hce package intro

Background

The package supports the simulation and analysis of univariate hierarchical composite endpoints (HCEs). The rationale for constructing a univariate endpoint, in contrast to the multivariate version of Generalized Pairwise Comparisons, which typically yields summary statistics rather than a single endpoint, is described in Gasparyan, Koch, and Brunner (Gasparyan, Koch, and Brunner 2026). The framework is broad: univariate HCEs can be derived from different outcome types, including time-to-event, continuous, and binary outcomes. However, it applies only to fixed follow-up designs without early dropout.

In this setting, several approaches can be used to derive a patient-level ordinal outcome, which is the essence of a univariate HCE. Gasparyan, Koch, and Brunner (Gasparyan, Koch, and Brunner 2026) derived the distribution for the setting with multiple time-to-event outcomes and a single continuous (or ordinal) outcome assessed at the end of follow-up; in that construction, the event times also contribute to the HCE. Accordingly, our definition of an HCE focuses on this setting. Although the theoretical distribution is not required for estimation, understanding the distribution remains important for interpreting summary statistics in greater detail and for avoiding the Condorcet non-transitivity paradox (De Condorcet et al. 2014).

These endpoints have been implemented in clinical trials across multiple therapeutic areas. For example, see Gasparyan et al. (2022) for an implementation in a COVID-19 setting and for practical considerations in constructing hierarchical composite endpoints. For chronic kidney disease (CKD) applications, see (Little et al. 2023; Heerspink et al. 2023; Kondo et al. 2024).

The primary analysis method is win odds. Other win statistics, including win ratio and net benefit (Dong et al. 2023), are also implemented when there is no censoring. Win odds relies on the DeLong-DeLong-Clarke-Pearson formula (DeLong, DeLong, and Clarke-Pearson 1988) for the variance of the win proportion and is based on the Brunner-Munzel test (Brunner and Munzel 2000). We also include the Brunner-Konietschke version (Brunner and Konietschke 2025) of the Bamber estimator (Bamber 1975) for the variance of the win proportion. In addition, the package provides Wilson-type, range-preserving confidence intervals for the win proportion and win odds, following Schüürhuis, Konietschke, and Brunner (Schüürhuis, Konietschke, and Brunner 2025).

The power and sample size formulas cover several classes of alternatives: "shifted", "ordered", and "max" for the maximum value of the standard deviation. All formulas are derived from Bamber (Bamber 1975). By default, Noether’s formula (Noether 1987) is used for shifted distributions. Additional discussion of power calculations for shifted distributions is available in (Gasparyan, Kowalewski, et al. 2021; Gasparyan, Kowalewski, and Koch 2022).

For reviews of HCE design in clinical trials, see (Gasparyan et al. 2022), (Gasparyan et al. 2023), and (Little et al. 2023). The Basic Data Structure (BDS), which follows Analysis Data Model (ADaM) (CDISC 2009) principles for hierarchical composite endpoints, is described in Gasparyan et al. (2024). For visualization, the maraca plot (Karpefors, Lindholm, and Gasparyan 2023) can be used.

Stratified and adjusted win odds are calculated using randomization-based covariate adjustment theory (Koch et al. 1998); for a review, see (Gasparyan, Folkvaljon, et al. 2021).

Thresholds for pairwise comparisons involving the continuous component of the HCE are implemented according to the theory in Gasparyan, Koch, and Brunner (Gasparyan, Koch, and Brunner 2026).

All implementations are rank-based. For a methodological review, see (Brunner, Bathke, and Konietschke 2018).

Setup

Load the package hce and check the version

library(hce)
packageVersion("hce")
#> [1] '0.9.4'

For citing the package, run citation("hce") (Gasparyan 2026).

Contents

List the functions and the datasets in the package

ls("package:hce")
#>  [1] "ADET"        "ADLB"        "ADSL"        "COVID19"     "COVID19b"   
#>  [6] "COVID19plus" "HCE1"        "HCE2"        "HCE3"        "HCE4"       
#> [11] "HGLL"        "IWP"         "KHCE"        "as_formulae" "as_hce"     
#> [16] "calcWINS"    "calcWO"      "dGLL"        "deltaWO"     "hGLL"       
#> [21] "hce"         "minWO"       "pGLL"        "powerWO"     "propWINS"   
#> [26] "qGLL"        "rGLL"        "regWO"       "rweibullGF"  "simHCE"     
#> [31] "simKHCE"     "simORD"      "simTTE"      "sizeWO"      "sizeWR"     
#> [36] "stratWO"     "summaryWO"

The package contains the following Datasets: use data(package = "hce") for the list of all datasets included in the package.

