All methods were performed in accordance with the relevant guidelines and regulations.
Data
The incidence data used in this study are daily registered COVID-19 cases and deceased cases from Germany (see Fig. 1) and other countries from 1 June until 31 August, 2020. Due to the usual independent and identically distributed (iid) assumption on the measurement error (cf. King et al. [18]), only the daily incidence data will be used for optimization parameter estimation of the later introduced models. To accompany the modeling, population data from all countries in consideration are taken from UN data [19]. We only include European countries with available traveller statistics and countries outside of Europe with a total sum of more than 5000 travellers in the travelling statistics. For the close European countries, the number of travellers is estimated by the travel statistics of 2020 for German travellers [20] (for relative shares) and hospitality statistics in Germany for foreign travellers [21]; these numbers are generally subtracted from the total amount of flight passengers. The number of travellers from and to farther and non-European countries is gained from analysis of the flight passengers from the respective country [22]. In some larger countries, namely USA, Russia, China, and Japan, the data was problematic. Flight routes from and to these countries are often non-direct, so the plain values of flight passengers would underestimate the real amount of travellers to these countries. As a compromise, we assumed the amount of German travellers to those countries to be the same as the number of foreign visitors from those countries in Germany, which makes this estimation more meaningful. The populations and amount of travellers per month of this total of 55 countries is presented in Table 2.
Model
Traveller induced model
In the previous work we investigated the dynamics of COVID-19 disease until early May 2020 [17]; this study departs from this approach. Again we use a variation of the SIR-model introduced by Kermack and McKendrick [23]; see also Martcheva [24] for an overview of mathematical models in epidemiology. It builds up on delayed differential equation (DDE) system to describe the behaviour of the disease in Germany in summer 2020. While the use of stochastic variables can make the model more realistic, but may also lead to further technical questions including noise type, stable ergodicity, and predictability, which go beyond the original scope. Therefore, we tested a deterministic model for the main aim. The entire population N is subdivided into five compartments: susceptible S, exposed E, infected I, recovered R, and deceased D, so that we deal with a so-called SEIRD model. The virus is transmitted from infected persons to susceptible persons at a piecewise constant rate \(\beta\). After an incubation duration \(\kappa ^{-1}\) exposed individuals become infective. Loss of infectivity is gained after an average duration \(\gamma ^{-1}\); the death parameter \(\mu\) describes the probability for infected persons dying from the disease. A time lag \(\tau\) between the infected and the deceased state accounts for the fact that the number of people dying from the disease is attained from the infected number \(\tau\) days earlier. Here, we also introduce an additional compartment: travellers \(E_t\) which have been exposed to the disease abroad. Values for the fixed model parameters in Germany are given in Table 1.
Table 1 Used parameter values These assumptions lead us to the following five-dimensional ODE system.
$$\begin{aligned} &\dot{S}= - \frac{\beta }{N} \,S \,I - E_T(t) \\ &S(t_0)=S_0=N - E_0 - I_0 - R_0 - D_0>0 \end{aligned}$$
(1a)
$$\begin{aligned} \dot{E}= \frac{\beta }{N} \,S\, I + E_T(t) - \kappa \, E \qquad E(t_0)=E_0\ge 0 \end{aligned}$$
(1b)
$$\begin{aligned} & \dot{I}= \kappa \, E - \gamma \,\big ( (1-\mu )\,I +\mu \,I(t-\tau ) \big )\\&I(t_0-\tau \le t\le t_0) = \varphi (t)>0 \end{aligned}$$
(1c)
$$\begin{aligned} \dot{R}= \left( 1 - \mu \right) \gamma \,I \qquad R(t_0)=R_0 \ge 0 \end{aligned}$$
(1d)
