jointModel: Joint Models for Longitudinal and Survival Data

Description Usage Arguments Details Value Note Author(s) References See Also Examples

Description

This function fits shared parameter models for the joint modelling of normal longitudinal responses and time-to-event data under a maximum likelihood approach. Various options for the survival model are available.

Usage

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jointModel(lmeObject, survObject, timeVar, 
  parameterization = c("value", "slope", "both"),
  method = c("weibull-PH-aGH", "weibull-PH-GH", "weibull-AFT-aGH", 
    "weibull-AFT-GH", "piecewise-PH-aGH", "piecewise-PH-GH", 
    "Cox-PH-aGH", "Cox-PH-GH", "spline-PH-aGH", "spline-PH-GH", 
    "ch-Laplace"),
  interFact = NULL, derivForm = NULL, lag = 0, scaleWB = NULL,
  CompRisk = FALSE, init = NULL, control = list(), ...)

Arguments

lmeObject

an object inheriting from class lme (see also Note).

survObject

an object inheriting from class coxph or class survreg. In the call to coxph() or survreg(), you need to specify the argument x = TRUE such that the design matrix is contained in the object fit. See Examples.

timeVar

a character string indicating the time variable in the linear mixed effects model.

parameterization

a character string indicating the type of parameterization. See Details

method

a character string specifying the type of joint model to fit. See Details.

interFact

a list with components value a formula for the interaction terms corresponding to the value parameterization, slope a formula for the interaction terms corresponding to the slope parameterization, data a data frame containing these variables (this should have the same number of rows and ordering of subjects, as the one in survObject).

derivForm

a list with components fixed a formula representing the derivative of the fixed-effects part of the liner mixed model with respect to time, indFixed a numeric vector indicating which fixed effects of lmeObject correspond to the derivative, random a formula representing the derivative of the random-effects part of the liner mixed model with respect to time, and indRamdom a numeric vector indicating which random effects of lmeObject correspond to the derivative. When a random intercepts linear mixed model is assumed, then random = ~ 1 and indRandom = FALSE. Required only when parameterization == "slope" or parameterization == "both". See Examples.

lag

a numeric scalar denoting a lag effect in the time-dependent covariate represented by the mixed model; default is 0.

scaleWB

a numeric scalar denoting a fixed value for the scale parameter of the Weibull hazard; used only when method = "weibull-AFT-GH" or method = "weibull-PH-GH". The default NULL means that the scale parameter is estimated.

CompRisk

logical; should a competing risks joint model be fitted.

init

a named list of user-specified initial values:

betas

the vector of fixed effects for the linear mixed effects model.

sigma

the measurement error standard deviation for the linear mixed effects model.

D

the variance-covariance matrix of the random effects.

gammas

the vector of baseline covariates for the survival model. For method = "ch-Laplace" this vector should first contain initial values for the sorted B-spline coefficients used to model the log cumulative baseline hazard.

alpha

the association parameters.

Dalpha

the association parameters for the true slopes parameterization

xi

the vector of baseline risk function values within the intervals specified by the knots; specified only when method = "piecewise-PH-GH".

gammas.bs

the vector of spline coefficients; specified only when method = "spline-PH-GH".

sigma.t

the scale parameter for the Weibull baseline risk function; specified only when method = "weibull-AFT-GH" or method = "weibull-PH-GH".

lambda0

a vector of the baseline hazard values at the sorted unique event times; specified only when method = "Cox-PH-GH".

When this list of initial values does not contain some of these components or contains components not of the appropriate length, then the default initial values are used instead.

control

a list of control values with components:

only.EM

logical; if TRUE only the EM algorithm is used in the optimization, otherwise if convergence has not been achieved a quasi-Newton algorithm is initiated. Default is FALSE except for method = "Cox-PH-GH" for which only the EM algorithm is available.

iter.EM

the number of EM iterations. Default is 50 except for method = "Cox-PH-GH" for which the default is 200.

iter.qN

the number of quasi-Newton iterations. Default is 150.

optimizer

a character string indicating which optimizer to use; options are "optim" (default) and "nlminb".

tol1

tolerance value for convergence in the parameters; see Details. Default is 1e-03.

tol2

tolerance value for convergence in the parameters; see Details. Default is 1e-04.

tol3

tolerance value for convergence in the log-likelihood; see Details. Default is sqrt(.Machine$double.eps).

numeriDeriv

a character string indicating which type of numerical derivative to use to compute the Hessian matrix; options are "fd" (default) denoting the forward difference approximation, and "cd" denoting the central difference approximation.

eps.Hes

tolerance value used in the numerical derivative method. Default is 1e-06; if you choose numeriDeriv = "cd" a larger value (e.g., 1e-04) is suggested.

parscale

the parscale control argument for optim(), or the scale argument for nlminb(). It should be a numeric vector of length equal to the number of parameters. Default is 0.01 for all parameters.

