# The wild bootstrap for multivariate Nelson–Aalen estimators

## Abstract

We rigorously extend the widely used wild bootstrap resampling technique to the multivariate Nelson–Aalen estimator under Aalen’s multiplicative intensity model. Aalen’s model covers general Markovian multistate models including competing risks subject to independent left-truncation and right-censoring. This leads to various statistical applications such as asymptotically valid confidence bands or tests for equivalence and proportional hazards. This is exemplified in a data analysis examining the impact of ventilation on the duration of intensive care unit stay. The finite sample properties of the new procedures are investigated in a simulation study.

## Keywords

Conditional central limit theorem Counting process Equivalence test Proportional hazards Kolmogorov–Smirnov test Survival analysis Weak convergence## 1 Introduction

One of the most crucial quantities within the analysis of time-to-event data with independently right-censored and left-truncated survival times is the cumulative hazard function, also known as cumulative transition intensity. Most commonly, it is nonparametrically estimated by the well-known *Nelson–Aalen estimator* (Andersen et al. 1993, Chapter IV). In this context, time-simultaneous confidence bands are the perhaps best interpretative tool to account for related estimation uncertainties.

The construction of confidence bands is typically based on the asymptotic behavior of the underlying stochastic processes, more precisely, the (properly standardized) Nelson–Aalen estimator asymptotically behaves like a Wiener process. Early approaches utilized this property to derive confidence bands for the cumulative hazard function; see e.g., Bie et al. (1987) or Section IV.1.3 in Andersen et al. (1993).

However, Dudek et al. (2008) found that this approach applied to small samples can result in considerable deviations from the nominal level. To improve small sample properties, Efron (1979, 1981) suggested a computationally convenient and flexible resampling technique, called *bootstrap*, where the unknown non-Gaussian quantile is approximated via repeated generation of point estimates based on random samples of the original data. For a detailed discussion within the standard right-censored survival setup, see also Akritas (1986), Lo and Singh (1986), and Horvath and Yandell (1987). The simulation study of Dudek et al. (2008) particularly reports improvements of bootstrap-based confidence bands for the hazard function as compared to those using asymptotic quantiles. An alternative is the so-called *wild bootstrap* firstly proposed in the context of regression analyses (Wu 1986). As done in Lin et al. (1993), the basic idea is to replace the (standardized) residuals with independent standardized variates—so-called multipliers—while keeping the data fixed. One advantage compared to Efron’s bootstrap is to gain robustness against variance heteroscedasticity (Wu 1986). Using standard normal multipliers, this resampling procedure has been applied to construct time-simultaneous confidence bands for survival curves under the Cox proportional hazards model (Lin et al. 1994) and adapted to cumulative incidence functions in the competing risks setting (Lin 1997). The latter approach has recently been extended to general wild bootstrap multipliers with mean zero and variance one (Beyersmann et al. 2013), which indicate possible improved small sample performances. This result was confirmed in Dobler and Pauly (2014) as well as Dobler et al. (2017), where more general resampling schemes are discussed. In all these references, only one multiplier, typically standard normal, was required per individual, because each individual experienced at most one event. If an individual may experience more than one event, multiple multipliers per individual were, e.g., considered by Dabrowska and Ho (2000) in the context of Cox modelling, see also Shu et al. (2007) for Cox models in a semi-Markov illness-death model, and Liu et al. (2008) in a progressive multistate model for current leukemia free survival.

The present article focuses on the nonparametric estimation of cumulative hazard functions and proposes a general and flexible wild bootstrap resampling technique, which is valid for a large class of time-to-event models. In particular, the procedure is not limited to the standard survival or competing risks framework. The key assumption is that the involved counting processes satisfy the so-called *multiplicative intensity model* (Andersen et al. 1993). Consequently, arbitrary Markovian multistate models with finite state space are covered, as well as various other intensity models (e.g., excess or relative mortality models, cf. Andersen and Væth 1989) and specific semi-Markov situations (Andersen et al. 1993, Example X.1.7). Independent right-censoring and left-truncation can straightforwardly be incorporated.

The main aim of this article is to mathematically justify the wild bootstrap technique for the multivariate Nelson–Aalen estimator in this general framework, while using not necessarily normally distributed but possibly multiple multipliers per counting process in the resampling step, This is accomplished by a novel martingale-based proof that discloses the close connection between the estimator and its wild bootstrap version. This insight would not have been possible by generalizing the elementary approach for showing bootstrap validity in competing risks given in Beyersmann et al. (2013) and Dobler and Pauly (2014) to the present set-up. Compared to the standard survival or competing risks setting, with at most one transition per individual, the major difficulty is to account for counting processes having an arbitrarily large random number of jumps. We will see that utilizing only one multiplier per individual counting process leads to the wrong covariance structure in general; instead, one multiplier per increment is required. As Beyersmann et al. (2013) suggested in the competing risks setting, we also allow for more general multipliers with expectation 0 and variance 1 and extend the resulting weak convergence theorems to resample the multivariate Nelson–Aalen estimator in our general setting. For practical applications, this result allows, for instance, within- or two-sample comparisons and the formulation of statistical tests.

