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More than one way: exploring the capabilities of different estimation approaches to joint models for longitudinal and time-to-event outcomes

  • Anja Rappl EMAIL logo , Andreas Mayr and Elisabeth Waldmann
Published/Copyright: April 5, 2021
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The International Journal of Biostatistics
From the journal The International Journal of Biostatistics Volume 18 Issue 1

Abstract

The development of physical functioning after a caesura in an aged population is still widely unexplored. Analysis of this topic would need to model the longitudinal trajectories of physical functioning and simultaneously take terminal events (deaths) into account. Separate analysis of both results in biased estimates, since it neglects the inherent connection between the two outcomes. Thus, this type of data generating process is best modelled jointly. To facilitate this several software applications were made available. They differ in model formulation, estimation technique (likelihood-based, Bayesian inference, statistical boosting) and a comparison of the different approaches is necessary to identify their capabilities and limitations. Therefore, we compared the performance of the packages JM, joineRML, JMbayes and JMboost of the R software environment with respect to estimation accuracy, variable selection properties and prediction precision. With these findings we then illustrate the topic of physical functioning after a caesura with data from the German ageing survey (DEAS). The results suggest that in smaller data sets and theory driven modelling likelihood-based methods (expectation maximation, JM, joineRML) or Bayesian inference (JMbayes) are preferable, whereas statistical boosting (JMboost) is a better choice with high-dimensional data and data exploration settings.

Keywords: Bayesian statistics; expectation maximization; joint models; longitudinal and time-to-event; model-based statistical boosting
Corresponding author: Anja Rappl, Friedrich-Alexander-Universität Erlangen-Nürnberg, Institut für Medizininformatik, Biometrie und Epidemiologie, Waldstraße 6, Erlangen 91054, Germany, E-mail:
  1. 3

    Note: Anja Rappl performed the present work in partial fulfilment of the requirements for obtaining the degree ‘Dr. rer. biol. hum.’ at Friedrich-Alexander-Universität Erlangen-Nürnberg.

  2. Author contribution: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Research funding: The work on this article was supported by the DFG (Projekt WA 4249/2-1) and the Volkswagen Foundation.

  4. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

Appendix A: MSE-values for section estimation accuracy

Calculation of MSE

R : number of simulated data sets θ : parameter of interest θ ̂ r : estimate for parameter of interest in data set r M S E = 1 R ∑ r = 1 R θ − θ ̂ r 2
Table 4:

Average MSE-values by model and software.

Model Parameter JM joineRML JMbayes JMboost
AM1 β l0 0.026 0.028 0.029 0.039
β ls1 0.026 0.025 0.024 0.031
β ls2 0.019 0.018 0.020 0.028
β ls3 0.026 0.028 0.026 0.037
β ls4 0.017 0.018 0.018 0.024
β ls5 0.027 0.026 0.025 0.029
β ls6 0.025 0.028 0.030 0.037
β ls7 0.027 0.028 0.028 0.035
β ls8 0.028 0.028 0.026 0.037
β ls9 0.019 0.019 0.020 0.023
β ls10 0.021 0.022 0.023 0.029
β t 0.016 0.016 0.017 0.130
β s 0.038 0.042 0.042 0.038
α 0.007 0.031 0.007 0.011
σ 2 0.040 0.002 0.035 1.019
B 00 0.169 0.164 0.141
B 01/10 0.028 0.028 0.084
B 11 0.029 0.028 337.920
AM2 β l0 0.026 0.026 0.056 0.044
β l1 0.002 0.002 0.002 0.135
β l2 0.002 0.002 0.002 0.132
β l3 0.002 0.002 0.002 0.131
β l4 0.002 0.002 0.002 0.082
β l5 0.001 0.001 0.001 0.137
β l6 0.001 0.001 0.001 0.121
β t 0.021 0.021 0.019 0
β s 0.048 0.050 0.052 0.033
α 0.013 0.029 0.014 Inf
σ 2 0.039 0.002 0.036 1.444
B 00 0.115 0.113 0.097
B 01/10 0.042 0.041 0.099
B 11 0.034 0.033 126.073
AM3 β l0 0.028 0.028 0.032 0.040
β l1 0.002 0.002 0.002 0.150
β l2 0.002 0.002 0.002 0.144
β l3 0.002 0.002 0.002 0.141
β l4 0.002 0.002 0.002 0.082
β l5 0.001 0.001 0.001 0.149
β ls1 0.022 0.022 0.238 0.031
β ls2 0.024 0.023 0.037 0.029
β ls3 0.023 0.023 0.296 0.030
β ls4 0.023 0.022 0.020 0.024
β ls5 0.027 0.026 0.051 0.030
β t 0.021 0.022 0.032 0.160
β s 0.044 0.044 0.047 0.040
α 0.008 0.026 0.008 0.022
σ 2 0.039 0.002 0.037 1.298
B 00 0.125 0.128 0.093
B 01/10 0.041 0.040 0.113
B 11 0.035 0.034 620.771
Appendix B: Median false-positive and false-negative rates (min, max)