$$\begin{aligned} \dot{D}= \mu \, \gamma \,I(t-\tau ) \qquad D(t_0)=D_0 \ge 0 \end{aligned}$$
(1e)
Let \(X=(X_i)\) and \(Z=(Z_i)\) denote the daily new confirmed cases and deaths related to COVID-19 in Germany. The subscript i serves to point out the measurement at time point \(t_i\) as reported by the JHU [2]. Not all infections are by nature detected, from which case we introduce detection rates \(\delta\) for Germany and \(\delta _j\) for the destination country, respectively. For the persons which are currently infected or have recovered, we assume that only this proportion \(\delta\) or \(\delta _j\) is tested and detected and hence appears in the statistics; however, we assume no undetected deceased cases. We assume that the proportion of detected cases versus real infections is constant over the whole time interval, so that no temporal change of the detection rate is needed in our model. The initial value of the infected cases at the starting date \(t_0\) is later on subject of the estimation procedure. Therefore, we use the infected data as the real data divided by the detection rate, for Germany and destination countries, respectively:
$$\begin{aligned} \varphi (t):= \frac{\text {interp}\{(X_i)\}(t)}{\delta } \qquad t_0-\tau \le t\le t_0. \end{aligned}$$
(2)
As travel measures are relaxed as of June 15, we designed the starting time \(t_0\) of this model as June 1. This way we allow parameter estimation of the transmission rate \(\beta\) in the first two weeks which is fully independent of the travel impact rate \(\alpha\), so those parameters are not correlated during the optimization process (note that in Eq. (3) those parameters are multiplied with each other). The end date is fixed to 31 August because of the end of summer holidays (in most German states) and new restrictions in other countries from September onwards, e.g. a travel warning for Spain [4], which will affect the transmission parameters. The initial values are either gained from the JHU data sets [2] or introduced as free parameters which have to be optimized in the Metropolis algorithm. The function \(\varphi :[t_0-\tau , t_0]\rightarrow {\mathbb {R}}_+\) denotes the initial history of the infected required for the well-posedness of the above DDE; the value \(\tau\) is another free parameter. The number of travellers which have been exposed to the disease is defined as
$$\begin{aligned} E_T(t)= \alpha (t)\, \sum _j \frac{\beta ^{(j)}(t)}{N^{(j)}} \, { T_{\text {(0)}\leftrightarrow (j)}(t)\, I^{(j)}(t)}. \end{aligned}$$
(3)
The values \(I^{(j)}\) and \(N^{(j)}\) are defined by the number of infected people and respectively the resident population in country \((j)\ne (0)\) at time t. The function \(T_{\text {(0)}\leftrightarrow (j)}(t)\) describes the number of travellers from Germany to country j, whereby the superscript (0) denotes Germany from now on. Travellers are assumed to have a higher risk of getting infected, due to being more active, visiting places and travelling (e.g., in a plane) with more contacts than an average resident. Therefore, we define \(\alpha (t)\) to quantify the special risk of getting infected as a traveller. If \(\alpha \equiv 1\), then the transmission rate for travellers is equal to the country’s specific transmission rate \(\beta ^{(j)}(t)\). This rate is piecewise constant with switching returned from imposition or relaxation of certain measures. No inclusion of travellers due to bans or closed borders are identical to \(\alpha \equiv 0\).
Infection rate induced model
As we aim to estimate \(\beta _j(t)\) and \(I^{(j)}\) for all relevant countries, we have to set up another ODE system modelling the disease dynamics. Let (j) therefore be the specific country. For all countries \((j), j\in \{1,2,\dots ,M-1,M\}\) with M being the amount of observed countries, we estimate the local transmission rate \(\beta _j(t)\) as well as the amount of infected persons \(I^{(j)}(t)\) for all relevant time points by using an SEIRD model without a traveller compartment, while the total population \(N^{(j)}\) is assumed to be constant over time.
