    Let D=(d0,d1), d0<d1, be an open interval, where d0 can be finite or and d1 can be finite or +.

    Let

    Φ:D(c0,c1) (2.1)

    be a transformation with continuous and positive derivatives Φ(x)=ϕ(x). A special example is (c0,c1)=(0,1), and Φ:D(0,1) is the cumulative distribution function (CDF) of a random variable with a continuous and positive density.

    Given a continuous random variable s, let f and F be respectively its density and CDF. For constants a and b>0, let

    y=Φ(a+bs), (2.2)

    where we assume that the range of variable (a+bs) is in the domain D of Φ. Let g(y,a,b) and G(y,a,b) denote respectively the density and CDF of y in (2.2).

    Proposition 2.1. Given Φ1(y), functions g(y,a,b) and G(y,a,b) are given as:

    g(y,a,b)=U1/(bU2) (2.3)
    G(y,a,b)=F[Φ1(y)ab]. (2.4)

    where

    U1=f{[Φ1(y)a]/b},U2=ϕ[Φ1(y)] (2.5)

    Proof. A proof for the case when (c0,c1)=(0,1) can be found in [18]. The proof here is similar. Since G(y,a,b) is the CDF of y, it follows:

    G(y,a,b)=P[Φ(a+bs)y]
    =P{s[Φ1(y)a]/b}
    =F{[Φ1(y)a]/b}.

    By chain rule and the relationship Φ[Φ1(y)]=y, the derivative of Φ1(y) with respect to y is

    Φ1(y)y=1ϕ[Φ1(y)]. (2.6)

    Taking the derivative of G(y,a,b) with respect to y, we have

    G(y,a,b)y=f{[Φ1(y)a]/b}bϕ[Φ1(y)]=U1bU2.

    One can explore into these interval distributions for their shapes, including skewness and modality. For stress testing purposes, we are more interested in tail risk behaviours for these distributions.

    Recall that, for a variable X over (− ,+), we say that the distribution of X has a fat right tail if there is a positive exponent α>0, called tailed index, such that P(X>x)xα. The relation refers to the asymptotic equivalence of functions, meaning that their ratio tends to a positive constant. Note that, when the density is a continuous function, it tends to 0 when x+. Hence, by L’Hospital’s rule, the existence of tailed index is equivalent to saying that the density decays like a power law, whenever the density is a continuous function.

    For a risk outcome over a finite interval (c0,c1), c0,<c1, however, its density can be + when approaching boundaries c0 and c1. Let y0 be the largest lower bound for all values of y under (2.2), and y1 the smallest upper bound. We assume y0=c0 and y1=c1.

    We say that an interval distribution has a fat right tail if the limit limyy1  g(y,a,b)=+, and a fat left tail if limyy+0  g(y,a,b)=+, where yy+0 and yy1 denote respectively y approaching y0 from the right-hand-side, and y1 from the left-hand-side. For simplicity, we write yy0 for yy+0, and yy1 for yy1.

    Given α>0, we say that an interval distribution has a fat right tail with tailed index α if limyy1  g(y,a,b)(y1y)β=+ whenever 0<β<α, and limyy1  g(y,a,b)(y1y)β=0 for β>α. Similarly, an interval distribution has a fat left tail with tailed index α if limyy0  g(y,a,b)(yy0)β=+ whenever 0<β<α, and limyy0  g(y,a,b)(yy0)β=0 for β>α. Here the status at β=α is left open. There are examples (Remark 3.4), where an interval distribution has a fat right tail with tailed index α, but the limit limyy1  g(y,a,b)(y1y)α can either be + or 0. Under this definition, a tailed index of an interval distribution with a continuous density is always larger than 0 and less or equal to 1, if it exists.

    Recall that, for a Beta distribution with parameters α>0 and β>0, its density is given by f(x)=xα1(1x)β1B(α,β), where B(α,β) is the Beta function . Under the above definition, Beta distribution has a fat right tail with tailed index (1β) when 0<β<1, and a fat left tail with tailed index (1α) when 0<α<1.