HCE1; HCE2; HCE3; HCE4
COVID19; COVID19b; COVID19plus
ADET; ADLB; ADSL; KHCE

  • Simulated datasets: HCE1 - HCE4 contain two treatment groups and analysis values AVAL for a hierarchical composite endpoint.

  • COVID-19 datasets: COVID19, COVID19b, and COVID19plus contain COVID-19 ordinal scale outcomes (Beigel et al. 2020; Kalil et al. 2021).

  • Synthetic kidney disease datasets: ADET contains event-time data, ADLB contains laboratory data, and ADSL contains subject-level baseline characteristics. Based on these data, KHCE provides the derived kidney hierarchical composite endpoint for the same patients (Heerspink et al. 2023).

In Brief

Calculations

calcWO()
calcWINS()
summaryWO()
regWO()
stratWO()
IWP()

The main functions for calculating the so-called win statistics—win probability, win odds, win ratio, and net benefit—are calcWO() for win odds and calcWINS() for all win statistics, including win odds. To summarize wins, losses, and ties, use summaryWO(), which also reports the win probability, win odds, and win ratio, together with the standard errors of the win probability and win odds. By default, all of these functions use the DeLong-DeLong-Clarke-Pearson formula (DeLong, DeLong, and Clarke-Pearson 1988) to estimate the standard error of the win probability and win odds.

In calcWINS(), the SE_WP_Type argument can be set to unbiased to use the Brunner-Konietschke version (Brunner and Konietschke 2025) of the Bamber estimator (Bamber 1975) for the variance of the win proportion, or to biased to use the DeLong-DeLong-Clarke-Pearson variance estimator, which is the same method used in calcWO() and may be biased in small samples. In the same function, the CI_WP_Type argument can be set to Wilson to obtain Wilson-type, range-preserving confidence intervals for the win proportion and win odds, following Schüürhuis, Konietschke, and Brunner (Schüürhuis, Konietschke, and Brunner 2025). The function calcWINS() also implements Goodman-Kruskal’s gamma (Goodman and Kruskal 1954, 1963). All reported statistics include confidence intervals.

The functions regWO() and stratWO() compute adjusted and stratified win odds, respectively, based on the randomization-based covariate adjustment theory developed in Koch et al. (Koch et al. 1998); for a review, see Gasparyan et al. (Gasparyan, Folkvaljon, et al. 2021).

In principle, all of these functions operate on ordinal outcomes when each patient contributes a single analysis value. Therefore, the input data should be at the patient level. Any patient-level dataset with a numeric analysis value can be used to calculate these statistics. In this setting, the use of win statistics is equivalent to ordinal analysis. Specifically, win odds corresponds to the classical Mann-Whitney odds, win ratio is the number of concordances divided by the number of discordances and can be derived from Goodman-Kruskal’s gamma, and net benefit corresponds to Somers’ D C/R. Therefore, any software that computes these statistics should produce the same results. For example, although the implementation here is fully rank-based, the estimate of Goodman-Kruskal’s gamma and its confidence interval agree with DescTools::GoodmanKruskalGamma() (Signorell 2025).

All calculations are rank-based and therefore computationally efficient. The basic building blocks are the individual win proportions, defined for each patient as the proportion of wins plus one-half of the proportion of ties. The function IWP() computes these individual win proportions for each patient in the dataset and returns an updated dataset with a new column. Any win-odds-related calculation can be based on these quantities (Gasparyan, Folkvaljon, et al. 2021).

Univariate hierarchical composite endpoints

hce()
as_hce()

The idea behind univariate hierarchical composite endpoints (Gasparyan, Koch, and Brunner 2026) is to derive a single ordinal outcome from multiple outcomes of different types, such as time-to-event, continuous, and binary outcomes, by prioritizing the most clinically important outcome for each patient. The resulting ordinal outcome can then be used to calculate win statistics.