$$\begin{aligned} & \dot{S}^{(j)}= - \frac{\beta _j(t)}{N^{(j)}} \,S^{(j)}\, I^{(j)} \\ & S^{(j)}(t_0)=S^{(j)}_{0}=N^{(j)} - E^{(j)}_0 - I^{(j)}_0 - R^{(j)}_0 - D^{(j)}_0>0 \end{aligned}$$
(4a)
$$\begin{aligned} \dot{E}^{(j)}= \frac{\beta _j(t)}{N^{(j)}}\, S^{(j)} \,I^{(j)} - \kappa \quad E^{(j)} \dot{E}^{(j)}(t_0)=E^{(j)}_0\ge 0 \end{aligned}$$
(4b)
$$\begin{aligned} &\dot{I}^{(j)}= \kappa \, E^{(j)} - \gamma \,\big ( (1-\mu _j)\,I^{(j)} +\mu _j\, I^{(j)}(t-\tau _j) \big ) \\ & I^{(j)}(t\le t_0) = \varphi ^{(j)}(t) >0 \end{aligned}$$
(4c)
$$\begin{aligned} \dot{R}^{(j)}= \left( 1 - \mu _j\right) \,\gamma \,I^{(j)} \qquad R^{(j)}(t_0)= R^{(j)}_0 \ge 0 \end{aligned}$$
(4d)
$$\begin{aligned} \dot{D}^{(j)}= \mu _j\, \gamma \,I^{(j)}(t-\tau _j) \qquad D^{(j)}(t_0)=D^{(j)}_0 \ge 0 \end{aligned}$$
(4e)
Let again \(X^{(j)}=(X^{(j)}_i)\) and \(Z^{(j)}=(Z^{(j)}_i)\) denote the daily infection and death cases in the respective destination country as reported by the JHU [2]. Then, the history function is denoted analogously to before by
$$\begin{aligned} \varphi _j(t)&:= \frac{\text {interp}\{(X^{(j)}_i)\}(t)}{\delta _j}\qquad&t_0-\tau _j\le t\le t_0. \end{aligned}$$
(5)
The values for \(\kappa\) and \(\gamma\) are assumed to be independent of country (j). In the datasets for the countries, we find a sudden ‘step’ in the infection rates. This can not be modelled by travellers like in the model for Germany, which has two reasons: (1) Traveller data is not available for each country. (2) The reasons for the raised infection numbers in other countries are not of interest for the traveller model in Germany. Instead of using an additional parameter \(\alpha\) and a traveller compartment, we assume the transmission rates to be piecewise constant. By performing various simulations, the best-fitting ‘switching date’ where the rate is allowed to change value is found to be 20 July:
$$\begin{aligned} \beta _j(t) := {\left\{ \begin{array}{ll} \beta ^{(j)}_0, &{} t \le 19 \text { July} \\ \beta ^{(j)}_1, &{} 20 \text { July} \le t \\ \end{array}\right. } \end{aligned}$$
(6)
This system (4) is used both for the destination countries of German travellers and also for the model for Germany which does not include travellers (later on to be called model A). In the latter case, we can see the system as a special case of system (1) with \(j=0\), representing Germany. Travel restrictions are being relaxed as of 15 June [26]. This date is therefore assigned to be the starting time \(t_0\) for the destination countries, while the starting date remains 1 June for the no-travel model for Germany. The end date remains 31 August (in both cases) as we require the values of \(\beta _j\) and \(I^{(j)}\) until the end of the observed time interval, and of course nothing changes for the German model. The parameters \(N^{(j)}\) reflect the current total populations in all regarded countries which are the destination or origin of travellers from and to Germany; the population values are taken from UN data [19]. Results using the optimized parameters are also shown in Table 2.
Table 2 Fixed parameter values for the population \(N_j\) as well as the (estimated) number of Germans travelling to the respective country j, namely \(T_{\text {Germany}\leftrightarrow j}\), per month in summer 2020 and the transmission parameters \(\beta _{j,1/2}\) by application of Eq. (4) Travellers and travel impact rate
We only include European countries with available traveller statistics and countries outside of Europe with a total sum of more than 5000 travellers in the travelling statistics. For the close European countries, the number of travellers is estimated by the travel statistics of 2019 and 2020 for German travellers [20] (for relative shares) and hospitality statistics in Germany for foreign travellers [21]. The number of travellers from and to farther and non-European countries is gained from analysis of the flight passengers from the respective country [22]. In some larger countries, namely USA, Russia, China, and Japan, the data was problematic. Flight routes from and to these countries are often non-direct, so the plain values of flight passengers would underestimate the real amount of travellers to these countries. As a compromise, we assumed the amount of German travellers to those countries to be the same as the number of foreign visitors from those countries in Germany, which makes this estimation more meaningful. The populations and amount of travellers per month of this total of \(M=55\) countries is presented in Table 2.
By using this table, we can compute the daily value for \(T_{\text {(0)}\leftrightarrow (j)}\) by the number of travellers divided by the days in the respective month. E.g., for June, only the 16 days from 15 June to 30 June are considered. Average time of spending time here is 12 days so e.g. for July, we have \(T_{(0)\leftrightarrow (j)}=\) 331,894 \(\cdot \frac{12}{31\text {d}} \approx\) 128,475 day\(^{-1}\). The uncertainty in the value of 12 days for the average travel length is mitigated by the estimation of \(\alpha\), as these two values are directly multiplied and thus only the product of those two values is important.