The wild bootstrap is exemplified to statistically assess the impact of mechanical ventilation in the intensive care unit (ICU) on the length of stay. A related problem is to investigate ventilation-free days, which was established as an efficacy measure in patients subject to acute respiratory failure (Schoenfeld et al. 2002). However, applications of their methodology (see e.g., Sauaia et al. 2009; Stewart et al. 2009) rely on the constant hazards assumption. Other publications like de Wit et al. (2008), Trof et al. (2012), or Curley et al. (2015) used a Kaplan–Meier-type procedure that does not account for the more complex multistate structure. In contrast, we propose an illness-death model with recovery that methodologically works under the more general time-inhomogeneous Markov assumption and captures both the time-dependent structure of mechanical ventilation and the competing endpoint ‘death in ICU’.

The remainder of this article is organized as follows: Sect. 2 introduces cumulative hazard functions and their Nelson–Aalen estimators using counting process formulations. After summarizing its asymptotic properties, Sect. 3 offers our main theorem on conditional weak convergence for the wild bootstrap. This allows for various statistical applications in Sect. 4: Two-sided hypothesis tests and various sorts of time-simultaneous confidence bands are deduced, as well as simultaneous confidence intervals for a finite set of time points. Furthermore, tests for equivalence, inferiority and superiority as well as for proportionality of two hazard functions constitute useful criteria in practical data analyses. A simulation study assessing small and large sample performances of both the derived confidence bands in comparison to the algebraic approach based on the time-transformed Brownian motion and the tests for proportional hazards is reported in Sect. 5. The SIR-3 data on patients in ICU (Beyersmann et al. 2006; Wolkewitz et al. 2008) serves as its template and is practically revisited in Sect. 6. Concluding remarks and a discussion are given in Sect. 7. All proofs are deferred to Appendix A and the non-applicability of the ordinary multiplier resampling is verified in Appendix B.

## 2 Nonparametric estimation under the multiplicative intensity structure

Throughout, we adopt the notation of Andersen et al. (1993). For \({k\in \mathbb {N}}\), let \(\mathbf N =\left( N_1,\ldots ,N_k\right) '\) be a multivariate counting process which is adapted to a filtration \(({\mathcal {F}}_t)_{t \ge 0}\). Each entry \(N_j, j=1,\dots ,k,\) is supposed to be a càdlàg function, zero at time zero, and to have piecewise constant paths with jumps of size one. In addition, assume that no two components jump at the same time and that each \(N_{j}(t)\) satisfies the *multiplicative intensity model* of Aalen (1978) with intensity process given by \(\lambda _j(t) = \alpha _j(t) Y_j(t)\). Here, \(Y_j(t)\) defines a predictable process not depending on unknown parameters and \(\alpha _j\) describes a non-negative (hazard) function. For well-definiteness, the observation of \(\mathbf N \) is restricted to the interval \([0,\tau ]\), where \(\tau< \tau _j = {\sup }\big \{ u \ge 0 :\int _{(0,u]}\alpha _j(s)ds<\infty \big \} \ \text {for all } j = 1, \dots , k.\) The multiplicative intensity structure covers several customary frameworks in the context of time-to-event analysis. The following overview specifies frequently used models.

### Example 1

- (a)
Markovian multistate models with finite state space \({\mathcal {S}}\) are very popular in biostatistics. In this setting, \(Y_\ell (t)\) represents the total number of individuals in state \(\ell \) just prior to

*t*(‘number at risk’), whereas \(\alpha _{\ell m}(t)\) is the instantaneous risk (‘transition intensity’) to switch from state \(\ell \) to*m*, where \(\ell , m \in {\mathcal {S}}\), \(\ell \ne m\). Here, \(N_\ell = \sum _{i=1}^n N_{\ell ;i}\) is the aggregation over individual-specific counting processes with \(n \in \mathbb {N}\) individuals under study. For specific examples (such as competing risks or the illness-death model) and details including the incorporation of independent left-truncation and right-censoring, see Andersen et al. (1993) and Aalen et al. (2008). - (b)
Other examples are the relative or excess mortality model, where not all individuals necessarily share the same hazard rate \(\alpha \). In this case

*Y*cannot be interpreted as the total number of individuals at risk as in part (a); see Example IV.1.11 in Andersen et al. (1993) for details. - (c)The time-inhomogeneous Markov assumption required in part (a) can even be relaxed in specific situations: Following Example X.1.7 in Andersen et al. (1993), consider an illness-death model without recovery. Assuming that the transition intensity \(\alpha _{12}\) depends on the duration
*d*in the intermediate state, but not on time*t*, leads to a semi-Markov process not satisfying the multiplicative intensity structure. This is because the intensity process of \(N_{12}(t)\) is given by \(\alpha _{12}(t-T)Y_1(t)\), where the first factor of the product is not deterministic anymore. Here,*T*is the random transition time into state 1. However, when \(d=t-T\) is used as the basic timescale, the counting process \(K(d)=N_{12}(d+T)\) has intensity \(\alpha _{12}(d)Y_1(d)\) with respect to the filtration$$\begin{aligned} {\mathcal {F}}_d=\left( \sigma \lbrace (N_{01}(t), N_{02}(t)): 0<t<\tau \rbrace \vee \sigma \lbrace K(d): 0<d<\infty \rbrace \right) . \end{aligned}$$

Thus, the multiplicative intensity structure is fulfilled.

