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Introduction to MixedEffects Models Specifying MixedEffects Models Using Output Functions with MixedEffects Models 
In statistics, an effect is anything that influences the value of a response variable at a particular setting of the predictor variables. Effects are translated into model parameters. In linear models, effects become coefficients, representing the proportional contributions of model terms. In nonlinear models, effects often have specific physical interpretations, and appear in more general nonlinear combinations.
Fixed effects represent population parameters, assumed to be the same each time data is collected. Estimating fixed effects is the traditional domain of regression modeling. Random effects, by comparison, are sampledependent random variables. In modeling, random effects act like additional error terms, and their distributions and covariances must be specified.
For example, consider a model of the elimination of a drug from the bloodstream. The model uses time t as a predictor and the concentration of the drug C as the response. The nonlinear model term C_{0}e^{–rt} combines parameters C_{0} and r, representing, respectively, an initial concentration and an elimination rate. If data is collected across multiple individuals, it is reasonable to assume that the elimination rate is a random variable r_{i} depending on individual i, varying around a population mean $$\overline{r}$$. The term C_{0}e^{–rt} becomes
$${C}_{0}{e}^{[\overline{r}+({r}_{i}\overline{r})]t}={C}_{0}{e}^{(\beta +{b}_{i})t}\text{,}$$
where β = $$\overline{r}$$ is a fixed effect and b_{i} = $${r}_{i}\overline{r}$$ is a random effect.
Random effects are useful when data falls into natural groups. In the drug elimination model, the groups are simply the individuals under study. More sophisticated models might group data by an individual's age, weight, diet, etc. Although the groups are not the focus of the study, adding random effects to a model extends the reliability of inferences beyond the specific sample of individuals.
Mixedeffects models account for both fixed and random effects. As with all regression models, their purpose is to describe a response variable as a function of the predictor variables. Mixedeffects models, however, recognize correlations within sample subgroups. In this way, they provide a compromise between ignoring data groups entirely and fitting each group with a separate model.
Suppose data for a nonlinear regression model falls into one of m distinct groups i = 1, ..., m. To account for the groups in a model, write response j in group i as:
$${y}_{ij}=f(\phi ,{x}_{ij})+{\epsilon}_{ij}$$
y_{i}_{j} is the response, x_{i}_{j} is a vector of predictors, φ is a vector of model parameters, and ε_{i}_{j} is the measurement or process error. The index j ranges from 1 to n_{i}, where n_{i} is the number of observations in group i. The function f specifies the form of the model. Often, x_{i}_{j} is simply an observation time t_{i}_{j}. The errors are usually assumed to be independent and identically, normally distributed, with constant variance.
Estimates of the parameters in φ describe the population, assuming those estimates are the same for all groups. If, however, the estimates vary by group, the model becomes
$${y}_{ij}=f({\phi}_{i},{x}_{ij})+{\epsilon}_{ij}$$
In a mixedeffects model, φ_{i} may be a combination of a fixed and a random effect:
$${\phi}_{i}=\beta +{b}_{i}$$
The random effects b_{i} are usually described as multivariate normally distributed, with mean zero and covariance Ψ. Estimating the fixed effects β and the covariance of the random effects Ψ provides a description of the population that does not assume the parameters φ_{i} are the same across groups. Estimating the random effects b_{i} also gives a description of specific groups within the data.
Model parameters do not have to be identified with individual effects. In general, design matrices A and B are used to identify parameters with linear combinations of fixed and random effects:
$${\phi}_{i}=A\beta +B{b}_{i}$$
If the design matrices differ among groups, the model becomes
$${\phi}_{i}={A}_{i}\beta +{B}_{i}{b}_{i}$$
If the design matrices also differ among observations, the model becomes
$$\begin{array}{l}{\phi}_{ij}={A}_{ij}\beta +{B}_{ij}{b}_{i}\\ {y}_{ij}=f({\phi}_{ij},{x}_{ij})+{\epsilon}_{ij}\end{array}$$
Some of the groupspecific predictors in x_{i}_{j} may not change with observation j. Calling those v_{i}, the model becomes
$${y}_{ij}=f({\phi}_{ij},{x}_{ij},{v}_{i})+{\epsilon}_{ij}$$
Suppose data for a nonlinear regression model falls into one of m distinct groups i = 1, ..., m. (Specifically, suppose that the groups are not nested.) To specify a general nonlinear mixedeffects model for this data:
Define groupspecific model parameters φ_{i} as linear combinations of fixed effects β and random effects b_{i}.