In model B, \(\alpha (t)\) is assumed to be constant over time as soon as the travel ban is loosened:
$$\begin{aligned} \alpha (t) := {\left\{ \begin{array}{ll} 0 &{}t \le \text {14 June} \\ \alpha &{} 15 \text { June} \le t \le 31 \text { August} \\ \end{array}\right. } \end{aligned}$$
(7)
In model C, we define a piecewise constant function \(\alpha (t)\) as follows:
$$\begin{aligned} \alpha (t) := {\left\{ \begin{array}{ll} 0 &{}t \le \text {14 June} \\ \alpha _{0} &{} 15 \text { June} \le t \le 30 \text { June} \\ \alpha _{1} &{} 1 \text { July} \le t \le 31 \text { July} \\ \alpha _{2} &{} 1 \text { August} \le t \le 31 \text { August} \\ \end{array}\right. } \end{aligned}$$
(8)
This way, we are able to identify temporal differences in the travelling compartment, e.g. caused by a different social behaviour or loosened restrictions. The last three ‘switching points’ are arbitrarily chosen at the beginning of each month to account for the time-dependency of \(\alpha\).
Models, parameter bounds and initial values
The parameters to be estimated in Eqs. (1) and (4) are transmission rate, detection rate, lethality, time lag, travel impact rate and numbers of exposed on 1 June 2020 (Germany) respectively 15 June 2020 (all other countries). The optimal parameters \(u^{(j)*}\) and \(u^*\) are determined by solving the following maximization problems in the respective models. This results in consideration of the following three models, with an auxiliary model being pre-evaluated before handling models B and C.
Model A: Time-dependent transmission rate, starting 1 June
$$\begin{aligned}&\max _{u^{(0)}}\, L(u^{(0)}) \qquad \text {subject to ODE (4)} \\ \text {where}\quad &u^{(0)} = \left( \beta ^{(0)}_0,\beta ^{(0)}_1,\delta _0,\mu _0,\tau _0,E^{(0)}_0\right) \in {\mathbb {R}}^{6} \end{aligned}$$
(9)
Auxiliary model for models B and C: For all countries \(j=1,\dots , 55\), starting 15 June
$$\begin{aligned}&\max _{u^{(j)}}\, L(u^{(j)}) \qquad \text {subject to ODE (4)} \\ \text {where}\quad &u^{(j)} = \left( \beta ^{(j)}_0,\beta ^{(j)}_1,\delta _j,\mu _j,\tau _j,E^{(j)}_0\right) \in {\mathbb {R}}^{6}&\end{aligned}$$
(10)
Model B: Constant travel transmission parameter \(\alpha (t)\) from 15 June onwards
$$\begin{aligned}&\max _{u}\, L(u) \qquad \text {subject to ODE (1)} \\ \text {where}\quad &u = \left( \beta ,\delta ,\mu ,\tau , \alpha ,E_0\right) \in {\mathbb {R}}^{6} \end{aligned}$$
(11)
Model C: Piecewise linear travel transmission function \(\alpha (t)\) starting 15 June and jumps on 1 July and 1 August
$$\begin{aligned} &\max _{u}\, L(u) \qquad\, \text {subject to ODE (1)} \\ \text {where}\quad &u = \left( \beta ,\delta ,\mu ,\tau , \alpha _0, \alpha _1, \alpha _2,E_0\right) \in {\mathbb {R}}^{8} \end{aligned}$$
(12)
Table 3 shows the constraints for all parameters in the three models, which can also be used for \(u_j\) (with the starting values \(R_0\) and \(Z_0=D_0\) as listed on the JHU website [2]).