*Nelson–Aalen estimator*

*j*, define the normalized Nelson–Aalen process \(W_{jn}:=\sqrt{n} ( \hat{A}_{jn}-A_j )\) possessing the asymptotic martingale representation

*k*-dimensional space \(\mathfrak {D}[0,\tau ]^k\) of càdlàg functions endowed with the product Skorohod topology.

### Theorem 1

*Aalen-type*

*Greenwood-type*estimator

*s*.

## 3 Inference via Brownian bridges and the wild bootstrap

As discussed in Andersen et al. (1993), the limit process \({{\varvec{U}}}\) can analytically be approximated via Brownian bridges. However, improved coverage probabilities in the simulation study in Sect. 5 suggest that the proposed wild bootstrap approach may be preferable. First, we sum up the classic result.

### 3.1 Inference via transformed Brownian bridges

*g*be a positive (weight) function on an interval \([t_1,t_2]\subset [0,\tau ]\) of interest and \(B^0\) a standard Brownian bridge process. Then, as \(n \rightarrow \infty \), it is established in Section IV.1 in Andersen et al. (1993) that

*g*, they can be approximated via standard statistical software.

Even though relation (3.1) enables statistical inference based on the asymptotics of a central limit theorem, appropriate resampling procedures usually showed improved properties; see e.g., Hall and Wilson (1991), Good (2005) and Pauly et al. (2015).

### 3.2 Wild bootstrap resampling

*n*, the number \(N_{j}(\tau )\) is not necessarily bounded in our setup only assuming Aalen’s multiplicative intensity model. Hence, a modification of the multiplier resampling scheme under competing risks suggested by Lin (1997) and elaborated by Beyersmann et al. (2013) is required. For this purpose, introduce counting process-specific stochastic processes indexed by \(s \in [0,\tau ]\) that are independent of \(N_j, Y_j\) for all \(j=1,\dots ,k\). Let \((G_j(s))_{s \in [0,\tau ]}, 1 \le j \le k,\) be independently and identically distributed (i.i.d.) white noise processes such that each \(G_j(s)\) satisfies \(\mathbb {E}(G_j(s)) = 0\) and \(var(G_j(s))=1\), \(j=1,\dots ,k\), \(s \in [0,\tau ]\). That is, all \(\ell \)-dimensional marginals of \(G_1\), \(\ell \in \mathbb {N}\), shall be the same \(\ell \)-fold product-measure. Then, a

*wild bootstrap version*of the normalized multivariate Nelson–Aalen estimator \({{\varvec{W}}}_n\) is defined as

*observable*quantities \(G_{j} N_{j}\). Even though only the values of each \(G_j\) at the jump times of \(N_j\) are relevant, this construction in terms of white noise processes enables a consideration of the wild bootstrap process on a product probability space; see the Appendix for details.

Consider for a moment the special case of a multistate model with *n* i.i.d. individuals (Example 1(a)). For instance, the competing risks model in Lin (1997) involves at most one transition (and thus one multiplier) per individual, while Glidden (2002) introduces only one multiplier per individual for estimating state occupation probabilities in general non-Markov multistate models. In contrast, our resampling approach is a new approach in the sense that it involves independent weightings of all jumps even within the same individual. The consequence is that, instead of considering one multiplier per individual, we need to utilize a white noise processes as done in (3.2) in order to account for randomly many numbers of events per individual.

The limit distribution of \(\hat{{{\varvec{W}}}}_n\) may be approximated by simulating a large number of replicates of the *G*’s, while the data is kept fixed. For a competing risks setting with standard normally distributed multipliers, our general scheme reduces to the one discussed in Lin (1997).

### Lemma 1

The following conditional weak convergence result justifies the approximation of the limit distribution of \({{\varvec{W}}}_{n}\) via \(\hat{{{\varvec{W}}}}_n\) given \(\mathcal {C}_0\). Both, the general framework requiring only Aalen’s multiplicative intensity structure as well as using possibly non-normal multipliers are original to the present paper.

### Theorem 2

### Remark 1

- (a)
Reconsider the ordinary multiplier resampling based on a sequence of (time-constant) i.i.d. random variables \(D_1, \dots , D_n\) with \(E(D_1) = 0\) and unit variance where, in the resampling step, the martingales \(M_j\) are replaced with \(D_j N_j\). In contrast to the wild bootstrap based on white noise processes, the wild bootstrap using the time-constant sequence \(D_1, \dots , D_n\) fails to reproduce the correct covariance structure of the Nelson–Aalen process. Even in the special univariate Markovian case, the limit process does not have independent increments and it hence necessarily differs from the asymptotics described in Theorem 2; see Appendix B for details.