See Table 5.

Table 5:

Median of false-positive and -negative rates of packages by model and dimensionality.

Model Software No. of available simulations No. of failures Median false-positive rate [min; max] Median false-negative rate [min; max]
V1M1 JM 96 4 0.846 [0.538; 0.923] 0.000 [0.000; 1.000]
joineRML 100 0 0.923 [0.692; 0.923] 0.000 [0.000; 0.500]
JMbayes 88 12 0.923 [0.692; 0.923] 0.000 [0.000; 0.500]
JMboost 100 0 0.538 [0.231; 0.769] 0.188 [0.062; 0.375]
V1M2 JM 98 2 0.923 [0.538; 0.923] 0.000 [0.000; 1.000]
joineRML 99 1 0.923 [0.769; 0.923] 0.000 [0.000; 0.500]
JMbayes 83 17 0.923 [0.692; 0.923] 0.000 [0.000; 1.000]
JMboost 100 0 0.385 [0.077; 0.538] 0.375 [0.167; 0.583]
V1M3 JM 95 5 0.923 [0.615; 0.923] 0.000 [0.000; 1.000]
joineRML 100 0 0.923 [0.615; 0.923] 0.000 [0.000; 0.500]
JMbayes 77 23 0.923 [0.769; 0.923] 0.000 [0.000; 1.000]
JMboost 97 3 0.462 [0.154; 0.692] 0.312 [0.125; 0.562]
V2M1 JM 2 98 0.764 [0.750; 0.777] 0.250 [0.000; 0.500]
joineRML 2 98 0.659 [0.635; 0.682] 0.500 [0.500; 0.500]
JMbayes 0 100
JMboost 100 0 0.128 [0.061; 0.223] 0.438 [0.188; 0.625]
V2M2 JM 10 90 0.818 [0.730; 0.912] 0.000 [0.000; 0.500]
joineRML 1 99 0.676 [0.676; 0.676] 0.500 [0.500; 0.500]
JMbayes 0 100
JMboost 100 0 0.068 [0.041; 0.270] 0.500 [0.250; 0.667]
V2M3 JM 12 88 0.780 [0.676; 0.865] 0.000 [0.000; 1.000]
joineRML 1 99 0.649 [0.649; 0.649] 0.500 [0.500; 0.500]
JMbayes 0 100
JMboost 100 0 0.088 [0.027; 0.331] 0.438 [0.250; 0.688]
V3M1 JM 0 100
joineRML 0 100
JMbayes 0 100
JMboost 100 0 0.028 [0.013; 0.056] 0.562 [0.250; 0.875]
V3M2 JM 0 100
joineRML 0 100
JMbayes 0 100
JMboost 100 0 0.020 [0.011; 0.057] 0.500 [0.333; 0.667]
V3M3 JM 0 100
joineRML 0 100
JMbayes 0 100
JMboost 100 0 0.019 [0.007; 0.123] 0.562 [0.375; 0.750]
Appendix C: Average mean squared prediction error (MSPE)-values by model