Table 3 Parameter constraints with the respective constraints of the fitted parameters Previous investigations by Götz and Heidrich [27] and Heidrich et al. [17] already give us orders of magnitude for the initial values of the optimization for \(\beta _i\) and \(\delta\). The order of magnitude of the time interval between the onset of infectiousness and death is derived from RKI modelling studies [25]. We allow a larger span in \(\tau\) and \(\tau _j\) than in [17] because the onset between infection and death is also dependent of the date on which the death case is registered in the statistics, where significantly different values depending on the country are possible here. A potential reason for this lies in different policies and procedures in reporting infection and death cases. The starting values at time \(t_0\) for the detected cumulated infected \(X_0\), detected recovered \(Y_0=\delta R_0\) and detected dead \(Z_0\) can be taken from the statistics. The initial number of infected is then defined as \(I_0=(X_0-Y_0-Z_0)/\delta\). Depending on the detection rate \(\delta\), the ‘real’ numbers \(I_0\) and \(R_0\) can be calculated by dividing those detected values by \(\delta\). For the initial guess on the ‘real’ number of exposed individuals \(E_0\) at time \(t_0\), we use a derivation using the Basic Reproduction Number \({\mathscr {R}}_0\), which indicates how many new infections an infected individual causes on average during its illness in an otherwise susceptible population. In our model, the share of infected persons \(I_0\) can either be at the start, the middle or the end of the infection, so several possible time stages of the infections are possible. The middle of this time interval is assumed to be the mean of all infected persons at time \(t_0\). Thus, up to this point in time they could infect about \({\mathscr {R}}_0/2\cdot I_0\) persons on average which then become exposed to the virus, i.e. this is identical to \(E_0\). Here, we assume that the initial basic reproductive number is approximately \({{\mathscr {R}}}_0\approx 1\) because of the stagnation of cases on a low level at the beginning of June.
Likelihood function
As seen in the previous section, the unknown parameter sets \(u^{(j)}\) and u will be estimated by maximisation of a likelihood function, which will be developed in this section. Note that the derivation of the function is described in detail only for u, but is equivalent for the likelihood function of \(u^{(j)}\).
We denote \({{\tilde{I}}}\) and \({{\tilde{R}}}\) as the difference between the daily infection cases, i.e. for \(i=1 \dots N\):
$$\begin{aligned} {{\tilde{I}}}_i&= \{\delta [I(t_{i+1})+R(t_{i+1})]+D(t_{i+1})\}-\{\delta [I(t_i)+R(t_i)]+D(t_i)\}\\ {{\tilde{D}}}_i&= D(t_{i+1})-D(t_i) \end{aligned}$$
(13)
Hence we compare the data X to the model output \({{\tilde{I}}}\) and \(X^{(j)}\) to \({{\tilde{I}}}^{(j)}\), as well as Z with \({{\tilde{D}}}\) and \(Z^{(j)}\) with \({{\tilde{D}}}^{(j)}\). At time \(t_i\), our model validation is subject to measurement error, which is assumed to be of degenerate multivariate Gaussian distribution with mean \((X_i,Z_i)\) or \((X^j_i,Z^j_i)\) and covariance matrix \(\Sigma\) or \(\Sigma ^j\), where one covariate corresponds to the measurement error from confirmed cases and the other to the deceased cases. The time invariance of the covariance matrix was opted only for the sake of simplicity. Further simplification may assert prior assumption that the covariance terms in the measurement error are zero, meaning that each error is an independent process. This leads us to \(\Sigma = \text {diag}(\sigma _Y,\sigma _Z)\) or \(\Sigma ^j = \text {diag}(\sigma ^j_X,\sigma ^j_Z)\). Our likelihood function for only time point \(t_i\) reads as
$$\begin{aligned} L_i(u):=\frac{1}{2\pi \sigma _X\sigma _Z}\exp \left( -\frac{({{\tilde{I}}}_i-X_i)^2}{\sigma _X^2}-\frac{({{\tilde{D}}}_i-Z_i)^2}{\sigma _Z^2}\right) . \end{aligned}$$
(14)
Assuming iid processes for all measurements at all time points, Kalbfleisch [28] pointed out a constant \(K=(2\pi )^N\) that serves to simplify the joint likelihood function
$$\begin{aligned} L(u) &=K\prod _i L_i(u) \\ &= \frac{1}{\sigma _X^N\sigma _Z^N}\exp \left( -\sum _i\frac{({{\tilde{I}}}_i-X_i)^2}{\sigma _X^2}+\frac{({{\tilde{D}}}_i-Z_i)^2}{\sigma _Z^2}\right) . \end{aligned}$$
(15)
Our study designates the standard deviations as to approximate the means of confirmed and deceased cases, \(\sigma _Y:=\Vert X\Vert /N\) and \(\sigma _Z:=\Vert Z\Vert /N\). Defining J(u) as the sum of squares error of the difference between data and estimation using the parameter set u, i.e.,