Define response values y_{i} as a nonlinear function f of the parameters and groupspecific predictor variables X_{i}.
The model is:
$$\begin{array}{l}{\phi}_{i}={A}_{i}\beta +{B}_{i}{b}_{i}\\ {y}_{i}=f({\phi}_{i},{X}_{i})+{\epsilon}_{i}\\ {b}_{i}\sim N(0,\Psi )\\ {\epsilon}_{i}\sim N(0,{\sigma}^{2})\end{array}$$
This formulation of the nonlinear mixedeffects model uses the following notation:
φ_{i}  A vector of groupspecific model parameters 
β  A vector of fixed effects, modeling population parameters 
b_{i}  A vector of multivariate normally distributed groupspecific random effects 
A_{i}  A groupspecific design matrix for combining fixed effects 
B_{i}  A groupspecific design matrix for combining random effects 
X_{i}  A data matrix of groupspecific predictor values 
y_{i}  A data vector of groupspecific response values 
f  A general, realvalued function of φ_{i} and X_{i} 
ε_{i}  A vector of groupspecific errors, assumed to be independent, identically, normally distributed, and independent of b_{i} 
Ψ  A covariance matrix for the random effects 
σ^{2}  The error variance, assumed to be constant across observations 
For example, consider a model of the elimination of a drug from the bloodstream. The model incorporates two overlapping phases:
An initial phase p during which drug concentrations reach equilibrium with surrounding tissues
A second phase q during which the drug is eliminated from the bloodstream
For data on multiple individuals i, the model is
$${y}_{ij}={C}_{pi}{e}^{{r}_{pi}{t}_{ij}}+{C}_{qi}{e}^{{r}_{qi}{t}_{ij}}+{\epsilon}_{ij},$$
where y_{ij} is the observed concentration in individual i at time t_{ij}. The model allows for different sampling times and different numbers of observations for different individuals.
The elimination rates r_{pi} and r_{qi} must be positive to be physically meaningful. Enforce this by introducing the log rates R_{pi} = log(r_{pi}) and R_{qi} = log(r_{qi}) and reparametrizing the model:
$${y}_{ij}={C}_{pi}{e}^{\mathrm{exp}({R}_{pi}){t}_{ij}}+{C}_{qi}{e}^{\mathrm{exp}({R}_{qi}){t}_{ij}}+{\epsilon}_{ij}$$
Choosing which parameters to model with random effects is an important consideration when building a mixedeffects model. One technique is to add random effects to all parameters, and use estimates of their variances to determine their significance in the model. An alternative is to fit the model separately to each group, without random effects, and look at the variation of the parameter estimates. If an estimate varies widely across groups, or if confidence intervals for each group have minimal overlap, the parameter is a good candidate for a random effect.
To introduce fixed effects β and random effects b_{i} for all model parameters, reexpress the model as follows:
$$\begin{array}{lll}{y}_{ij}\hfill & =\hfill & [{\overline{C}}_{p}+({C}_{pi}{\overline{C}}_{p})]{e}^{\mathrm{exp}[{\overline{R}}_{p}+({R}_{pi}{\overline{R}}_{p})]{t}_{ij}}+\hfill \\ \hfill & \hfill & [{\overline{C}}_{q}+({C}_{qi}{\overline{C}}_{q})]{e}^{\mathrm{exp}[{\overline{R}}_{q}+({R}_{qi}{\overline{R}}_{q})]{t}_{ij}}+{\epsilon}_{ij}\hfill \\ \hfill & =\hfill & ({\beta}_{1}+{b}_{1i}){e}^{\mathrm{exp}({\beta}_{2}+{b}_{2i}){t}_{ij}}+\hfill \\ \hfill & \hfill & ({\beta}_{3}+{b}_{3i}){e}^{\mathrm{exp}({\beta}_{4}+{b}_{4i}){t}_{ij}}+{\epsilon}_{ij}\hfill \end{array}$$
In the notation of the general model:
$$\beta =\left(\begin{array}{c}{\beta}_{1}\\ \vdots \\ {\beta}_{4}\end{array}\right),{b}_{i}=\left(\begin{array}{c}{b}_{i1}\\ \vdots \\ {b}_{i4}\end{array}\right),{y}_{i}=\left(\begin{array}{c}{y}_{i1}\\ \vdots \\ {y}_{i{n}_{i}}\end{array}\right),{X}_{i}=\left(\begin{array}{c}{t}_{i1}\\ \vdots \\ {t}_{i{n}_{i}}\end{array}\right),$$
where n_{i} is the number of observations of individual i. In this case, the design matrices A_{i} and B_{i} are, at least initially, 4by4 identity matrices. Design matrices may be altered, as necessary, to introduce weighting of individual effects, or time dependency.