Calculation of MSPE for longitudinal outcomes

y ̃ i : new observation of individual  i y ̂ i : predicted value for new observation of individual  i n ̃ : number of new observations M S P E = 1 n ̃ ∑ i = 1 n ̃ y ̃ i − y ̂ i 2

Calculation of MSPE for survival outcomes

n :  number of observations T i :  observed event time of individual (censored or actual event)  i u :  arbitrary future time point t n i :  last observed longitudinal time point for individual  i δ i :  event indicator for individual  i η ̂ ⋅ i :  estimated (longitudianl, shared, survival) predictorgiven the data of individual  i
M S P E = 1 n ∑ i = 1 n I T i ≥ u ( 1 − Pr ( T i ≥ u ∣ T i ≥ t n i , η ̂ l i ( t ) , η ̂ ls i , η ̂ s i ) ) 2 + δ i I T i < u ( 0 − Pr ( T i ≥ u ∣ T i ≥ t n i , η ̂ l i ( t ) , η ̂ ls i , η ̂ s i ) ) 2 + ( 1 − δ i ) I T i < u Pr ( T i ≥ u ∣ T i ≥ t n i , η ̂ l i ( t ) , η ̂ ls i , η ̂ s i ) ( 1 − Pr ( T i ≥ u ∣ T i ≥ t n i , η ̂ l i ( t ) , η ̂ ls i , η ̂ s i ) ) 2   + ( 1 − Pr ( T i ≥ u ∣ T i ≥ t n i , η ̂ l i ( t ) , η ̂ ls i , η ̂ s i ) ) ( 0 − Pr ( T i ≥ u ∣ T i ≥ t n i , η ̂ l i ( t ) , η ̂ ls i , η ̂ s i ) ) 2
Table 6:

MSPE-values for marginal prediction of longitudinal outcome by model, dimensionality and package.

Dimension Model JM joineRML JMbayes JMboost
PA M1 2.76 [2.47; 3.12] 2.77 [2.46; 3.32] 2.77 [2.47; 3.23] 2.82 [2.49; 3.44]
PA M2 2.53 [2.30; 2.83] 2.53 [2.30; 2.83] 2.54 [2.35; 3.02] 3.22 [2.83; 3.83]
PA M3 2.63 [2.39; 3.19] 2.63 [2.40; 3.18] 3.21 [2.44; 4.04] 3.30 [2.96; 4.04]
PV1 M1 2.94 [2.56; 3.43] 2.95 [2.56; 3.46] 2.82 [2.50; 3.37] 2.99 [2.51; 3.59]
PV1 M2 2.63 [2.34; 3.07] 2.64 [2.35; 3.08] 2.57 [2.36; 3.18] 3.25 [2.87; 3.83]
PV1 M3 2.76 [2.47; 3.21] 2.77 [2.47; 3.22] 3.29 [2.66; 3.91] 3.44 [2.99; 4.14]
PV2 M1 6.28 [5.67; 6.89] 6.65 [6.03; 7.27] 3.54 [2.79; 4.74]
PV2 M2 4.70 [4.00; 6.24] 4.64 [4.64; 4.64] 3.21 [2.86; 3.83]
PV2 M3 5.40 [4.40; 6.24] 5.89 [5.89; 5.89] 3.71 [3.18; 5.83]
PV3 M1 4.17 [3.29; 7.35]
PV3 M2 3.23 [2.87; 3.80]
PV3 M3 4.14 [3.32; 6.23]
Table 7:

MSPE-values for subject-specific prediction of the survival probability by model, dimensionality and package.