$$\begin{aligned} J(u)&= \sum _{i}\frac{({{\tilde{I}}}_i-X_i)^2}{\Vert X\Vert ^2}+\frac{({{\tilde{D}}}_i-Z_i)^2}{\Vert Z\Vert ^2}, \end{aligned}$$
(16)
the likelihood and log-likelihood function then read as
$$\begin{aligned} L(u)&= \frac{N^{2N}}{\Vert X\Vert ^N\Vert Z\Vert ^N}\exp \left( -N^2 J(u)\right) , \end{aligned}$$
(17)
$$\begin{aligned} \log L(u)&= \log \left( \frac{N^{2N}}{\Vert X\Vert ^N\Vert Z\Vert ^N}\right) -N^2 J(u). \\ &=N \left[2\log N- \log \Vert X\Vert -\log \Vert Z\Vert -NJ(u)\right]. \end{aligned}$$
(18)
As the calculation can be done equivalently for the destination countries (j), the log-likelihood \(\log L^{(j)}(u)\) is defined as
$$\begin{aligned} \log L^{(j)}(u)= N^{(j)} &\left[ 2\log N^{(j)} - \log \Vert X^{(j)}\Vert \right. \\ & \left. -\log \Vert Z^{(j)}\Vert -N^{(j)}J^{(j)}(u) \right]. \end{aligned}$$
(19)
Model specification
The aim in model specification for the fitting of the data is that we have a measure (criterion) based on fit and complexity (information-type criterion). Therefore, regarding models A, B, and C, we opt for a minimal value of the Bayesian Information Criterion
$$\begin{aligned} \text {BIC}=\log N \cdot |u|-2\log L(u) \end{aligned}$$
(20)
according to Raftery [29], whose first term measures complexity represented by the observation size N and the number of parameters |u|, while the second term represents the maximal likelihood function. Note that for the travel destination countries, we do not compare the model output as we only allow the travel-independent system (4). The BIC penalizes the number of parameters more than the Akaike Information Criterion (AIC) [30], where the latter would have replaced the factor \(\log (N)\) by 2. As far as model specification is concerned, our aim will be to choose between three models by selecting the model with minimal BIC as well as amending the question if the role of travellers is significant.
Metropolis algorithm
In our study, we use a Metropolis algorithm (cf. Metropolis et al. [31], Gelman et al. [32] or Gilks et al. [33]) for estimation of parameters in the ODE systems (1) and (4) according to the procedure described in Schäfer and Götz [34] and Heidrich, Schäfer et al. [17]. Using the parameter set \(u_0\) as of Table 4 as starting conditions, we assign random draws \(u_{new}\) from a normally distributed (and thus symmetric) proposal function q, i.e. \(u_{new} \sim q(u_{new}|u_{i-1})\), in every iteration i.
Table 4 Orders of magnitude of the initial values for adapting the model to the available data Using the previously defined J(u) as the target distribution, we calculate the approximative distribution by
$$\begin{aligned} \pi (u)=c \cdot \exp {\left( -{\frac{J(u)^2}{2 \sigma ^2}}\right) }, \end{aligned}$$
(21)
whereby c is an arbitrary real value. For the acceptance probability, it follows
$$\begin{aligned} p(u_{new}|u_{i-1})&=\min \left\{ 1, \frac{\pi (u_{new})\cdot q(u_{i-1}|u_i)}{\pi (u_{i})\cdot q(u_{i}|u_{i-1}))}\right\} \\ &=\min \left\{ 1, \frac{\pi (u_{new})}{\pi (u_{i})}\right\} . \end{aligned}$$
(22)
In Eq. (22) we can see that the value of c is redundant as it cancels out in the division. If the sample is accepted with the probability p, we set \(u_i=u_{new}\); with the probability \(1-p\), the sample is declined, meaning \(u=u_{i-1}\) according to Rusatsi [35] or Schäfer and Götz [34].
Confidence intervals of the parameters
Considering that the observation size N and the number of parameters |u| hold the relation \(N\gg |u|\), we adopt the idea of asymptotic confidence interval proposed in Teukolsky et al. [36]. Together with Raue et al. [37], these authors suggest that the asymptotic confidence interval can be a good approximation of the uncertainty in the optimal parameters \(u^*\) providing that, besides the aforementioned relation, the measurement error is relatively small as compared to the data. The formula of the confidence interval for each parameter \(u^*_k\) is given by \(\text {CI}_k:=\left[ u_k^*-\psi , u_k^*+\psi \right]\), with \(\psi\) being defined as
$$\begin{aligned} \psi :=\sqrt{2\chi ^2(q,df)\cdot \left( \nabla ^{-2}(-\log L(u^*))\right) _{kk}}. \end{aligned}$$
(23)
The operator \(\nabla ^{-2}\) denotes the inverse of the Hessian while \(\chi ^2(q,df)\) denotes the q quantile of the \(\chi ^2\) distribution with the degree of freedom df. The degree of freedom can be chosen between two that further determines the type of confidence interval: \(df=1\) gives the pointwise asymptotic confidence interval (PACI) that works on the individual parameter, \(df=|u|\) gives the simultaneous asymptotic confidence interval (SACI) that works jointly for all the parameters [36].