Fitting the model and estimating the covariance matrix Ψ often leads to further refinements. A relatively small estimate for the variance of a random effect suggests that it can be removed from the model. Likewise, relatively small estimates for covariances among certain random effects suggests that a full covariance matrix is unnecessary. Since random effects are unobserved, Ψ must be estimated indirectly. Specifying a diagonal or blockdiagonal covariance pattern for Ψ can improve convergence and efficiency of the fitting algorithm.
Statistics Toolbox™ functions nlmefit and nlmefitsa fit the general nonlinear mixedeffects model to data, estimating the fixed and random effects. The functions also estimate the covariance matrix Ψ for the random effects. Additional diagnostic outputs allow you to assess tradeoffs between the number of model parameters and the goodness of fit.
If the model in Specifying MixedEffects Models assumes a groupdependent covariate such as weight (w) the model becomes:
$$\left(\begin{array}{c}{\phi}_{1}\\ {\phi}_{2}\\ {\phi}_{3}\end{array}\right)=\left(\begin{array}{ccc}1& 0& 0\\ 0& 1& 0\\ 0& 0& 1\end{array}\begin{array}{c}wi\\ 0\\ 0\end{array}\right)\left(\begin{array}{c}{\beta}_{1}\\ {\beta}_{2}\\ \begin{array}{l}{\beta}_{3}\\ {\beta}_{4}\end{array}\end{array}\right)+\text{\hspace{0.17em}}\left(\begin{array}{ccc}1& 0& 0\\ 0& 1& 0\\ 0& 0& 1\end{array}\right)\left(\begin{array}{c}{b}_{1}\\ {b}_{2}\\ {b}_{3}\end{array}\right)$$
Thus, the parameter φ_{i} for any individual in the ith group is:
$$\left(\begin{array}{c}{\phi}_{{1}_{i}}\\ {\phi}_{{2}_{i}}\\ {\phi}_{{3}_{i}}\end{array}\right)=\left(\begin{array}{c}{\beta}_{1}+{\beta}_{4}*{w}_{i}\\ {\beta}_{2}\\ {\beta}_{3}\end{array}\right)+\text{\hspace{0.17em}}\left(\begin{array}{c}{b}_{{1}_{i}}\\ {b}_{{2}_{i}}\\ {b}_{{3}_{i}}\end{array}\right)$$
To specify a covariate model, use the 'FEGroupDesign' option.
'FEGroupDesign' is a pbyqbym array specifying a different pbyq fixedeffects design matrix for each of the m groups. Using the previous example, the array resembles the following:
Create the array.
% Number of parameters in the model (Phi) num_params = 3; % Number of covariates num_cov = 1; % Assuming number of groups in the data set is 7 num_groups = 7; % Array of covariate values covariates = [75; 52; 66; 55; 70; 58; 62 ]; A = repmat(eye(num_params, num_params+num_cov),... [1,1,num_groups]); A(1,num_params+1,1:num_groups) = covariates(:,1)
Create a struct with the specified design matrix.
options.FEGroupDesign = A;
Specify the arguments for nlmefit (or nlmefitsa) as shown in MixedEffects Models Using nlmefit and nlmefitsa.
Statistics Toolbox provides two functions, nlmefit and nlmefitsa for fitting nonlinear mixedeffects models. Each function provides different capabilities, which may help you decide which to use.
nlmefit provides the following four approximation methods for fitting nonlinear mixedeffects models:
'LME' — Use the likelihood for the linear mixedeffects model at the current conditional estimates of beta and B. This is the default.
'RELME' — Use the restricted likelihood for the linear mixedeffects model at the current conditional estimates of beta and B.
'FO' — Firstorder Laplacian approximation without random effects.
'FOCE' — Firstorder Laplacian approximation at the conditional estimates of B.
nlmefitsa provides an additional approximation method, Stochastic Approximation ExpectationMaximization (SAEM) [24] with three steps :
Simulation: Generate simulated values of the random effects b from the posterior density p(bΣ) given the current parameter estimates.
Stochastic approximation: Update the expected value of the log likelihood function by taking its value from the previous step, and moving part way toward the average value of the log likelihood calculated from the simulated random effects.
Maximization step: Choose new parameter estimates to maximize the log likelihood function given the simulated values of the random effects.