To support this, the package provides helper functions for deriving hce objects from different types of outcomes. In particular, hce() and as_hce() check the structure of the input data and attempt to convert it to an hce object. Once this conversion is complete, that is, once the univariate HCE has been derived, the subsequent theory and analysis are the same as for any other ordinal outcome.

Thresholds

deltaWO()

The function deltaWO() calculates threshold-adjusted win odds (Gasparyan, Koch, and Brunner 2026).

Simulations

simORD()
simHCE()
simTTE()
simKHCE()

Power and sample size

powerWO()
sizeWO()
sizeWR()
minWO()
propWINS()

The functions powerWO(), sizeWO(), and minWO() provide tools for calculating power, sample size, and the minimum detectable treatment effect for win odds under different classes of alternatives: "shifted", "ordered", and "max", where "max" refers to the maximum value of the standard deviation. All formulas are based on Bamber (Bamber 1975). For shifted distributions, the default is Noether’s formula (Noether 1987). See also (Gasparyan, Kowalewski, et al. 2021; Gasparyan, Kowalewski, and Koch 2022) for further discussion of shifted distributions. The function sizeWR() provides sample size calculations for the win ratio (Yu and Ganju 2022).

The function propWINS() is a convenient tool for deriving the proportions of wins, losses, and ties for each treatment group from the win odds and win ratio.

Ordinal dominance graph and the maraca plot

plot.hce()

A plot method for hce objects (created by as_hce()) to provide the ordinal dominance graph (Bamber 1975).

Extras

rweibullGF()
dGLL()
pGLL()
qGLL()
rGLL()
hGLL()
HGLL()

The generalized log-logistic (GLL) distributions arise as the marginal distributions of the Weibull-Gamma frailty model. For comparison, one can use rweibullGF(), which implements the random frailty formulation, and compare its output with the generalized log-logistic distribution functions: density dGLL(), distribution function pGLL(), quantile function qGLL(), random generation rGLL(), hazard function hGLL(), and cumulative hazard function HGLL().

These distributions form the basis for constructing two-outcome hierarchical composite endpoints with death and hospitalization in the generalized illness-death model implemented in simTTE().

Helpers

print.hce_results()
plot.hce_results()
as_formulae.formula()

To facilitate visualization and review of sample size and power calculations, print() and plot() methods are implemented for hce_results objects generated by the functions powerWO(), sizeWO(), and minWO().

The function as_formulae() is an internal helper that decomposes formula objects into treatment, response, covariate, and grouping variables using the standardized names TRTP, AVAL, COVAR, and GROUP, respectively.

hce Objects

hce() Function

hce objects can be constructed using the helper function hce(), which has the following arguments:

args("hce")
#> function (GROUP, TRTP, AVAL0 = NULL, PADY = NULL) 
#> NULL

We see that the required arguments are GROUP, which specifies the clinically most important event of a patient to be included in the analysis, and TRTP, which specifies the (planned) treatment group of a patient (exactly two treatment groups should be present). Note that:

  • The hce structure assumes that only one event per patient is present for the analysis, meaning that the resulting hce object created by the hce() function is a patient-level dataset. The function hce() does not select the clinically most important event of the patient but requires it to be already done when calling it.

  • The argument TRTP should have exactly two levels.

Consider the following example of ordinal outcomes ‘I’, ‘II’, and ‘III’:

set.seed(2022)
n <- 100
dat <- hce(GROUP = rep(x = c("I", "II", "III"), each = 100), 
           TRTP = sample(x = c("Active", "Control"), size = n*3, replace = TRUE))
class(dat)
#> [1] "hce"        "data.frame"

This dataset has the appropriate structure of hce objects, but its class inherits from an object of class data.frame. This means that all functions available for data frames can be applied to hce objects, for example, the function head():

head(dat)
#>      TRTP GROUP PARAMN AVAL
#> 1 Control     I      1    1
#> 2  Active     I      1    1
#> 3 Control     I      1    1
#> 4  Active     I      1    1
#> 5  Active     I      1    1
#> 6 Control     I      1    1

We see that the dataset has a very specific structure. The column PARAMN shows how the function hce() generated the order of given events (it uses usual alphabetic order for the unique values in the GROUP column to determine the clinical importance of events):

unique(dat[, c("GROUP", "PARAMN")])
#>     GROUP PARAMN
#> 1       I      1
#> 101    II      2
#> 201   III      3