step.max

tolerance value for the maximum step size in the Newton-Raphson algorithm used to update the parameters of the survival submodel for method = "ch-Laplace". Default is 0.1.

backtrackSteps

the number of backtrack steps to use when updating the parameters of the survival submodel under method = "ch-Laplace".

knots

a numeric vector of the knots positions for the piecewise constant baseline risk function of for the log times used in the B-splines approximation of the log cumulative baseline hazard; therefore, this argument is relevant only when method = "piecewise-PH-GH", method = "spline-PH-GH" or method = "ch-Laplace". The default is to place equally-spaced lng.in.kn knots in the quantiles of the observed event times. For stratified models fitted with method = "spline-PH-GH" this should be a list with elements numeric vectors of knots positions for each strata.

ObsTimes.knots

logical; if TRUE (default) the positions of the knots are specified based in the observed event times, otherwise the positions of the knots are specified using only the true event times.

lng.in.kn

the number of internal knots; relevant only when when method = "piecewise-PH-GH" where it denotes the number of internal knots for the piecewise constant baseline risk function or when method = "spline-PH-GH" or method = "ch-Laplace" where it denotes the number of internal knots for B-splines approximation of the log baseline hazard. Default is 6 when method = "piecewise-PH-GH" and 5 otherwise.

equal.strata.knots

logical; if TRUE (the default), then the same knots are used in the approximation of the baseline risk function in different strata when method = "spline-PH-GH".

ord

a positive integer denoting the order of the B-splines used to approximate the log cumulative hazard (default is 4); relevant only when method = "spline-PH-GH" or method = "ch-Laplace".

typeGH

a character string indicating the type of Gauss-Hermite rule to be used. Options are "simple" and "adaptive". The default is "simple" but it is turned to adaptive when the user specifies in the method argument an option that contains aGH.

GHk

the number of Gauss-Hermite quadrature points used to approximate the integrals over the random effects. The default is 15 for one- or two-dimensional integration and for N < 2000, and 9 otherwise for the simple Gauss-Hermite rule, and 5 for one-, two-dimensional or three-dimensional integration and for N < 2000, and 3 otherwise for the pseudo adaptive Gauss-Hermite rule, where N denotes the total number of longitudinal measurements.

GKk

the number of Gauss-Kronrod points used to approximate the integral involved in the calculation of the survival function. Two options are available, namely 7 or 15. For method = "weibull-PH-GH", method = "weibull-AFT-GH" and method = "spline-PH-GH" 15 are used, whereas for method = "piecewise-PH-GH" 7.

verbose

logical; if TRUE, the parameter estimates and the log-likelihood value are printed during the optimization procedure. Default is FALSE.

...

options passed to the control argument.

Details

Function jointModel fits joint models for longitudinal and survival data (more detailed information about the formulation of these models can be found in Rizopoulos (2010)). For the longitudinal responses the linear mixed effects model represented by the lmeObject is assumed. For the survival times let w_i denote the vector of baseline covariates in survObject, with associated parameter vector γ, m_i(t) the value of the longitudinal outcome at time point t as approximated by the linear mixed model (i.e., m_i(t) equals the fixed-effects part + random-effects part of the linear mixed effects model for sample unit i), α the association parameter for m_i(t), m_i'(t) the derivative of m_i(t) with respect to t, and α_d the association parameter for m_i'(t). Then, for method = "weibull-AFT-GH" a time-dependent Weibull model under the accelerated failure time formulation is assumed. For method = "weibull-PH-GH" a time-dependent relative risk model is postulated with a Weibull baseline risk function. For method = "piecewise-PH-GH" a time-dependent relative risk model is postulated with a piecewise constant baseline risk function. For method = "spline-PH-GH" a time-dependent relative risk model is assumed in which the log baseline risk function is approximated using B-splines. For method = "ch-Laplace" an additive model on the log cumulative hazard scale is assumed (see Rizopoulos et al., 2009 for more info). Finally, for method = "Cox-PH-GH" a time-dependent relative risk model is assumed where the baseline risk function is left unspecified (Wulfsohn and Tsiatis, 1997). For all these options the linear predictor for the survival submodel is written as

eta = gamma' w_i + alpha m_i{max(t-k,0)},

when parameterization = "value",

eta = gamma' w_i + alpha m_i'{max(t-k, 0)}

when parameterization = "slope", and

eta = gamma' w_i + alpha m_i{max(t-k, 0)} + α_s m_i'{max(t-k, 0)},

when parameterization = "both", where in all the above the value of k is specified by the lag argument and m_i'(t) = d m_i(t) / dt. If interFact is specified, then m_i\{max(t-k, 0)\} and/or m_i'\{max(t-k, 0)\} are multiplied with the design matrices derived from the formulas supplied as the first two arguments of interFact, respectively. In this case α and/or α_s become vectors of association parameters.