- (b)
It is due to the martingale property of the wild bootstrapped multivariate Nelson–Aalen estimator that we anticipate a good finite sample approximation of the unknown distribution of the Nelson–Aalen estimator. In particular, the wild bootstrap, realized by white noise processes as above, succeeds in imitating the martingale structure of the original Nelson–Aalen estimator. The predictable variation process of the wild bootstrap process equals the optional variation process of the centered Nelson–Aalen process. Hence, both processes share the same properties and approximately the same covariance structure.

- (c)
Suppose that \(E(n^k J_1(u) / Y_1^k(u)) = O(1)\) for some \(k \in \mathbb {N}\) and all \(u \in [0,\tau ]\), which for example holds for any \(k \in \mathbb {N}\) if \(Y_1\) has a number at risk interpretation. Since different increments of \({{\varvec{W}}}_n\) (to arbitrary powers) are uncorrelated, it can be shown that the convergence in Theorem 1 for single \(t \in [0,\tau ]\) even holds in the Mallows metric \(d_p\) for any \(0 < p \le k\); see, for instance, Bickel and Freedman (1981) for such theorems related to the classical bootstrap. Provided that the

*r*th moment of \(G_1(u)\) exists, similar arguments show that the convergence in probability in Theorem 2 for single \(t \in [0,\tau ]\) holds in the Mallows metric \(d_p\) for any even \(0 < p \le r\) as well. This of course includes white noise processes with centered*Poi*(1) or standard normal marginals, as applied later on.

## 4 Statistical applications

Throughout this section denote by \(\alpha \in (0,1)\) the nominal level of all inference procedures.

### 4.1 Confidence bands

*g*in relation (3.1). The resulting confidence bands are commonly known as

*equal precision*and

*Hall–Wellner*bands, respectively. We apply a log-transformation in order to improve small sample level \(\alpha \) control. Combining the previous sections’ convergences with the functional delta-method and Slutsky’s lemma yields

### Theorem 3

*dN*(

*s*).

*g*equals either \(g_1\) or \(g_2\) and \(\hat{\phi } = \frac{\hat{\sigma }^2}{1+\hat{\sigma }^2}\). Note, that \(\tilde{c}_{1-\alpha }^g\) is, in fact, a random variable. The results are back-transformed into four confidence bands for

*A*abbreviated with

*HW*and

*EP*for the Hall–Wellner and equal precision bands and

*a*and

*w*for bands based on quantiles of the asymptotic distribution and the wild bootstrap, respectively. In our simulation studies these bands are also compared with the linear confidence band \(CB_{dir}^w\), which is based on the critical value

### Corollary 1

### Remark 2

- 1.
Note that the wild bootstrap quantile \(\tilde{c}_{1-\alpha }\) does not require an estimate of \(\phi \), thereby eliminating one possible cause of inaccuracy within the derivation of the other bands. However, the corresponding band \(\textit{CB}_{dir}^w\) has the disadvantage to possibly include negative values.

- 2.
The confidence bands are only well-defined if the left endpoint \(t_1\) of the bands’ time interval is larger than the first observed event. In particular, these bands yield unstable results for small values of \(\hat{A}_n(t_1)\) due to the division in the exponential function; see Lin et al. (1994) for a similar observation.

- 3.The present approach directly allows the construction of confidence bands for within-sample comparisons of multiple \(A_1, \dots , A_k\). For instance, a confidence band for the difference \(A_1 - A_2\) may be obtained via quantiles based on the conditional convergence in distribution \(\hat{W}_{1n} - \hat{W}_{2n} {\mathop {\longrightarrow }\limits ^{d}} U_1 - U_2 \sim Gauss( 0, \psi _1 + \psi _2)\) in probability by simply applying the continuous mapping theorem and taking advantage of the independence of \(U_1\) and \(U_2\); see Whitt (1980) for the continuity of the difference functional. For that purpose, the distribution ofwith positive weight function$$\begin{aligned} D(t)=\sqrt{n} g(t)(\hat{A}_{1n}(t)-A_1(t)-(\hat{A}_{2n}(t)-A_2(t))), \end{aligned}$$(4.4)
*g*can be approximated by the conditional distribution of \(\hat{D}(t)= g(t) (\hat{W}_{1n}(t)-\hat{W}_{2n}(t))\). With \(g\equiv 1\), an approximate \((1-\alpha )\cdot 100\%\) confidence band for the difference \(A_1 - A_2\) of two cumulative hazard functions on \([t_1,t_2]\) iswhere$$\begin{aligned} \left[ \left( \hat{A}_1(s)-\hat{A}_2(s)\right) \pm \tilde{q}_{1-\alpha } / \sqrt{n}\right] _{s\in [t_1,t_2]}, \end{aligned}$$(4.5)Similar arguments additionally enable common two-sample comparisons. A practical data analysis using other weight functions$$\begin{aligned} \quad \tilde{q}_{1-\alpha }&= (1-\alpha ) \text { quantile of} \quad \mathfrak {L} \Big ( \sup _{s \in [t_1,t_2]} \big |\hat{W}_{1n}(s)-\hat{W}_{2n}(s) \big | \Big | \ \mathcal {C}_0 \Big ). \end{aligned}$$*g*in the context of cumulative incidence functions is given in Hieke et al. (2013).