In the class hce, higher values for the ordering mean clinically less important events. For example, death, which is the most important event, should always get the lowest ordinal value. If there is a need to specify the order of outcomes, then the GROUP argument can be provided as a factor with the levels specifying the necessary order:

set.seed(2022)
n <- 100
GROUP = rep(x = c("I", "II", "III"), each = 100) 
GROUP <- factor(GROUP, levels = c("III", "II", "I"))
dat <- hce(GROUP = GROUP, 
           TRTP = sample(x = c("Active", "Control"), size = n*3, replace = TRUE))
unique(dat[, c("GROUP", "PARAMN")])
#>     GROUP PARAMN
#> 1       I      3
#> 101    II      2
#> 201   III      1

This means that the clinically most important event is ‘III’ instead of ‘I’. The argument AVAL0 is meant to help in cases where we want to introduce sub-ordering within each GROUP category. For example, if two events in the group ‘I’ can be compared based on other parameters, then the AVAL0 argument can be specified to take that into account.

Below we use the built-in data frame HCE1 to construct an hce object. Before specifying the order of events, it is a good idea to check what are the unique events included in the GROUP column:

data(HCE1)
unique(HCE1$GROUP)
#> [1] "C"    "TTE4" "TTE1" "TTE2" "TTE3"

Therefore, we can construct the following object using the hce() function:

HCE <- hce(GROUP = factor(HCE1$GROUP, levels = c("TTE1", "TTE2", "TTE3", "TTE4", "C")), 
           TRTP = HCE1$TRTP, AVAL0 = HCE1$AVAL0, PADY = 1080)
class(HCE)
#> [1] "adhce"      "hce"        "data.frame"
head(HCE)
#>   TRTP GROUP  AVAL0 PARAMN    AVAL PADY GROUPN
#> 1    A     C  -2.21      5 5446.32 1080   5400
#> 2    P     C  17.06      5 5465.59 1080   5400
#> 3    A  TTE4 966.00      4 5286.00 1080   4320
#> 4    P  TTE4 352.00      4 4672.00 1080   4320
#> 5    A     C -12.45      5 5436.08 1080   5400
#> 6    P     C  44.62      5 5493.15 1080   5400

The object’s class is adhce, which inherits from hce. This design indicates that the object includes additional columns.

Create an hce Object from a Data Frame

Consider the dataset HCE1, which is part of the package hce:

data(HCE1, package = "hce")
class(HCE1)
#> [1] "data.frame"
head(HCE1)
#>   ID TRTP GROUP GROUPN AVALT  AVAL0    AVAL PADY
#> 1  1    A     C   5400  1080  -2.21 5446.32 1080
#> 2  2    P     C   5400  1080  17.06 5465.59 1080
#> 3  3    A  TTE4   4320   966 966.00 5286.00 1080
#> 4  4    P  TTE4   4320   352 352.00 4672.00 1080
#> 5  5    A     C   5400  1080 -12.45 5436.08 1080
#> 6  6    P     C   5400  1080  44.62 5493.15 1080

This dataset has the appropriate structure of hce objects, but its class is data.frame. A generic way of coercing data structures to an hce object is to use the function as_hce(). This function performs checks (using an internal validator function) and creates an hce object from the given data structure (using an internal constructor function). If coercion is not possible, it will throw an error explaining the issue.

dat1 <- as_hce(HCE2)
str(dat1)
#> Classes 'adhce', 'hce' and 'data.frame': 1000 obs. of  9 variables:
#>  $ ID    : int  1 2 3 4 5 6 7 8 9 10 ...
#>  $ TRTP  : chr  "A" "P" "A" "P" ...
#>  $ GROUP : Factor w/ 5 levels "TTE1","TTE2",..: 1 5 5 1 2 3 5 2 1 5 ...
#>  $ GROUPN: num  1080 5400 5400 1080 2160 3240 5400 2160 1080 5400 ...
#>  $ AVALT : num  120 1080 1080 577 782 985 1080 293 313 1080 ...
#>  $ AVAL0 : num  120 3.35 22.8 577 782 ...
#>  $ AVAL  : num  1200 5461 5480 1657 2942 ...
#>  $ PADY  : num  1080 1080 1080 1080 1080 1080 1080 1080 1080 1080 ...
#>  $ PARAMN: num  1 5 5 1 2 3 5 2 1 5 ...