Both nlmefit and nlmefitsa attempt to find parameter estimates to maximize a likelihood function, which is difficult to compute. nlmefit deals with the problem by approximating the likelihood function in various ways, and maximizing the approximate function. It uses traditional optimization techniques that depend on things like convergence criteria and iteration limits.
nlmefitsa, on the other hand, simulates random values of the parameters in such a way that in the long run they converge to the values that maximize the exact likelihood function. The results are random, and traditional convergence tests don't apply. Therefore nlmefitsa provides options to plot the results as the simulation progresses, and to restart the simulation multiple times. You can use these features to judge whether the results have converged to the accuracy you desire.
The following parameters are specific to nlmefitsa. Most control the stochastic algorithm.
Cov0 — Initial value for the covariance matrix PSI. Must be an rbyr positive definite matrix. If empty, the default value depends on the values of BETA0.
ComputeStdErrors — true to compute standard errors for the coefficient estimates and store them in the output STATS structure, or false (default) to omit this computation.
LogLikMethod — Specifies the method for approximating the log likelihood.
NBurnIn — Number of initial burnin iterations during which the parameter estimates are not recomputed. Default is 5.
NIterations — Controls how many iterations are performed for each of three phases of the algorithm.
NMCMCIterations — Number of Markov Chain Monte Carlo (MCMC) iterations.
There are some differences in the capabilities of nlmefit and nlmefitsa. Therefore some data and models are usable with either function, but some may require you to choose just one of them.
Error models — nlmefitsa supports a variety of error models. For example, the standard deviation of the response can be constant, proportional to the function value, or a combination of the two. nlmefit fits models under the assumption that the standard deviation of the response is constant. One of the error models, 'exponential', specifies that the log of the response has a constant standard deviation. You can fit such models using nlmefit by providing the log response as input, and by rewriting the model function to produce the log of the nonlinear function value.
Random effects — Both functions fit data to a nonlinear function with parameters, and the parameters may be simple scalar values or linear functions of covariates. nlmefit allows any coefficients of the linear functions to have both fixed and random effects. nlmefitsa supports random effects only for the constant (intercept) coefficient of the linear functions, but not for slope coefficients. So in the example in Specifying Covariate Models, nlmefitsa can treat only the first three beta values as random effects.
Model form — nlmefit supports a very general model specification, with few restrictions on the design matrices that relate the fixed coefficients and the random effects to the model parameters. nlmefitsa is more restrictive:
The fixed effect design must be constant in every group (for every individual), so an observationdependent design is not supported.
The random effect design must be constant for the entire data set, so neither an observationdependent design nor a groupdependent design is supported.
As mentioned under Random Effects, the random effect design must not specify random effects for slope coefficients. This implies that the design must consist of zeros and ones.
The random effect design must not use the same random effect for multiple coefficients, and cannot use more than one random effect for any single coefficient.
The fixed effect design must not use the same coefficient for multiple parameters. This implies that it can have at most one nonzero value in each column.
If you want to use nlmefitsa for data in which the covariate effects are random, include the covariates directly in the nonlinear model expression. Don't include the covariates in the fixed or random effect design matrices.
Convergence — As described in the Model form, nlmefit and nlmefitsa have different approaches to measuring convergence. nlmefit uses traditional optimization measures, and nlmefitsa provides diagnostics to help you judge the convergence of a random simulation.
In practice, nlmefitsa tends to be more robust, and less likely to fail on difficult problems. However, nlmefit may converge faster on problems where it converges at all. Some problems may benefit from a combined strategy, for example by running nlmefitsa for a while to get reasonable parameter estimates, and using those as a starting point for additional iterations using nlmefit.
The Outputfcn field of the options structure specifies one or more functions that the solver calls after each iteration. Typically, you might use an output function to plot points at each iteration or to display optimization quantities from the algorithm. To set up an output function:
Write the output function as a MATLAB^{®} file function or local function.
Use statset to set the value of Outputfcn to be a function handle, that is, the name of the function preceded by the @ sign. For example, if the output function is outfun.m, the command
options = statset('OutputFcn', @outfun);
specifies OutputFcn to be the handle to outfun. To specify multiple output functions, use the syntax:
options = statset('OutputFcn',{@outfun, @outfun2});
Call the optimization function with options as an input argument.
For an example of an output function, see Sample Output Function.
The function definition line of the output function has the following form:
stop = outfun(beta,status,state)
where
beta is the current fixed effects.
status is a structure containing data from the current iteration. Fields in status describes the structure in detail.
state is the current state of the algorithm. States of the Algorithm lists the possible values.
stop is a flag that is true or false depending on whether the optimization routine should quit or continue. See Stop Flag for more information.