Dimension Model JM joineRML JMbayes JMboost
PA M1 0.12 [0.08; 0.19] 0.24 [0.12; 0.44] 0.11 [0.08; 0.14] 0.14 [0.11; 0.16]
PA M2 0.13 [0.09; 0.20] 0.23 [0.13; 0.42] 0.11 [0.09; 0.14]
PA M3 0.13 [0.10; 0.21] 0.24 [0.12; 0.43] 0.11 [0.09; 0.14] 0.14 [0.11; 0.17]
PV1 M1 0.13 [0.08; 0.20] 0.24 [0.12; 0.44] 0.11 [0.09; 0.14] 0.14 [0.11; 0.17]
PV1 M2 0.13 [0.09; 0.20] 0.23 [0.13; 0.42] 0.11 [0.09; 0.14] 0.14 [0.11; 0.17]
PV1 M3 0.13 [0.10; 0.22] 0.24 [0.12; 0.43] 0.11 [0.09; 0.14] 0.14 [0.11; 0.17]
PV2 M1 0.13 [0.13; 0.13] 0.31 [0.30; 0.33] 0.14 [0.11; 0.17]
PV2 M2 0.14 [0.12; 0.15] 0.14 [0.14; 0.14] 0.14 [0.11; 0.17]
PV2 M3 0.12 [0.11; 0.16] 0.16 [0.16; 0.16] 0.14 [0.12; 0.17]
PV3 M1 0.14 [0.11; 0.17]
PV3 M2 0.14 [0.11; 0.17]
PV3 M3 0.14 [0.11; 101293.98]
Appendix D: Boosted coefficient paths of “healthy ageing”

The update mechanism of statistical boosting algorithms yield characteristic coefficient paths across their set iteration times. They reflect that per iteration only one coefficient per gradient is updated by a small proportion, that coefficients are selected at different times throughout the algorithm and that earlier selected coefficients tend to be larger once the algorithm stops. An example of a standard image of coefficient paths is given in Figure 9.

Figure 9: Ideal behaviour of coefficient paths in statistical boosting.
Figure 9:

Ideal behaviour of coefficient paths in statistical boosting.

In comparison Figure 10 shows the coefficient paths of the data example of “healthy ageing”. The paths oscillate heavily, which is a sign of instability. This becomes particularly problematic with the effect of obstime, since it alternates between positive and negative values. The values for mstop_l, mstop_ls and mstop_s indicate the optimal iteration number for the predicted likelihood to be at its minimum (cross-validation). A potential remedy for this behaviour is for the algorithm to be forced to run longer at the compromise of less optimal prediction. In this case, however, the oscillation will not stop even when the iteration numbers are increased. Thus, boosting will not yield entirely satisfying results for this data problem.

Figure 10: Suboptimal trajectory of coefficient paths of the data model “healthy ageing” when boosted.
Figure 10:

Suboptimal trajectory of coefficient paths of the data model “healthy ageing” when boosted.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/ijb-2020-0067).

Received: 2020-05-18
Revised: 2021-01-24
Accepted: 2021-03-12
Published Online: 2021-04-05

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/ijb-2020-0067
Keywords for this article
Bayesian statistics; expectation maximization; joint models; longitudinal and time-to-event; model-based statistical boosting

Articles in the same Issue

  1. Frontmatter
  2. Research Articles
  3. Integrating additional knowledge into the estimation of graphical models
  4. Asymptotic properties of the two one-sided t-tests – new insights and the Schuirmann-constant
  5. Bayesian optimization design for finding a maximum tolerated dose combination in phase I clinical trials
  6. A Bayesian mixture model for changepoint estimation using ordinal predictors
  7. Power prior for borrowing the real-world data in bioequivalence test with a parallel design
  8. Bayesian approaches to variable selection: a comparative study from practical perspectives
  9. Bayesian adaptive design of early-phase clinical trials for precision medicine based on cancer biomarkers
  10. More than one way: exploring the capabilities of different estimation approaches to joint models for longitudinal and time-to-event outcomes
  11. Designing efficient randomized trials: power and sample size calculation when using semiparametric efficient estimators
  12. Power formulas for mixed effects models with random slope and intercept comparing rate of change across groups
  13. The effect of data aggregation on dispersion estimates in count data models
  14. A zero-inflated non-negative matrix factorization for the deconvolution of mixed signals of biological data
  15. Multiple scaled symmetric distributions in allometric studies
  16. Estimation of semi-Markov multi-state models: a comparison of the sojourn times and transition intensities approaches
  17. Regularized bidimensional estimation of the hazard rate
  18. The effect of random-effects misspecification on classification accuracy
  19. The area under the generalized receiver-operating characteristic curve
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