Simulate hce Objects Using simHCE()

To simulate values from a hierarchical composite endpoint, we use the function simHCE(), which has the following arguments:

args("simHCE")
#> function (n, n0 = n, TTE_A, TTE_P, CM_A, CM_P, CSD_A = 1, CSD_P = CSD_A, 
#>     fixedfy = 1, yeardays = 360, pat = 100, shape = 1, theta = 1, 
#>     logC = FALSE, seed = NULL, dec = 2, all_data = FALSE) 
#> NULL

  • The vector arguments TTE_A and TTE_P specify the event rates per year for time-to-event outcomes in the active and control groups, respectively. The function assumes a Weibull survival function with the same shape parameter for simulating all time-to-event outcomes in both treatment groups (by default shape = 1, which assumes an exponential survival function). These two vectors should have the same length, which indicates the number of time-to-event outcomes.

  • By default, the event rates are presented per 100 patient-years (pat = 100), which can be changed using the argument pat. The function simulates event times in days, and the yeardays = 360 argument can be used to change the number of days in a year (e.g., 365 or 365.25).

  • The function simulates events during a fixed follow-up period only, and the fixedfy argument can be used to change the length of the follow-up (in years).

  • The function simulates the continuous outcome from a normal (default) or log-normal (if logC = TRUE) distribution with given means and standard deviations for two treatment groups.

Rates_A <- c(1.72, 1.74, 0.58, 1.5, 1) 
Rates_P <- c(2.47, 2.24, 2.9, 4, 6) 
dat3 <- simHCE(n = 2500, n0 = 1500, TTE_A = Rates_A, 
               TTE_P = Rates_P, 
               CM_A = -3, CM_P = -6, 
               CSD_A = 16, CSD_P = 15, 
               fixedfy = 3, seed = 2023)
class(dat3)
#> [1] "adhce"      "hce"        "data.frame"
head(dat3)
#>   ID TRTP GROUP GROUPN AVALT  AVAL0    AVAL seed PADY PARAMN
#> 1  1    A     C   6480  1080  -9.32 6526.85 2023 1080      6
#> 2  2    A     C   6480  1080   0.11 6536.28 2023 1080      6
#> 3  3    A     C   6480  1080  27.06 6563.23 2023 1080      6
#> 4  4    A     C   6480  1080  -4.78 6531.39 2023 1080      6
#> 5  5    A  TTE2   2160   390 390.00 2550.00 2023 1080      2
#> 6  6    A     C   6480  1080   4.56 6540.73 2023 1080      6

Generics for hce Objects

As we see, the function simHCE() creates an object of type hce, which inherits from the built-in class data.frame. We can check all implemented methods for this new class as follows:

methods(class = "hce")
#> [1] calcWINS  calcWO    plot      summaryWO
#> see '?methods' for accessing help and source code

The function calcWO() calculates the win odds and its confidence interval, while summaryWO() provides a more detailed calculation of win odds, including the number of wins, losses, and ties by GROUP categories.