The solver passes the values of the input arguments to outfun at each iteration.
The following table lists the fields of the status structure:
Field  Description 

procedure 

iteration  An integer starting from 0. 
inner  A structure describing the status of the inner iterations within
the ALT and LAP procedures,
with the fields:

fval  The current log likelihood 
Psi  The current randomeffects covariance matrix 
theta  The current parameterization of Psi 
mse  The current error variance 
The following table lists the possible values for state:
state  Description 

'init'  The algorithm is in the initial state before the first iteration. 
'iter'  The algorithm is at the end of an iteration. 
'done'  The algorithm is in the final state after the last iteration. 
The following code illustrates how the output function might use the value of state to decide which tasks to perform at the current iteration:
switch state case 'iter' % Make updates to plot or guis as needed case 'init' % Setup for plots or guis case 'done' % Cleanup of plots, guis, or final plot otherwise end
The output argument stop is a flag that is true or false. The flag tells the solver whether it should quit or continue. The following examples show typical ways to use the stop flag.
Stopping an Optimization Based on Intermediate Results. The output function can stop the estimation at any iteration based on the values of arguments passed into it. For example, the following code sets stop to true based on the value of the log likelihood stored in the 'fval'field of the status structure:
stop = outfun(beta,status,state) stop = false; % Check if loglikelihood is more than 132. if status.fval > 132 stop = true; end
Stopping an Iteration Based on GUI Input. If you design a GUI to perform nlmefit iterations, you can make the output function stop when a user clicks a Stop button on the GUI. For example, the following code implements a dialog to cancel calculations:
function retval = stop_outfcn(beta,str,status) persistent h stop; if isequal(str.inner.state,'none') switch(status) case 'init' % Initialize dialog stop = false; h = msgbox('Press STOP to cancel calculations.',... 'NLMEFIT: Iteration 0 '); button = findobj(h,'type','uicontrol'); set(button,'String','STOP','Callback',@stopper) pos = get(h,'Position'); pos(3) = 1.1 * pos(3); set(h,'Position',pos) drawnow case 'iter' % Display iteration number in the dialog title set(h,'Name',sprintf('NLMEFIT: Iteration %d',... str.iteration)) drawnow; case 'done' % Delete dialog delete(h); end end if stop % Stop if the dialog button has been pressed delete(h) end retval = stop; function stopper(varargin) % Set flag to stop when button is pressed stop = true; disp('Calculation stopped.') end end
nmlefitoutputfcn is the sample Statistics Toolbox output function for nlmefit and nlmefitsa. It initializes or updates a plot with the fixedeffects (BETA) and variance of the random effects (diag(STATUS.Psi)). For nlmefit, the plot also includes the loglikelihood (STATUS.fval).
nlmefitoutputfcn is the default output function for nlmefitsa. To use it with nlmefit, specify a function handle for it in the options structure:
opt = statset('OutputFcn', @nlmefitoutputfcn, …) beta = nlmefit(…, 'Options', opt, …)
To prevent nlmefitsa from using of this function, specify an empty value for the output function:
opt = statset('OutputFcn', [], …) beta = nlmefitsa(…, 'Options', opt, …)
nlmefitoutputfcn stops nlmefit or nlmefitsa if you close the figure that it produces.
Load the sample data.
load indomethacin
The data in indomethacin.mat records concentrations of the drug indomethacin in the bloodstream of six subjects over eight hours.
Plot the scatter plot of indomethacin in the bloodstream grouped by subject.
gscatter(time,concentration,subject) xlabel('Time (hours)') ylabel('Concentration (mcg/ml)') title('{\bf Indomethacin Elimination}') hold on
Specifying MixedEffects Models page discusses a useful model for this type of data.
Construct the model via an anonymous function.
model = @(phi,t)(phi(1)*exp(exp(phi(2))*t) + ...
phi(3)*exp(exp(phi(4))*t));
Use the nlinfit function to fit the model to all of the data, ignoring subjectspecific effects.
phi0 = [1 2 1 1]; [phi,res] = nlinfit(time,concentration,model,phi0);
Compute the mean squared error.
numObs = length(time); numParams = 4; df = numObsnumParams; mse = (res'*res)/df
mse = 0.0304
Super impose the model on the scatter plot of data.
tplot = 0:0.01:8; plot(tplot,model(phi,tplot),'k','LineWidth',2) hold off
Draw the boxplot of residuals by subject.
colors = 'rygcbm'; h = boxplot(res,subject,'colors',colors,'symbol','o'); set(h(~isnan(h)),'LineWidth',2) hold on boxplot(res,subject,'colors','k','symbol','ko') grid on xlabel('Subject') ylabel('Residual') hold off
The box plot of residuals by subject shows that the boxes are mostly above or below zero, indicating that the model has failed to account for subjectspecific effects.