### Remark 3

(*Construction of confidence intervals*)

- 1.
In particular, Theorem 3 yields a convergence result on \(\mathbb {R}^m\) for a finite set of time points \(\{s_1, \dots , s_m \}\subset [0,\tau ] , m \in \mathbb {N}\). Hence, using critical values \(\tilde{c}_{1-\alpha }\) and \(\tilde{c}_{1-\alpha }^g\) obtained from the law of the maximum \(\max _{s_1, \dots , s_m}\) instead of the supremum, a variant of Corollary 1 specifies simultaneous confidence intervals \(I_1 \times \dots \times I_m\) for \((A(s_1), \dots , A(s_m))\) with asymptotic coverage probability \(1-\alpha \). Since the error multiplicity is taken into account, the asymptotic coverage probability of a single such interval \(I_j\) for \(A(s_j)\) is greater than \(1-\alpha \).

- 2.
Due to the asymptotic independence of the entries of the multivariate Nelson–Aalen estimator, a confidence region for the value of a multivariate cumulative hazard function \((A_1(t), \dots , A_k(t))\) at time \(t \in [0,\tau ]\) may be found using Šidák’s correction: Letting \(J_1, \dots , J_k\) be pointwise confidence intervals for \(A_1(t),\)\(\dots ,\)\(A_k(t)\) with asymptotic coverage probability \((1-\alpha )^{1/k}\), each found using the wild bootstrap principle, the coverage probability of \(J_1 \times \dots \times J_k\) for \(A_1(t) \times \dots \times A_k(t)\) clearly goes to \(1 -\alpha \) as \(n \rightarrow \infty \).

### 4.2 Hypothesis tests for equivalence, inferiority, superiority, and equality

*A*shall be tested. More precisely:

### Corollary 2

Under the assumptions of Theorem 3, a hypothesis test \(\psi _n\) of asymptotic level \(\alpha \) for *H* vs *K* is given by the following decision rule: Reject *H* if and only if the combined two-sided confidence band \((a_n(s),b_n(s))_{s \in [t_1,t_2]}\) is fully contained in the region spanned by \((A_0(s) - \ell (s), A_0(s) + u(s))_{s \in [t_1,t_2]} \). Further, it holds under *K* that \(\mathbb {E}(\psi _n) \rightarrow 1\) as \(n\rightarrow \infty \), i.e., \(\psi _n\) is consistent.

### Corollary 3

*g*again be a positive weight function,

### 4.3 Tests for proportionality

A major assumption of the widely used Cox (1972) regression model is the assumption of proportional hazards over time. Several authors have developed procedures for testing the null hypothesis of proportionality, see e.g., Gill and Schumacher (1987), Lin (1991), Grambsch and Therneau (1994), Hess (1995), Scheike and Martinussen (2004), Kraus (2007), Bagdonavičius et al. (2010), or Chen et al. (2015), and the references cited therein. However, most of these approaches have mainly been investigated for the standard survival framework under (independent) right-censoring and left-truncation mechanisms, even though they may be generalized to more general settings. In the context of the proposed wild bootstrap resampling technique, this motivates the explicit formulation of a two-sample proportionality test for the general setting only assuming a multiplicative intensity structure. This covers, for instance, arbitrary Markovian multistate models.

### Theorem 4

## 5 Simulation study

*illness-death model with recovery*. As illustrated in the multistate pattern of Fig. 1, the model has state space \({\mathcal {S}}=\lbrace 0,1,2\rbrace \) and includes the transition hazards \(\alpha _{01},\ \alpha _{10},\ \alpha _{02},\) and \(\alpha _{12}\). The simulation of the underlying quantities is based on the methodology suggested by Allignol et al. (2011) generalized to the time-inhomogeneous Markovian multistate framework, which can be seen as a nested series of competing risks experiments. More precisely, the individual initial states are derived from the proportions of individuals at \(t=0\) and the censoring times are obtained from a multinomial experiment using probability masses equal to the increments of the censoring Kaplan–Meier estimate originated from the SIR-3 data. Similarly, event times are generated according to a multinomial distribution with probabilities given by the increments of the original Nelson–Aalen estimators. These times are subsequently included into the multistate simulation algorithm described in Beyersmann et al. (2012), Section 8.2. Since censoring times are sampled independently and each simulation step is only based on the current time and the current state, the resulting data follows a Markovian structure. A more formal justification of the multistate simulation algorithm can be found in Gill and Johansen (1990) and Theorem II.6.7 in Andersen et al. (1993).