    Next, because the derivative of Φ is assumed to be continuous and positive, it is strictly monotonic. Hence Φ1(y) is defined. Let

    z=Φ1(y) (2.7)

    Then limyy0z exists (can be ), and the same for limyy1z (can be +). Let limyy0  z=z0, and limyy1  z=z1. Rewrite g(y,a,b) as g(Φ(z),a,b) by (2.7). Let [g(Φ(z),a,b)]1β/z denote the derivative of [g(Φ(z),a,b)]1/β with respect to z.

    Lemma 2.2. Given β>0, the following statements hold:

    (ⅰ) limyy0  g(y,a,b)(yy0)β=limzz0  g(Φ(z),a,b)(Φ(z)y0)β and limyy1  g(y,a,b)(y1y)β=limzz1  g(Φ(z),a,b)(y1Φ(z))β.

    (ⅱ) If limyy0  g(y,a,b)=+ and limzz0{[g(Φ(z),a,b)]1β/z}/ϕ(z) is 0 (resp. +), then limyy0  g(y,a,b)(yy0)β=+ (resp. 0).

    (ⅲ) If limyy1  g(y,a,b)=+ and limzz1{[g(Φ(z),a,b)]1β/z}/ϕ(z)) is 0 (resp. +), then limyy1  g(y,a,b)(y1y)β=+ (resp. 0).

    Proof. The first statement follows from the relationship y=Φ(z). For statements (ⅱ) and (ⅲ), we show only (ⅲ). The proof for (ⅱ) is similar. Notice that

    [g(y,a,b)(y1y)β]1/β=[g(y,a,b)]1/βy1y=[g(Φ(z),a,b)]1/βy1Φ(z). (2.8)

    By L’Hospital’s rule and taking the derivatives of the numerator and the denominator of (2.8) with respect to z, we have limyy1[g(y,a,b)(y1y)β]1/β=0 (resp. +) if limzz0{[g(Φ(z),a,b)]1/β/z}/ϕ(z) is 0 (resp. +). Hence limyy1  g(y,a,b)(y1y)β=+ (resp. 0).

    For tail convexity, we say that the right tail of an interval distribution is convex if g(y,a,b) is convex for y1є<y<y1 for sufficiently small є>0. Similarly, the left tail is convex if g(y,a,b) is convex for y0<y<y0+є for sufficiently small є>0. One sufficient condition for convexity for the right (resp. left) tail is gyy(y,a,b)0 when y is sufficiently close to y1 (resp. y0).

    Again, write g(y,a,b)=g(Φ(z),a,b). Let

    h(z,a,b)=log[g(Φ(z),a,b)], (2.9)

    where log(x) denotes the natural logarithmic function. Then

    g(y,a,b)=exp[h(z,a,b)]. (2.10)

    By (2.9), (2.10), using (2.6) and the relationship z=Φ1(y), we have

    gy=[hz(z)/ϕ(z)]exp[h(Φ1(y),a,b)],gyy=[hzz(z)ϕ2(z)hz(z)ϕz(z)ϕ3(z)+hz(z)hz(z)ϕ2(z)]exp[h(Φ1(y),a,b)]. (2.11)

    The following lemma is useful for checking tail convexity, it follows from (2.11).

    Lemma 2.3. Suppose ϕ(z)>0, and derivatives hz(z),hz(z), and ϕz(z), with respect to z, all exist. If hzz(z)0 and hz(z)ϕz(z)0, then gyy(y,a,b)0.

    In this section, we focus on the case where (c0,c1)=(0,1), and Φ:D(0,1) in (2.2) is the CDF of a continuous distribution . This includes, for example, the CDFs for standard normal and standard logistic distributions.

    One can explore into a wide list of densities with different choices for Φ and s under (2.2). We consider here only the following four interval distributions:

    A. sN(0,1) and Φ is the CDF for the standard normal distribution.

    B. s follows the standard logistic distribution and Φ is the CDF for the standard normal distribution.

    C. s follows the standard logistic distribution and Φ is its CDF.

    D.D. sN(0,1) and Φ is the CDF for standard logistic distribution.