To account for subjectspecific effects, fit the model separately to the data for each subject.
phi0 = [1 2 1 1]; PHI = zeros(4,6); RES = zeros(11,6); for I = 1:6 tI = time(subject == I); cI = concentration(subject == I); [PHI(:,I),RES(:,I)] = nlinfit(tI,cI,model,phi0); end PHI
PHI = 2.0293 2.8277 5.4683 2.1981 3.5661 3.0023 0.5794 0.8013 1.7498 0.2423 1.0408 1.0882 0.1915 0.4989 1.6757 0.2545 0.2915 0.9685 1.7878 1.6354 0.4122 1.6026 1.5069 0.8731
Compute the mean squared error.
numParams = 24; df = numObsnumParams; mse = (RES(:)'*RES(:))/df
mse = 0.0057
Plot the scatter plot of the data and superimpose the model for each subject.
gscatter(time,concentration,subject) xlabel('Time (hours)') ylabel('Concentration (mcg/ml)') title('{\bf Indomethacin Elimination}') hold on for I = 1:6 plot(tplot,model(PHI(:,I),tplot),'Color',colors(I)) end axis([0 8 0 3.5]) hold off
PHI gives estimates of the four model parameters for each of the six subjects. The estimates vary considerably, but taken as a 24parameter model of the data, the meansquared error of 0.0057 is a significant reduction from 0.0304 in the original fourparameter model.
Draw the box plot of residuals by subject.
h = boxplot(RES,'colors',colors,'symbol','o'); set(h(~isnan(h)),'LineWidth',2) hold on boxplot(RES,'colors','k','symbol','ko') grid on xlabel('Subject') ylabel('Residual') hold off
Now the box plot shows that the larger model accounts for most of the subjectspecific effects. The spread of the residuals (the vertical scale of the box plot) is much smaller than in the previous box plot, and the boxes are now mostly centered on zero.
While the 24parameter model successfully accounts for variations due to the specific subjects in the study, it does not consider the subjects as representatives of a larger population. The sampling distribution from which the subjects are drawn is likely more interesting than the sample itself. The purpose of mixedeffects models is to account for subjectspecific variations more broadly, as random effects varying around population means.
Use the nlmefit function to fit a mixedeffects model to the data. You can also use nlmefitsa in place of nlmefit .
The following anonymous function, nlme_model , adapts the fourparameter model used by nlinfit to the calling syntax of nlmefit by allowing separate parameters for each individual. By default, nlmefit assigns random effects to all the model parameters. Also by default, nlmefit assumes a diagonal covariance matrix (no covariance among the random effects) to avoid overparametrization and related convergence issues.
nlme_model = @(PHI,t)(PHI(:,1).*exp(exp(PHI(:,2)).*t) + ... PHI(:,3).*exp(exp(PHI(:,4)).*t)); phi0 = [1 2 1 1]; [phi,PSI,stats] = nlmefit(time,concentration,subject, ... [],nlme_model,phi0)
phi = 2.8277 0.7729 0.4606 1.3459 PSI = 0.3264 0 0 0 0 0.0250 0 0 0 0 0.0124 0 0 0 0 0.0000 stats = dfe: 57 logl: 54.5882 mse: 0.0066 rmse: 0.0787 errorparam: 0.0815 aic: 91.1765 bic: 93.0506 covb: [4x4 double] sebeta: [0.2558 0.1066 0.1092 0.2244] ires: [66x1 double] pres: [66x1 double] iwres: [66x1 double] pwres: [66x1 double] cwres: [66x1 double]
The meansquared error of 0.0066 is comparable to the 0.0057 of the 24parameter model without random effects, and significantly better than the 0.0304 of the fourparameter model without random effects.
The estimated covariance matrix PSI shows that the variance of the fourth random effect is essentially zero, suggesting that you can remove it to simplify the model. To do this, use the 'REParamsSelect' namevalue pair to specify the indices of the parameters to be modeled with random effects in nlmefit .