Mean number of events per transition on [5, 30] provided by the simulation study of Sect. 5

Sample size | Transition | |||
---|---|---|---|---|

\(1\rightarrow 0\) | \(0\rightarrow 1\) | \(0\rightarrow 2\) | \(1\rightarrow 2\) | |

93 | 20.1 | 4.3 | 43.9 | 10.1 |

186 | 42.7 | 8.3 | 96.5 | 21.7 |

373 | 85.6 | 17.0 | 193.4 | 43.7 |

747 | 170.9 | 33.9 | 387.4 | 87.4 |

\(747^{\mathrm{a}}\) | 171 | 34 | 387 | 87 |

We consider three different sample sizes: The original number of 747 patients is stepwisely reduced to 373, 186, and 93 patients. For each scenario we simulate 1000 studies. As an overview, the mean number of events for each possible transition and scenario is illustrated in Table 1.

The mean number of events regarding 747 patients reflects the original number of events. All numbers are restricted to the time interval [5,30], which is chosen due to a small amount of events before \(t=5\) (left panel of Fig. 2). Further, less than 10% of all individuals are still under observation after day 30. In particular, asymptotic approximations tend to be poor at the left- and right-hand tails; cf. Remark 2(b) and Lin (1997).

Empirical coverage probabilities (%) from the simulation study of Sect. 5 separately for each transition and different simulated number of individuals

Transition | | Type of confidence band | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|

Brownian bridge | Wild bootstrap | ||||||||||

95% log EP | 95% log HW | 95% log EP | 95% log HW | 95% direct | |||||||

Aalen | Greenwood | Aalen | Greenwood | Poisson | Standard normal | Poisson | Standard normal | Poisson | Standard normal | ||

\(0\rightarrow 1\) | 373 | 96.4 | 95.9 | 95.5 | 95.3 | 92.5 | 92.5 | 92.5 | 92.5 | 91.4 | 91.9 |

747 | 97.7 | 97.3 | 97.2 | 97.0 | 95.0 | 94.9 | 95.2 | 95.0 | 92.9 | 93.2 | |

\(0\rightarrow 2\) | 93 | 98.0 | 97.1 | 98.4 | 97.3 | 97.6 | 97.8 | 97.3 | 96.0 | 96.6 | 96.6 |

186 | 98.3 | 95.5 | 98.9 | 97.4 | 97.2 | 98.2 | 98.0 | 96.1 | 96.2 | 96.2 | |

373 | 98.1 | 95.0 | 98.2 | 96.9 | 97.2 | 97.3 | 97.1 | 97.1 | 96.0 | 96.3 | |

747 | 98.6 | 96.2 | 98.8 | 97.7 | 97.7 | 97.8 | 97.4 | 97.8 | 96.0 | 96.2 | |

\(1\rightarrow 0\) | 93 | 97.0 | 94.9 | 97.0 | 95.2 | 95.1 | 95.1 | 94.8 | 94.8 | 93.7 | 93.7 |

186 | 97.3 | 95.8 | 97.7 | 96.1 | 95.6 | 95.7 | 95.7 | 95.4 | 94.5 | 94.3 | |

373 | 97.2 | 96.3 | 97.9 | 97.0 | 95.2 | 95.3 | 95.9 | 96.3 | 95.2 | 95.3 | |

747 | 97.8 | 96.8 | 97.5 | 96.9 | 96.6 | 96.6 | 95.9 | 96.0 | 96.1 | 96.3 | |

\(1\rightarrow 2\) | 186 | 97.5 | 96.7 | 97.2 | 96.2 | 94.7 | 94.5 | 94.3 | 94.7 | 93.2 | 93.3 |

373 | 98.2 | 97.7 | 98.2 | 97.8 | 95.8 | 95.8 | 95.1 | 95.2 | 94.6 | 94.3 | |

747 | 97.2 | 96.6 | 96.6 | 96.0 | 94.4 | 95.5 | 94.3 | 94.7 | 94.9 | 95.1 |

Following Table 2, almost all bands constructed via Brownian bridges consistently tend to be rather conservative in our setting, i.e., result in too broad bands. Here, the usage of the Greenwood-type variance estimate yields more accurate coverage probabilities compared to the Aalen-type estimate. In contrast, the wild bootstrap approach mostly outperforms the Brownian bridge procedures: The log-transformed wild bootstrap bands approximately keep the nominal level even in the smaller sample sizes, except for the \(0 \rightarrow 1\) transition with smallest sample size (corresponding to only 17 events in the mean; cf. Table 1). We also observe that the log-transformation in general improves coverage for the wild bootstrap procedure. The current simulation study showed no clear preference for the choice of weight. Note that all wild bootstrap bands for transition \(0\rightarrow 2\) show a similar, but mostly reduced conservativeness compared to the bands provided by Brownian bridges. We have to emphasize that coverage probabilities for the cumulative hazard functions are drastically decreased to approximately 75% in all sample sizes if log-transformed pointwise confidence intervals would wrongly be interpreted time-simultaneously (results not shown).

The second set of simulations follows the test for proportional hazards derived in Theorem 4 with regard to keeping the preassigned error level under the null hypothesis. For that purpose, we assume a competing risks model with two competing events separately for two unpaired patient groups. For an illustration, see for instance, Figure 3.1 in Beyersmann et al. (2012).