For method = "spline-PH-GH" it is also allowed to include stratification factors. These should be included in the specification of the survObject using function strata(). Note that in this case survObject must only be a 'coxph' object.

For all survival models except for the time-dependent proportional hazards model, the optimization algorithm starts with EM iterations, and if convergence is not achieved, it switches to quasi-Newton iterations (i.e., BFGS in optim() or nlminb(), depending on the value of the optimizer control argument). For method = "Cox-PH-GH" only the EM algorithm is used. During the EM iterations, convergence is declared if either of the following two conditions is satisfied: (i) L(θ^{it}) - L(θ^{it - 1}) < tol_3 \{ | L(θ^{it - 1}) | + tol_3 \} , or (ii) \max \{ | θ^{it} - θ^{it - 1} | / ( | θ^{it - 1} | + tol_1) \} < tol_2, where θ^{it} and θ^{it - 1} is the vector of parameter values at the current and previous iterations, respectively, and L(.) is the log-likelihood function. The values for tol_1, tol_2 and tol_3 are specified via the control argument. During the quasi-Newton iterations, the default convergence criteria of either optim() or nlminb() are used.

The required integrals are approximated using the standard Gauss-Hermite quadrature rule when the chosen option for the method argument contains the string "GH", and the (pseudo) adaptive Gauss-Hermite rule when the chosen option for the method argument contains the string "aGH". For method = "ch-Laplace" the fully exponential Laplace approximation described in Rizopoulos et al. (2009) is used. The (pseudo) adaptive Gauss-Hermite and the Laplace approximation are particularly useful when high-dimensional random effects vectors are considered (e.g., when modelling nonlinear subject-specific trajectories with splines or high-order polynomials).

Value

See jointModelObject for the components of the fit.

Note

1. The lmeObject argument should represent a linear mixed model object with a simple random-effects structure, i.e., only the pdDiag() class is currently allowed.

2. The lmeObject object should not contain any within-group correlation structure (i.e., correlation argument of lme()) or within-group heteroscedasticity structure (i.e., weights argument of lme()).

3. It is assumed that the linear mixed effects model lmeObject and the survival model survObject have been fitted to the same subjects. Moreover, it is assumed that the ordering of the subjects is the same for both lmeObject and survObject, i.e., that the first line in the data frame containing the event times corresponds to the first set of lines identified by the grouping variable in the data frame containing the repeated measurements, and so on.

4. In the print and summary generic functions for class jointModel, the estimated coefficients (and standard errors for the summary generic) for the event process are augmented with the element "Assoct" that corresponds to the association parameter α and the element "Assoct.s" that corresponds to the parameter α_s when parameterization is "slope" or "both" (see Details).

5. The standard errors returned by the summary generic function for class jointModel when method = "Cox-PH-GH" are based on the profile score vector (i.e., given the NPMLE for the unspecified baseline hazard). Hsieh et al. (2006) have noted that these standard errors are underestimated.

6. As it is the case for all types of mixed models that require numerical integration, it is advisable (especially in difficult datasets) to check the stability of the maximum likelihood estimates with an increasing number of Gauss-Hermite quadrature points.

7. It is assumed that the scale of the time variable (e.g., days, months years) is the same in both lmeObject and survObject.

Author(s)

Dimitris Rizopoulos [email protected]

References

Henderson, R., Diggle, P. and Dobson, A. (2000) Joint modelling of longitudinal measurements and event time data. Biostatistics 1, 465–480.

Hsieh, F., Tseng, Y.-K. and Wang, J.-L. (2006) Joint modeling of survival and longitudinal data: Likelihood approach revisited. Biometrics 62, 1037–1043.

Rizopoulos, D. (2012a) Joint Models for Longitudinal and Time-to-Event Data: with Applications in R. Boca Raton: Chapman and Hall/CRC.

Rizopoulos, D. (2012b) Fast fitting of joint models for longitudinal and event time data using a pseudo-adaptive Gaussian quadrature rule. Computational Statistics and Data Analysis 56, 491–501.

Rizopoulos, D. (2011) Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data. Biometrics 67, 819–829.

Rizopoulos, D. (2010) JM: An R package for the joint modelling of longitudinal and time-to-event data. Journal of Statistical Software 35 (9), 1–33. http://www.jstatsoft.org/v35/i09/

Rizopoulos, D., Verbeke, G. and Lesaffre, E. (2009) Fully exponential Laplace approximations for the joint modelling of survival and longitudinal data. Journal of the Royal Statistical Society, Series B 71, 637–654.

Rizopoulos, D., Verbeke, G. and Molenberghs, G. (2010) Multiple-imputation-based residuals and diagnostic plots for joint models of longitudinal and survival outcomes. Biometrics 66, 20–29.