[phi,PSI,stats] = nlmefit(time,concentration,subject, ... [],nlme_model,phi0, ... 'REParamsSelect',[1 2 3])
phi = 2.8277 0.7728 0.4605 1.3460 PSI = 0.3270 0 0 0 0.0250 0 0 0 0.0124 stats = dfe: 58 logl: 54.5875 mse: 0.0066 rmse: 0.0780 errorparam: 0.0815 aic: 93.1750 bic: 94.8410 covb: [4x4 double] sebeta: [0.2560 0.1066 0.1092 0.2244] ires: [66x1 double] pres: [66x1 double] iwres: [66x1 double] pwres: [66x1 double] cwres: [66x1 double]
The loglikelihood logl is almost identical to what it was with random effects for all of the parameters, the Akaike information criterion aic is reduced from 91.1765 to 93.1750, and the Bayesian information criterion bic is reduced from 93.0506 to 94.8410. These measures support the decision to drop the fourth random effect.
Refitting the simplified model with a full covariance matrix allows for identification of correlations among the random effects. To do this, use the CovPattern parameter to specify the pattern of nonzero elements in the covariance matrix.
[phi,PSI,stats] = nlmefit(time,concentration,subject, ... [],nlme_model,phi0, ... 'REParamsSelect',[1 2 3], ... 'CovPattern',ones(3))
phi = 2.8149 0.8291 0.5611 1.1410 PSI = 0.4768 0.1152 0.0500 0.1152 0.0321 0.0033 0.0500 0.0033 0.0236 stats = dfe: 55 logl: 58.4718 mse: 0.0061 rmse: 0.0782 errorparam: 0.0781 aic: 94.9436 bic: 97.2342 covb: [4x4 double] sebeta: [0.3028 0.1104 0.1179 0.1662] ires: [66x1 double] pres: [66x1 double] iwres: [66x1 double] pwres: [66x1 double] cwres: [66x1 double]
The estimated covariance matrix PSI shows that the random effects on the first two parameters have a relatively strong correlation, and both have a relatively weak correlation with the last random effect. This structure in the covariance matrix is more apparent if you convert PSI to a correlation matrix using corrcov .
RHO = corrcov(PSI) clf; imagesc(RHO) set(gca,'XTick',[1 2 3],'YTick',[1 2 3]) title('{\bf Random Effect Correlation}') h = colorbar; set(get(h,'YLabel'),'String','Correlation');
RHO = 1.0000 0.9315 0.4716 0.9315 1.0000 0.1185 0.4716 0.1185 1.0000
Incorporate this structure into the model by changing the specification of the covariance pattern to blockdiagonal.
P = [1 1 0;1 1 0;0 0 1] % Covariance pattern [phi,PSI,stats,b] = nlmefit(time,concentration,subject, ... [],nlme_model,phi0, ... 'REParamsSelect',[1 2 3], ... 'CovPattern',P)
P = 1 1 0 1 1 0 0 0 1 phi = 2.7830 0.8981 0.6581 1.0000 PSI = 0.5180 0.1069 0 0.1069 0.0221 0 0 0 0.0454 stats = dfe: 57 logl: 58.0804 mse: 0.0061 rmse: 0.0768 errorparam: 0.0782 aic: 98.1608 bic: 100.0350 covb: [4x4 double] sebeta: [0.3171 0.1073 0.1384 0.1453] ires: [66x1 double] pres: [66x1 double] iwres: [66x1 double] pwres: [66x1 double] cwres: [66x1 double] b = 0.8507 0.1563 1.0427 0.7559 0.5652 0.1550 0.1756 0.0323 0.2152 0.1560 0.1167 0.0320 0.2756 0.0519 0.2620 0.1064 0.2835 0.1389
The blockdiagonal covariance structure reduces aic from 94.9462 to 98.1608 and bic from 97.2368 to 100.0350 without significantly affecting the loglikelihood. These measures support the covariance structure used in the final model. The output b gives predictions of the three random effects for each of the six subjects. These are combined with the estimates of the fixed effects in phi to produce the mixedeffects model.
Plot the mixedeffects model for each of the six subjects. For comparison, the model without random effects is also shown.