    Densities for cases A, B, C, and D are given respectively in (3.3) (section 3.1), (A.1), (A.3), and (A5) (Appendix A). Tail behaviour study is summarized in Propositions 3.3, 3.5, and Remark 3.6. Sketches of density plots are provided in Appendix B for distributions A, B, and C.

    Using the notations of section 2, we have ϕ=f and Φ=F. We claim that y=Φ(a+bs) under (2.2) follows the Vasicek distribution [13,14].

    By (2.5), we have

    log(U1U2)=z2+2aza2+b2z22b2 (3.1)
    =(1b2)(za1b2)2+b21b2a22b2. (3.2)

    Therefore, we have

    g(y,a,b)=1bexp{(1b2)(za1b2)2+b21b2a22b2}. (3.3)

    Again, using the notations of section 2, we have y0=0 and y1=1. With z=Φ1(y), we have limy0  z= and limy1  z=+. Recall that a variable 0<y<1 follows a Vasicek distribution [13,14] if its density has the form:

    g(y,p,ρ)=1ρρexp{12ρ[1ρΦ1(y)Φ1(p)]2+12[Φ1(y)]2} (3.4)

    where p is the mean of y , and ρ is a parameter called asset correlation.

    Proposition 3.1. Density (3.3) is equivalent to (3.4) under the relationships:

    a=Φ1(p)1ρ  and  b=ρ1ρ. (3.5)

    Proof. A similar proof can be found in [19]. By (3.4), we have

    g(y,p,ρ)=1ρρexp{1ρ2ρ[Φ1(y)Φ1(p)/1ρ]2+12[Φ1(y)]2}
    =1bexp{12[Φ1(y)ab]2}exp{12[Φ1(y)]2}
    =U1/(bU2)=g(y,a,b).

    The following relationships are implied by (3.5):

    ρ=b21+b2, (3.6)
    a=Φ1(p)1+b2. (3.7)

    Remark 3.2. The mode of g(y,p,ρ) in (3.4) is given in [14] as Φ(1ρ12ρΦ1(p)). We claim this is the same as Φ(a1b2). By (3.6), 12ρ=1b21+b2 and 1ρ=11+b2. Therefore, we have

    1ρ12ρΦ1(p)=1+b21b2Φ1(p)=a1b2.

    This means Φ(1ρ12ρΦ1(p))=Φ(a1b2).

    Proposition 3.3. The following statements hold for g(y,a,b) given in (3.3):

    (ⅰ) g(y,a,b) is unimodal if 0<b<1 with mode given by Φ(a1b2), and is in U-shape if b>1.

    (ⅱ) If b>1,then  g(y,a,b) has a fat left tail and a fat right tail with tailed index (11/b2).

    (ⅲ) If b>1, both tails of g(y,a,b) are convex , and is globally convex if in addition a=0.

    Proof. For statement (ⅰ), we have (1b2)<0 when 0<b<1. Therefore by (3.2) function log(U1U2) reaches its unique maximum at z=a1b2, resulting in a value for the mode at Φ(a1b2). If b>1, then (1b2)>0, thus by (3.2), g(y,a,b) is first decreasing and then increasing when y varying from 0 to 1. This means (y,a,b) is in U-shape.