We consider four different constant hazard scenarios: (I) the hazards for the type-1 event are set to \(\alpha ^{(1)}_{01}(t)=\alpha ^{(2)}_{01}(t)=2\) (no effect on the type-1 hazard, in particular, a hazard ratio of \(c=1\)); (II) \(\alpha ^{(1)}_{01}(t)=1\) and \(\alpha ^{(2)}_{01}(t)=2\) (large effect); (III) \(\alpha ^{(1)}_{01}(t)=\alpha ^{(2)}_{01}(t)=1\); (IV) \(\alpha ^{(1)}_{01}(t)=1\) and \(\alpha ^{(2)}_{01}(t)=1.5\) (moderate effect). In each scenario, we set \(\alpha ^{(1)}_{02}=\alpha ^{(2)}_{02}(t)=2\), in particular, we consistently assume no group effect on the competing hazard. Further, scenario-specific administrative censoring times are chosen such that approximately 25% of the individuals are censored. The simulations designs are selected such that we include different effect sizes as well as different type-1 hazard ratio configurations with respect to the competing hazards. We consider a balanced design with \(n_1=n_2=n\in \lbrace 125,250,500,1000\rbrace \). The right-hand tail of the domain of interest is set to \(\tau =0.3\). Simulation of the event times and types follows the procedure explained in Chapter 3.2 of Beyersmann et al. (2012). As before, we simulate 1000 studies for each scenario and sample size configuration, whereas the critical values of the Kolmogorov–Smirnov-type and Cramér-von-Mises-type statistics from Sect. 4.3 are derived from 1000 bootstrap samples utilizing both standard normal and centered Poisson variates with variance one.

Simulated size of \(\phi _{n_1,n_2}^{\text {prop}}\) for nominal size \(\alpha =5\%\) under different sample sizes and constant hazard configurations

Scenario I | Scenario II | Scenario III | Scenario IV | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|

KMS | CvM | KMS | CvM | KMS | CvM | KMS | CvM | |||||||||

\(n_i\) | SN | Poi | SN | Poi | SN | Poi | SN | CvM | SN | Poi | SN | Poi | SN | Poi | SN | Poi |

125 | 0.029 | 0.024 | 0.033 | 0.030 | 0.029 | 0.026 | 0.027 | 0.023 | 0.045 | 0.041 | 0.028 | 0.030 | 0.046 | 0.042 | 0.030 | 0.025 |

250 | 0.035 | 0.039 | 0.039 | 0.040 | 0.040 | 0.038 | 0.037 | 0.034 | 0.039 | 0.040 | 0.037 | 0.034 | 0.034 | 0.034 | 0.033 | 0.030 |

500 | 0.057 | 0.054 | 0.059 | 0.060 | 0.034 | 0.038 | 0.040 | 0.041 | 0.056 | 0.053 | 0.047 | 0.045 | 0.044 | 0.044 | 0.043 | 0.044 |

1000 | 0.050 | 0.050 | 0.047 | 0.047 | 0.048 | 0.049 | 0.043 | 0.046 | 0.047 | 0.049 | 0.045 | 0.048 | 0.058 | 0.059 | 0.053 | 0.056 |

## 6 Data example

*S*pread of Nosocomial

*I*nfections and

*R*esistant Pathogens) cohort study at the Charité University Hospital in Berlin, Germany, prospectively collected data on the occurrence and consequences of hopital-aquired infections in intensive care (Beyersmann et al. 2006; Wolkewitz et al. 2008). A device of particular interest in critically ill patients is mechanical ventilation. The present data analysis investigates the impact of ventilation on the length of intensive care unit stay which is, e.g., of interest in cost-benefit analyses in hospital epidemiology (Beyersmann et al. 2011). The analysis considers a random subset of 747 patients of the SIR-3 data which one of us has made publicly available (Beyersmann et al. 2012). Patients may either be ventilated (state 1 as in Fig. 1) or not ventilated (state 0) upon admission. Switches in device usage are modeled as transitions between the intermediate states 0 and 1. Patients move into state 2 upon discharge from the unit. The numbers of observed transitions are reported in the last row of Table 1. We start by separately considering the two cumulative end-of-stay hazards \(A_{12}\) and \(A_{02}\), followed by a more formal group comparison as in Remark 2(c). Based on the approach suggested by Beyersmann et al. (2012), Section 11.3, we find it reasonable to assume the Markov property. Figure 2 displays the Nelson–Aalen estimates of \(A_{12}\) and \(A_{02}\) accompanied by simultaneous 95% confidence bands utilizing the 1000 wild bootstrap versions with standard normal variates and restricted to the time interval [5,30] of intensive care unit days. As before, the left-hand tail of the interval is chosen, because Nelson–Aalen estimation regarding \(A_{12}\) picks up at \(t=5\), cf. the left panel of Fig. 2. Graphical validation of empirical means and variances of \(\hat{{\varvec{W}}}_{n}\) showed good compliance compared to the theoretical limit quantities stated in Remark 1. Bands using Poisson variates are similar (both results not shown). Figure 3 also displays the 95% pointwise confidence intervals based on a log-transformation. The performance of both equal precision and Hall–Wellner bands is comparable for transitions out of the ventilation state. However, the latter tend to be larger for the \(0\rightarrow 2\) transitions for later days due to more unstable weights at the right-hand tail. Equal precision bands are graphically competitive when compared to the pointwise confidence intervals. Ventilation significantly reduces the hazard of end-of-stay, since the upper half-space is not contained in the 95% confidence band of the cumulative hazard difference, see Fig. 4.