Current reproductive number
We also calculated the current 7-day reproduction number as of Götz et al. [38]: Defining the reproduction number \({\mathscr {R}}_{7,t}\) as the 7-day moving average of the infection cases at time t to the infection cases at time \(t-3\) (assuming an incubation period of \(\kappa ^{-1}=3\) days), we have
$$\begin{aligned} {\mathscr {R}}_{7,t}=\frac{\sum _{k=0}^{6} I_{t-k}}{ \sum _{k=0}^{6} I_{t-3-k}}. \end{aligned}$$
(24)
This ratio will be helpful to compare the results to the given infection data and find estimates on how the disease dynamics behave at least shortly after the investigated time interval.
Sensitivity analysis
To answer questions (Q1) and (Q2), the basic idea of sensitivity analysis lies in the definition of a certain measure \({\mathscr {M}}\) for variable change that is worth of investigation, especially when one would like to describe its sensitivity with respect to a parameter \(\vartheta\). The sensitivity of \({\mathscr {M}}\) with respect to \(\vartheta\) in the sense of first-order change can be measured using Taylor expansion. Suppose that \(\vartheta\) is increased to a certain percentage \(\varepsilon\) from its current value, i.e., \(\vartheta \mapsto \vartheta +\varepsilon \vartheta\). This way, the ratio \((\vartheta +\varepsilon \vartheta )/\vartheta =1+\varepsilon\) returns the total percentage post perturbation and \(\varepsilon\) denotes the additional percentage of gain. Note that imposing \(\varepsilon\) as the percentage is considered more robust than as simply the increase, considering that different parameters may live in disparate scales. Now, in the similar manner as for the parameter, the total percentage in \({\mathscr {M}}\) post perturbation on \(\vartheta\) is given by
$$\begin{aligned} \frac{{\mathscr {M}}(\vartheta +\varepsilon \vartheta )}{{\mathscr {M}}(\vartheta )}=1+\varepsilon \vartheta \frac{\partial _\vartheta {\mathscr {M}}(\vartheta )}{{\mathscr {M}}(\vartheta )}+{\mathscr {O}}(\varepsilon ^2) \end{aligned}$$
(25)
providing that \(\varepsilon\) is sufficiently small. Since the percentage of gain is usually considered similar across parameters, the role of \(\varepsilon\) in the preceding equation is often neglected. The remaining expression thus provides a measurement of the sensitivity. Usually, authors refer \(\partial _\vartheta {\mathscr {M}}(\vartheta )\) as the sensitivity index and \(\vartheta \partial _\vartheta {\mathscr {M}}(\vartheta )/{\mathscr {M}}(\vartheta )\) as the elasticity, cf. Rockenfeller et al. [39]. Between two parameters \(\vartheta _1,\vartheta _2\), it is logical to say that \({\mathscr {M}}\) is more sensitive to \(\vartheta _1\) than \(\vartheta _2\) when the absolute normalized sensitivity indices hold the relation
$$\begin{aligned} \left|\vartheta _1\frac{\partial _{\vartheta _1} {\mathscr {M}}(\vartheta _1)}{{\mathscr {M}}(\vartheta _1)}\right|> \left|\vartheta _2\frac{ \partial _{\vartheta _2} {\mathscr {M}}(\vartheta _2)}{ {\mathscr {M}}(\vartheta _2)}\right|. \end{aligned}$$
(26)
Time-dependent measures
The question (Q1) conveys the notion of model solution and addresses what our model solutions, including those excluded from the measurement or fitting, could have changed as we perturb the optimal parameter set, i.e. \(\Lambda =\{\beta , \alpha , E_T ,\kappa ,\mu ,\gamma ,\tau \}\). Our interest is now driven by all the measures \({\mathscr {M}}\) that represent model state variables \(\Psi =\{S,E,I,R,D\}\), which apparently are time-varying. To reveal the elasticity, one first compute the sensitivity index of state \(\psi _i\in \Psi\) with respect to parameter \(\lambda _j\in \Lambda\):
$$\begin{aligned} S_{ij}:=\frac{\text {d}}{\text {d} \lambda _j} \Psi _i \end{aligned}$$
(27)
from the sensitivity system of equations (cf. [39]):
$$\begin{aligned} S'_{ij}=\sum \limits _{k} S_{kj} \cdot \frac{\partial }{\partial \psi _k}f_i+\frac{\partial }{\partial \lambda _j}f_i, \qquad S_{ij}(0)=0 \;. \end{aligned}$$
(28)
The function f above defines the vector field of the model system, i.e., \({\dot{\Psi }}=f(t,\Psi ,\Lambda )\).