    Consider statement (ⅱ). First by (3.3), if b>1, then limy1  g(y,a,b)=+ and limy0  g(y,a,b)=+. Thus g(y,a,b) has a fat right and a fat left tail. Next for tailed index, we use Lemma 2.2 (ⅱ) and (ⅲ). By (3.1),

    [g(Φ(z),a,b)]1/β=b1/βexp((b21)z2+2aza22βb2) (3.8)

    By taking the derivative of (3.8) with respect to z and noting that ϕ(z)=12πexp(z22), we have

    {[g(Φ(z),a,b)]1β/z}/ϕ(z)=2πb1β(b21)z+aβb2exp((b21)z2+2aza22βb2+z22). (3.9)

    Thus limz+{[g(Φ(z),a,b)]1β/z}/ϕ(z) is 0 if b21βb2>1, and is + if b21βb2<1. Hence by Lemma 2.2 (ⅲ), g(y,a,b) has a fat right tail with tailed index (11/b2). Similarly, for the left tail, we have by (3.9)

    {[g(Φ(z),a,b)]1β/z}/ϕ(z)=2πb1β(b21)z+aβb2exp((b21)z2+2aza22βb2+z22). (3.10)

    Thus limz{[g(Φ(z),a,b)]1β/z}/ϕ(z) is 0 if b21βb2>1, and is + if b21βb2<1. Hence g(y,a,b) has a fat left tail with tailed index (11/b2) by Lemma 2.2 (ⅱ).

    For statement (ⅲ), we use Lemma 2.3. By (2.9) and using (3.2), we have

    h(z,a,b)=log(U1bU2)=(1b2)(za1b2)2+b21b2a22b2log(b).

    When b>1, it is not difficult to check out that hzz(z)0 and hz(z)ϕz(z)0 when z± or when a=0.

    Remark 3.4. Assume β=(11/b2) and b>1. By (3.9), we see

    limz+{[g(Φ(z),a,b)]1β/z}/ϕ(z)

    is + for a=0, and is 0 for a>0. Hence for this β, the limit limy1  g(y,a,b)(1y)β can be either 0 or +, depending on the value of a.

    For these distributions, we again focus on their tail behaviours. A proof for the next proposition can be found in Appendix A.

    Proposition 3.5. The following statements hold:

    (a) Density g(y,a,b) has a fat left tail and a fat right tail for case B for all b>0, and for case C if b>1. For case D, it does not have a fat right tail nor a fat left tail for any b>0.

    (b) The tailed index of g(y,a,b) for both right and left tails is 1 for case B for all b>0, and is (11b) for case C for B for b>1.

    Remark 3.6. Among distributions A, B, C, and Beta distribution, distribution B gets the highest tailed index of 1, independent of the choices of b>0.

    In this section, we assume that Φ in (2.2) is a function from R1 to (0,1) with positive continuous derivatives. We focus on parameter estimation algorithms for model (1.1).

    First, we consider a simple case, where risk outcome y is driven by a model:

    y=Φ(v+bs), (4.1)

    where b>0 is a constant, v=a0+a1x1++akxk, and sN(0,1), independent of fixed effects x=(x1,x2,,xk). The function Φ does not have to be the standard normal CDF. But when Φ is the standard normal CDF, the expected value E(y|x) can be evaluated by the formula ES[Φ(a+bs)]=Φ(a1+b2) [12].

    Given a sample {(x1i,x2i,,xki,yi)}ni=1, where (x1i,x2i,,xki,yi) denotes the ith data point of the sample, let zi=Φ1(yi). and vi=a0+a1x1i++akxki. By (2.3), the log-likelihood function for model (4.1) is:

    LL=ni=1{logf(zivib)logϕ(zi)logb} (4.2)

    where f is the density of s. The part of ni=1logϕ(zi) is constant, which can be dropped off from the maximization.

    Recall that the least squares estimators of a0,a1,,ak, as a row vector, that minimize the sum squares

    SS=ni=1(zivi)2 (4.3)

    has a closed form solution given by the transpose of (XTX)1XTZ [5,9] whenever the design matrix X has a rank of k, where

    X=1x11xk11x12xk21x1nxkn,Z=z1z2zn.

    The next proposition shows there exists an analytical solution for the parameters of model (4.1).