HCE <- hce(GROUP = factor(HCE3$GROUP, levels = c("TTE1", "TTE2", "TTE3", "TTE4", "C")), 
           TRTP = HCE3$TRTP, AVAL0 = HCE3$AVAL0, PADY = 1080)
calcWO(HCE)
#>         WO     LCL      UCL         SE WOnull alpha       Pvalue       WP
#> 1 1.332829 1.15078 1.543678 0.07493202      1  0.05 0.0001014229 0.571336
#>      LCL_WP    UCL_WP      SE_WP     SD_WP    N
#> 1 0.5353673 0.6073047 0.01835169 0.5803314 1000
calcWINS(HCE)  
#> $summary
#>      WIN   LOSS TIE  TOTAL Pties
#> 1 142824 107156  20 250000 8e-05
#> 
#> $WP
#>         WP       LCL       UCL       Pvalue
#> 1 0.571336 0.5353673 0.6073047 0.0001014229
#> 
#> $NetBenefit
#>   NetBenefit       LCL       UCL       Pvalue
#> 1   0.142672 0.0707347 0.2146093 0.0001014229
#> 
#> $WO
#>         WO     LCL      UCL       Pvalue
#> 1 1.332829 1.15078 1.543678 0.0001014229
#> 
#> $WR1
#>         WR     LCL1     UCL1     Pvalue1
#> 1 1.332861 1.150793 1.543733 0.000125974
#> 
#> $WR2
#>         WR     LCL2     UCL2      Pvalue2
#> 1 1.332861 1.155092 1.537987 8.351682e-05
#> 
#> $gamma
#>       gamma        LCL       UCL      Pvalue
#> 1 0.1426834 0.07074057 0.2146263 0.000101418
#> 
#> $SE
#>        WP_SE NetBenefit_SE  logWR_SE1  logWR_SE2   gamma_SE
#> 1 0.01835169    0.03670338 0.07493804 0.07303552 0.03670621
#> 
#> $ref
#> [1] "A vs P"
#> 
#> $Input
#>   alpha WOnull
#> 1  0.05      1
HCE$TRTP <- factor(HCE$TRTP, levels = c("P", "A"))
plot(HCE, fill = TRUE, col = "#865A4F", type = 'l', lwd = 2)
abline(a = 0, b = 1, lwd = 2, col = "#999999", lty = 2)

To check the generic functions available for the adhce class by running the following command:

methods(class = "adhce")
#> [1] deltaWO   summaryWO
#> see '?methods' for accessing help and source code

The main difference between summaryWO.hce() and summaryWO.adhce() is that summaryWO.adhce() also provides a group-wise summary, in addition to the overall summary:

summaryWO(HCE)
#> $summary
#>   TRTP    WIN   LOSS TIE  TOTAL        WR        WO
#> 1    A 142824 107156  20 250000 1.3328605 1.3328294
#> 2    P 107156 142824  20 250000 0.7502661 0.7502835
#> 
#> $summary_by_GROUP
#>    TRTP GROUP    WIN  LOSS TIE  TOTAL
#> 1     A  TTE1   2473 39525   2  42000
#> 2     P  TTE1   2985 29513   2  32500
#> 3     A  TTE2   6847 22648   5  29500
#> 4     P  TTE2  13857 45138   5  59000
#> 5     A  TTE3  13251 16745   4  30000
#> 6     P  TTE3  13356 25140   4  38500
#> 7     A  TTE4   9056  6443   1  15500
#> 8     P  TTE4  15383 19616   1  35000
#> 9     A     C 111197 21795   8 133000
#> 10    P     C  61575 23417   8  85000
#> 
#> $WO
#>         WO         SE       WP      SE_WP
#> 1 1.332829 0.07493202 0.571336 0.01835169
#> 
#> $cumsummary_by_GROUP
#>    GROUPN   WINS  COUNT  TOTAL     PROP
#> 1       1 A wins  23417 250000 0.093668
#> 6       1 P wins  21795 250000 0.087180
#> 11      1   Ties 204788 250000 0.819152
#> 2       2 A wins  52930 250000 0.211720
#> 7       2 P wins  61320 250000 0.245280
#> 12      2   Ties 135750 250000 0.543000
#> 3       3 A wins  98068 250000 0.392272
#> 8       3 P wins  83968 250000 0.335872
#> 13      3   Ties  67964 250000 0.271856
#> 4       4 A wins 123208 250000 0.492832
#> 9       4 P wins 100713 250000 0.402852
#> 14      4   Ties  26079 250000 0.104316
#> 5       5 A wins 142824 250000 0.571296
#> 10      5 P wins 107156 250000 0.428624
#> 15      5   Ties     20 250000 0.000080

An important addition to summaryWO.adhce() is the cumsummary_by_GROUP output, which reports cumulative wins, losses, and ties as outcomes are added sequentially according to the priority order:

res0 <- summaryWO(HCE, ref = "P")
res <- res0$cumsummary_by_GROUP
barplot(PROP ~ WINS + GROUPN, data = res, 
col = c("darkgreen", "darkred", "darkblue"), 
xlab = "Proportions", xlim = c(0, 1), 
ylab = "Cumulative components by prioritization", 
legend.text = unique(res$WINS), beside = TRUE, horiz = TRUE)
grid()

References

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