Tsiatis, A. and Davidian, M. (2004) Joint modeling of longitudinal and time-to-event data: an overview. Statistica Sinica 14, 809–834.

Wulfsohn, M. and Tsiatis, A. (1997) A joint model for survival and longitudinal data measured with error. Biometrics 53, 330–339.

See Also

jointModelObject, anova.jointModel, coef.jointModel, fixef.jointModel, ranef.jointModel, fitted.jointModel, residuals.jointModel, plot.jointModel, survfitJM, rocJM, dynCJM, aucJM, prederrJM

Examples

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## Not run: 
# linear mixed model fit (random intercepts)
fitLME <- lme(log(serBilir) ~ drug * year, random = ~ 1 | id, data = pbc2)
# survival regression fit
fitSURV <- survreg(Surv(years, status2) ~ drug, data = pbc2.id, x = TRUE)
# joint model fit, under the (default) Weibull model
fitJOINT <- jointModel(fitLME, fitSURV, timeVar = "year")
fitJOINT
summary(fitJOINT)

# linear mixed model fit (random intercepts + random slopes)
fitLME <- lme(log(serBilir) ~ drug * year, random = ~ year | id, data = pbc2)
# survival regression fit
fitSURV <- survreg(Surv(years, status2) ~ drug, data = pbc2.id, x = TRUE)
# joint model fit, under the (default) Weibull model
fitJOINT <- jointModel(fitLME, fitSURV, timeVar = "year")
fitJOINT
summary(fitJOINT)

# we also include an interaction term of log(serBilir) with drug
fitJOINT <- jointModel(fitLME, fitSURV, timeVar = "year",
    interFact = list(value = ~ drug, data = pbc2.id))
fitJOINT
summary(fitJOINT)


# a joint model in which the risk for and event depends both on the true value of
# marker and the true value of the slope of the longitudinal trajectory
lmeFit <- lme(sqrt(CD4) ~ obstime * drug, random = ~ obstime | patient, data = aids)
coxFit <- coxph(Surv(Time, death) ~ drug, data = aids.id, x = TRUE)

# to fit this model we need to specify the 'derivForm' argument, which is a list
# with first component the derivative of the fixed-effects formula of 'lmeFit' with
# respect to 'obstime', second component the indicator of which fixed-effects 
# coefficients correspond to the previous defined formula, third component the 
# derivative of the random-effects formula of 'lmeFit' with respect to 'obstime', 
# and fourth component the indicator of which random-effects correspond to the 
# previous defined formula
dForm <- list(fixed = ~ 1 + drug, indFixed = c(2, 4), random = ~ 1, indRandom = 2)
jointModel(lmeFit, coxFit, timeVar = "obstime", method = "spline-PH-aGH",
  parameterization = "both", derivForm = dForm)


# Competing Risks joint model
# we first expand the PBC dataset in the competing risks long format
# with two competing risks being death and transplantation
pbc2.idCR <- crLong(pbc2.id, "status", "alive")

# we fit the linear mixed model as before
lmeFit.pbc <- lme(log(serBilir) ~ drug * ns(year, 3), 
    random = list(id = pdDiag(form = ~ ns(year, 3))), data = pbc2)

# however, for the survival model we need to use the data in the long
# format, and include the competing risks indicator as a stratification
# factor. We also take interactions of the baseline covariates with the
# stratification factor in order to allow the effect of these covariates
# to be different for each competing risk
coxCRFit.pbc <- coxph(Surv(years, status2) ~ (drug + sex)*strata + strata(strata), 
    data = pbc2.idCR, x = TRUE)

# the corresponding joint model is fitted simply by including the above
# two submodels as main arguments, setting argument CompRisk to TRUE, 
# and choosing as method = "spline-PH-aGH". Similarly as above, we also 
# include strata as an interaction factor to allow serum bilirubin to 
# have a different effect for each of the two competing risks
jmCRFit.pbc <- jointModel(lmeFit.pbc, coxCRFit.pbc, timeVar = "year", 
    method = "spline-PH-aGH", 
    interFact = list(value = ~ strata, data = pbc2.idCR), 
    CompRisk = TRUE)
summary(jmCRFit.pbc)

# linear mixed model fit
fitLME <- lme(sqrt(CD4) ~ obstime * drug - drug, 
    random = ~ 1 | patient, data = aids)
# cox model fit
fitCOX <- coxph(Surv(Time, death) ~ drug, data = aids.id, x = TRUE)
# joint model fit with a spline-approximated baseline hazard function
fitJOINT <- jointModel(fitLME, fitCOX, 
    timeVar = "obstime", method = "spline-PH-aGH")
fitJOINT
summary(fitJOINT)

## End(Not run)

drizopoulos/JM documentation built on May 15, 2019, 2:12 p.m.