PHI = repmat(phi,1,6) + ... % Fixed effects [b(1,:);b(2,:);b(3,:);zeros(1,6)]; % Random effects RES = zeros(11,6); % Residuals colors = 'rygcbm'; for I = 1:6 fitted_model = @(t)(PHI(1,I)*exp(exp(PHI(2,I))*t) + ... PHI(3,I)*exp(exp(PHI(4,I))*t)); tI = time(subject == I); cI = concentration(subject == I); RES(:,I) = cI  fitted_model(tI); subplot(2,3,I) scatter(tI,cI,20,colors(I),'filled') hold on plot(tplot,fitted_model(tplot),'Color',colors(I)) plot(tplot,model(phi,tplot),'k') axis([0 8 0 3.5]) xlabel('Time (hours)') ylabel('Concentration (mcg/ml)') legend(num2str(I),'Subject','Fixed') end
If obvious outliers in the data (visible in previous box plots) are ignored, a normal probability plot of the residuals shows reasonable agreement with model assumptions on the errors.
clf; normplot(RES(:))
You can examine the stats structure, which is returned by both nlmefit and nlmefitsa, to determine the quality of your model. The stats structure contains fields with conditional weighted residuals (cwres field) and individual weighted residuals (iwres field). Since the model assumes that residuals are normally distributed, you can examine the residuals to see how well this assumption holds.
This example generates synthetic data using normal distributions. It shows how the fit statistics look:
Good when testing against the same type of model as generates the data
Poor when tested against incorrect data models
Initialize a 2D model with 100 individuals:
nGroups = 100; % 100 Individuals nlmefun = @(PHI,t)(PHI(:,1)*5 + PHI(:,2)^2.*t); % Regression fcn REParamSelect = [1 2]; % Both Parameters have random effect errorParam = .03; beta0 = [ 1.5 5]; % Parameter means psi = [ 0.35 0; ... % Covariance Matrix 0 0.51 ]; time =[0.25;0.5;0.75;1;1.25;2;3;4;5;6]; nParameters = 2; rng(0,'twister') % for reproducibility
Generate the data for fitting with a proportional error model:
b_i = mvnrnd(zeros(1, numel(REParamSelect)), psi, nGroups); individualParameters = zeros(nGroups,nParameters); individualParameters(:, REParamSelect) = ... bsxfun(@plus,beta0(REParamSelect), b_i); groups = repmat(1:nGroups,numel(time),1); groups = vertcat(groups(:)); y = zeros(numel(time)*nGroups,1); x = zeros(numel(time)*nGroups,1); for i = 1:nGroups idx = groups == i; f = nlmefun(individualParameters(i,:), time); % Make a proportional error model for y: y(idx) = f + errorParam*f.*randn(numel(f),1); x(idx) = time; end P = [ 1 0 ; 0 1 ];
Fit the data using the same regression function and error model as the model generator:
[~,~,stats] = nlmefit(x,y,groups, ... [],nlmefun,[1 1],'REParamsSelect',REParamSelect,... 'ErrorModel','Proportional','CovPattern',P);
Create a plotting routine by copying the following function definition, and creating a file plotResiduals.m on your MATLAB path:
function plotResiduals(stats) pwres = stats.pwres; iwres = stats.iwres; cwres = stats.cwres; figure subplot(2,3,1); normplot(pwres); title('PWRES') subplot(2,3,4); createhistplot(pwres); subplot(2,3,2); normplot(cwres); title('CWRES') subplot(2,3,5); createhistplot(cwres); subplot(2,3,3); normplot(iwres); title('IWRES') subplot(2,3,6); createhistplot(iwres); title('IWRES') function createhistplot(pwres) [x, n] = hist(pwres); d = n(2) n(1); x = x/sum(x*d); bar(n,x); ylim([0 max(x)*1.05]); hold on; x2 = 4:0.1:4; f2 = normpdf(x2,0,1); plot(x2,f2,'r'); end end
Plot the residuals using the plotResiduals function:
plotResiduals(stats);
The upper probability plots look straight, meaning the residuals are normally distributed. The bottom histogram plots match the superimposed normal density plot. So you can conclude that the error model matches the data.
For comparison, fit the data using a constant error model, instead of the proportional model that created the data:
[~,~,stats] = nlmefit(x,y,groups, ... [],nlmefun,[0 0],'REParamsSelect',REParamSelect,... 'ErrorModel','Constant','CovPattern',P); plotResiduals(stats);
The upper probability plots are not straight, indicating the residuals are not normally distributed. The bottom histogram plots are fairly close to the superimposed normal density plots.
For another comparison, fit the data to a different structural model than created the data:
nlmefun2 = @(PHI,t)(PHI(:,1)*5 + PHI(:,2).*t.^4); [~,~,stats] = nlmefit(x,y,groups, ... [],nlmefun2,[0 0],'REParamsSelect',REParamSelect,... 'ErrorModel','constant', 'CovPattern',P); plotResiduals(stats);
Not only are the upper probability plots not straight, but the histogram plot is quite skewed compared to the superimposed normal density. These residuals are not normally distributed, and do not match the model.