A second investigation exemplary applies the nonparametric proportionality test suggested in Sect. 4.3 to the present study example. For that purpose, we consider sex-specific subsamples (441 male vs. 306 female patients) and test \(H_{0,{ prop }}\) using both the Kolmogorov–Smirnov- and the Cramér-von-Mises-type test statistic. The Nelson–Aalen estimators separately displayed for males and females are given in Supplementary Figure S1. *p* values are computed from 1000 bootstrap samples utilizing standard normal variates and the right-hand limit of the interval of interest is set to 30 days. Tabulated results are in Supplementary Table S1 including the test statistics \(T_{n_1,n_2}\) and the bootstrap quantiles \(\tilde{q}_{0.95}\) of Theorem 4 as well as the corresponding bootstrap *p* values \(\tilde{p}\). Non-proportionality cannot be inferred for any of the transitions at the \(5\%\) level.

## 7 Discussion and further research

We have given a rigorous presentation of a weak convergence result for the wild bootstrap methodology for the multivariate Nelson–Aalen estimator in a general setting only assuming Aalen’s multiplicative intensity structure of the underlying counting processes. This allowed the construction of time-simultaneous confidence bands and intervals as well as asymptotically valid equivalence and equality tests for cumulative hazard functions. In the context of time-to-event analysis, our general framework is not restricted to the standard survival or competing risks setting, but also covers arbitrary Markovian multistate models with finite state space, other classes of intensity models like relative survival or excess mortality models, and even specific semi-Markov situations. Additionally, independent left-truncation and right-censoring can be incorporated. The procedure has also been used to construct a test for proportional hazards. We want to emphasize that the framework induces a random number of multipliers in relation (3.2); thus, goes beyond existing approaches for competing risks as done in Beyersmann et al. (2013) or Lin (1997). Easy and computationally convenient implementation and within- or two-sample comparisons demonstrate its attractiveness in various practical applications.

Future work will be on the approximation of the asymptotic distribution corresponding to the matrix of transition probabilities (see Aalen and Johansen 1978) and functionals thereof in general Markovian multistate models. This is of great practical interest, because no similar Brownian Bridge procedure is available to perform time-simultaneous statistical inference. In particular, previous implications rely on pointwise considerations. Note that such an approach would significantly simplify the original justifications given by Lin (1997) and generalizes his idea mainly used in the context of competing risks (Scheike and Zhang 2003; Hyun et al. 2009; Beyersmann et al. 2013). In addition, we plan to extend the utilized wild bootstrap technique to general semiparametric regression models; see Lin et al. (2000) for an application in the survival context. Current work investigates to what degree the martingale properties presented in this article may be exploited to obtain wild bootstrap consistencies for such functionals of Nelson–Aalen estimates or for estimators in semiparametric regression models. We are confident that the present approach will lead to reliable inference procedures in these contexts for which there has been only little research on such general methodology.

In contrast to the procedure of Schoenfeld et al. (2002) or the framework in Cube et al. (2017), the more general illness-death model with recovery does not rely on a constant hazards assumption and captures both the time-dependent structure of mechanical ventilation and the competing event ‘death in ICU’. This significantly improves medical interpretations. The widths of the confidence bands were competitive compared to the pointwise confidence intervals, i.e., demonstrated usefulness in practical situations.

In the present data analysis, the multistate perspective is the natural way to assess the impact of time-dependent exposures on complex survival outcomes. This is a current topic in various fields of applied research; thus, the wild bootstrap procedure in its very general formulation is practicable to analyses regarding, for instance, different stages of illicit drug use (Mayet et al. 2012), the clinical course of liver diseases (Jepsen et al. 2015), antibiotics in hospital epidemiology (Munoz-Price et al. 2016), alternative outcomes in leukemia trials (Schmoor et al. 2013; Eefting et al. 2016), or joint replacements in orthopaedic patients (Gillam et al. 2012). It has even been recently applied in a study investigating femoral fracture risk, disability, and mortality in an elderly population (Bluhmki et al. 2017).

It has to be emphasized that our simulation study suggested that the wild bootstrap approach leads to more powerful procedures (i.e., to narrower confidence bands) compared to the approximation via Brownian bridges. As expected, the applied log-transformation results in improved small sample properties compared to the untransformed wild bootstrap bands. Based on the current simulation study, however, it was difficult to clearly recommend which type of band and which type of multiplier should be used.

## Notes

### Acknowledgements

The authors would like to thank two referees and an associate editor for their helpful comments which increased the quality of this article.

## Supplementary material

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