    Proposition 4.1. Given a sample {(x1i,x2i,,xki,yi)}ni=1, assume that the design matrix has a rank of k. If sN(0,1), then the maximum likelihood estimates of parameters (a0,a1,,a), as a row vector, and parameter b are respectively given by the transpose of (XTX)1XTZ, and b2=1nni=1(zivi)2. In absence of fixed effects {x1,x2,,xk}, parameters a0 and b2 degenerate respectively to the sample mean and variance of z1, z2,,zn.

    Proof. Dropping off the constant term from (4.2) and noting f(z)=12πexp(z22), we have

    LL=12b2ni=1(zivi)2nlogb, (4.4)

    Hence the maximum likelihood estimates (a0,a1,,ak) are the same as least squares estimators of (4.3), which are given by the transpose of (XTX)1XTZ. By taking the derivative of (4.4) with respect to b and setting it to zero, we have b2=1nni=1(zivi)2.

    Next, we consider the general case of model (1.1), where the risk outcome y is driven by a model:

    y=Φ[v+ws], (4.5)

    where parameter w is formulated as w=exp(u), and u=b0+b1x1++bkxk. We focus on the following two cases:

    (a) sN(0,1),

    (b) s is standard logistic.

    Given a sample {(x1i,x2i,,xki,yi)}ni=1, let wi=exp(b0+b1x1i++bkxki) and ui=b0+b1x1i++bkxki. The log-likelihood functions for model (4.5), dropping off the constant part log(U2), for cases (a) and (b) are given respectively by (4.6) and (4.7):

    LL=ni=112[(zivi)2/w2iui], (4.6)
    LL=ni=1{(zivi)/wi2log[1+exp[(zivi)/wi]ui}, (4.7)

    Recall that a function is log-concave if its logarithm is concave. If a function is concave, a local maximum is a global maximum, and the function is unimodal. This property is useful for searching maximum likelihood estimates.

    Proposition 4.2. The functions (4.6) and (4.7) are concave as a function of (a0,a1,,ak). As a function of (b0,b1,,bk), (4.6) is concave.

    Proof. It is well-known that, if f(x) is log-concave, then so is f(Az+b), where Az+b : RmR1 is any affine transformation from the m-dimensional Euclidean space to the 1-dimensional Euclidean space. For (4.6), the function f(x)=(zv)2exp(2u) is concave as a function of v, thus function (4.6) is concave as a function of (a0,a1,,ak). Similarly, this function f(x) is concave as a function of u, so (4.6) is concave as a function of (b0,b1,,bk).

    For (4.7), the linear part (zivi)exp(ui), as a function of (a0,a1,,ak), in (4.7) is ignored. For the second part in (4.7), we know log{1+exp[(zv)/exp(u)]}, as a function of v, is the logarithm of the CDF of a logistic distribution. It is well-known that the CDF for a logistic distribution is log-concave. Thus (4.7) is concave with respect to (a0,a1,,ak).

    In general, parameters (a0,a1,,ak) and (b0,b1,,bk) in model (4.5) can be estimated by the algorithm below.

    Algorithm 4.3. Follow the steps below to estimate parameters of model (4.5):

    (a) Given (b0,b1,,bk), estimate (a0,a1,,ak) by maximizing the log-likelihood function;

    (b) Given (a0,a1,,ak), estimate (b0,b1,,bk) by maximizing the log-likelihood function;

    (c) Iterate (a) and (b) until a convergence is reached.

    With the interval distributions introduced in this paper, models with a random effect can be fitted for a continuous risk outcome by maximum likelihood approaches assuming an interval distribution. These models provide an alternative regression tool to the Beta regression model and fraction response model, and a tool for tail risk assessment as well.

    Authors are very grateful to the third reviewer for many constructive comments. The first author is grateful to Biao Wu for many valuable conversations. Thanks also go to Clovis Sukam for his critical reading for the manuscript.

    We would like to thank you for following the instructions above very closely in advance. It will definitely save us lot of time and expedite the process of your paper's publication.

    The views expressed in this article are not necessarily those of Royal Bank of Canada and Scotiabank or any of their affiliates. Please direct any comments to Bill Huajian Yang at h_y02@yahoo.ca.



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