Time-independent measures
The question (Q2) is concerned more with interventions. In this case, we focus more on parameters that can be changed with the help of humans. In our context, such parameters could be \(\beta\) and \(\alpha\). The direct transmission rate \(\beta\) has always been related to the proximity of the susceptible against infected humans and can be reduced with the aid of masks and social/physical distancing. The parameter \(\alpha\) is related additional factors that drive the infection more than it could have been in the origin and destination country. For example, travellers are more exposed to physical encounters with other humans during flights, in public transportation, or in touristic areas, whereas locals spend more time at home. More protective apparatuses and educational campaigns will help reduce \(\alpha\). In this regard, two different measures for the sensitivity can be considered. For the first choice, we may take, for example, \({\mathscr {M}}:=\int _0^TI\,\text {d}t\), which represents the total number of infected cases over all observations. If \(\alpha ,\beta >0\), \({\mathscr {M}}\) is then more sensitive to \(\beta\) rather than \(\alpha\) when it holds
$$\begin{aligned} \beta \cdot \left|\frac{ \int _0^T\partial _{\beta }I\,\text {d}t}{ \int _0^TI \,\text {d}t}\right|> \alpha \cdot \left|\frac{\int _0^T\partial _{\alpha }I\,\text {d}t}{\int _0^T I\,\text {d}t} \right|. \end{aligned}$$
(29)
This inequality, however, includes the terms \(|\int _0^T\partial _{\beta }I\,\text {d}t|,|\int _0^T\partial _{\alpha }I\,\text {d}t|\) that do not account for entropy or state of disorder. However, it is possible that the integral vanishes due to oscillations of the integrand \(\partial _{\alpha }I\). This will result in a small sensitivity index rather than \(\partial _{\beta }I\) that just forms a ‘calm’ trajectory above zero, so that the result would not be meaningful. To account for the entropy, we shall therefore consider the second measure
$$\begin{aligned} {\mathscr {M}}:=\int _0^{{{\hat{\beta }}}}\int _0^T|\partial _{\beta }I(t,s)|\,\text {d}t\text {d}s, \end{aligned}$$
(30)
which represents the total variation of I with respect to \(\beta\), evaluated up to the current parameter value \({{\hat{\beta }}}\). Now, \({\mathscr {M}}\) is said to be more sensitive to \(\beta\) than \(\alpha\) (or vice versa) if
$$\begin{aligned} {\hat{\beta \cdot }} \left|\frac{ \int _0^T|\partial _{\beta }I|\,\text {d}t}{ \int _0^{{{\hat{\beta }}}}\int _0^T|\partial _{\beta }I(t,s)|\,\text {d}t\text {d}s}\right|>{\hat{\alpha }}\cdot \left|\frac{ \int _0^T|\partial _{\alpha }I|\,\text {d}t}{ \int _0^{{{\hat{\alpha }}}}\int _0^T|\partial _{\alpha }I(t,s)|\,\text {d}t\text {d}s}\right|. \end{aligned}$$
(31)
From the computational perspective, one can define a certain grid representing domain of interest for the two parameters, for example \([\beta _{\min },\beta _{\max }]\times [\alpha _{\min },\alpha _{\max }]\). The next step follows from computing the sensitivity indices for all grid points and applies the ratio of actual total variation and accumulated total variation as in Eq. (31). Therefore, the left-hand side should be done via stepping \(\alpha\) (vertical mode) and the right-hand side via stepping \(\beta\) (right mode).