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\title{Spline terms in a Cox model}
\author{Terry Therneau}

\begin{document}
\maketitle
This is a trio of topics that comes up just often enough in my work 
that I end up re-discovering how to do it correctly about once a year.
A note showing how may be useful to others, it is certainly a useful
reference for me.

\section{Plotting smooth terms}
Here is a simple example using the MGUS data.
I prefer a simpler color palette than the default found in termplot.
<<mplot, fig=TRUE>>=
library(survival)
mfit <- coxph(Surv(futime, death) ~ sex + pspline(age, df=4), data=mgus)
mfit
termplot(mfit, term=2, se=TRUE, col.term=1, col.se=1)
@ 
Note that the \code{term=2} option is passed directly from the
\code{termplot} routine to a \code{predict(fit, type='terms')} call.
For coxph models, the \code{predict} function allows terms to be
specified either by position or name.
Other routines, e.g. \code{gam}, respond only to a name.
(This can be a bit of a pain since it must exactly match the 
\emph{printed} call
in both spelling and spacing; and the printed spacing
may not match what the user typed.)

Three questions are whether the curve is significantly 
non-linear, how the curve is centered and whether we
can easily plot it on the hazard as opposed to the log hazard scale.
The first question is answered by the printout,
the solution to the others is to use the plot=FALSE option of termplot,
which returns the data points that would be plotted back to the user.

<<mplot2>>=
ptemp <- termplot(mfit, se=TRUE, plot=FALSE)
attributes(ptemp)
ptemp$age[1:4,]
@ 

The termplot function depends on a call to predict with type='terms',
which returns a centered set of predictions.
Like a simple linear model fit, the intercept is a separate term, which is
found in the ``constant'' attribute above,
and each column of the result is centered so that the average predicted
value is zero.
Since any given $x$ value may appear multiple times in the data and thus in
the result of predict, 
and the termplot function removes duplicates, the data returned by
\code{termplot} may not be precisely centered at zero.

Now suppose we want to redraw this on log scale with age 50 as the reference,
i.e., the  risk is 1 for a 50 year old.  
Since the Cox model is a relative hazards model we can choose whatever center
we like.
(If there were no one of exactly age 50 in the data set the first line 
below would need to do an interpolation, e.g. by using the approx function.)

<<mplot3, fig=TRUE>>=
ageterm <- ptemp$age  # this will be a data frame
center <- with(ageterm, y[x==50])
ytemp <- ageterm$y + outer(ageterm$se, c(0, -1.96, 1.96), '*')
matplot(ageterm$x, exp(ytemp - center), log='y',
        type='l', lty=c(1,2,2), col=1, 
        xlab="Age at diagnosis", ylab="Relative death rate")
@ 

Voila! We now have a plot that is interpretable with respect to a fixed
reference.

The approach is appropriate for any term, not just psplines.
The above plot uses log scale for the y axis which is appropriate
for the question of whether a non-linear age effect was even necessary
for this model (it is not),
one could remove the log argument to emphasize the Gomperzian effect of
age on mortality.

\section{Monotone splines}
Consider the following model using the \code{mgus2} data set.
<<hgb, fig=TRUE>>=
fit <- coxph(Surv(futime, death) ~ age + pspline(hgb, 4), mgus2)
fit
termplot(fit, se=TRUE, term=2, col.term=1, col.se=1,
         xlab="Hemoglobin level")
@ 
Low hemoglobin or anemia is a recognized marker of frailty in older
age, so the rise in risk for low levels is not surprising.
The rise on the right hand portion of the curve is less 
believable --- the normal range of HGB is 12-15.5 for women and
13.5 to 17.5 for men, why would we expect a rise there?
A monotone fit that forces the curve to be horizontal from 14 
onward fits well within the confidence bands, so we might want
to force monotonicity.

There are two tools for this within the pspline function.  
The first is to decrease the overall degrees of freedom and the 
second is to use \code{combine} option to force equality of
selected coefficients.
Start by decreasing the degrees of freedom.
The pspline function automatically picks the number of basis
(nterms) to be ``sufficiently large'' for the given degrees
of freedom.  We fix it at a single value for the rest of
this example to better isolate the effects of degrees of freedom
and of constraints.

<<df, fig=TRUE>>=
termplot(fit, se=TRUE, col.term=1, col.se=1, term=2,
         xlab="Hemoglobin level", ylim=c(-.4, 1.3))
df <- c(3, 2.5, 2)
for (i in 1:3) {
    tfit <- coxph(Surv(futime, death) ~ age + 
                  pspline(hgb, df[i], nterm=8), mgus2)
    temp <- termplot(tfit, se=FALSE, plot=FALSE, term=2)
    lines(temp$hgb$x, temp$hgb$y, col=i+1, lwd=2)
}
legend(14, 1, paste("df=", c(4, df)), lty=1, col=1:4, lwd=2)
@ 

This has reduced, but not eliminated, the right hand rise at the
expense of a less sharp transition at the value of 14.
The \code{combine} option
makes use of a property of the P-spline basis, which is
that the curve will be monotone if and only if the coefficients
are monotone.
We can then use a pool adjacent violators algorithm to sequentially
force equality for those coefficients which go the wrong way.
Look at the coefficients for the fit with 2.5 degrees of freedom.

<<fit2a, fig=TRUE>>=
fit2a <- coxph(Surv(futime, death) ~ age + pspline(hgb, 2.5, nterm=8), mgus2)
coef(fit2a)
plot(1:10, coef(fit2a)[-1])
@ 

Now force the last 3 to be equal, then the last 4,
and see how this changes the fit.

<<fit2b, fig=TRUE>>=
temp <- c(1:7, 8,8,8)
fit2b <- coxph(Surv(futime, death) ~ age + 
               pspline(hgb, 2.5, nterm=8, combine=temp), 
               data= mgus2)
temp2 <- c(1:6, 7,7,7,7)
fit2c <- coxph(Surv(futime, death) ~ age + 
               pspline(hgb, 2.5, nterm=8, combine=temp2), 
               data= mgus2)
matplot(1:10, cbind(coef(fit2a)[-1], coef(fit2b)[temp+1], 
                    coef(fit2c)[temp2+1]), type='b', pch='abc',
                    xlab="Term", ylab="Pspline coef")
@ 

We see that constraining the last four terms along with a 
degrees of freedom of is almost enough to force monotonicity;
it may be sufficient if our goal is a simple plot for display.  

This dance between degrees of freedom, number of terms, and
constraints has a component of artistry.  When all three values
become large the result will begin to approach a step function,
reminiscent of non-parametric isotonic regression, whereas
small values begin to approach a linear fit. 
The best compromise of smoothness and constraints will be problem specific.

\section{Splines in an interaction}
As an example we will use the effect of age on survival in the 
\texttt{flchain} data set, a population based sample of subjects from
Olmsted County, Minnesota.
If we look at a simple model using age and sex we see that both 
are very significant.
<<fit1, fig=TRUE>>=
options(show.signif.stars=FALSE) # display intelligence
fit1 <- coxph(Surv(futime, death) ~ sex + pspline(age, 3), data=flchain)
fit1
termplot(fit1, term=2, se=TRUE, col.term=1, col.se=1,
         ylab="log hazard")
@ 

We used a \code{pspline} term rather than \code{ns}, say, 
because the printout for a pspline nicely
segregates the linear and non-linear age effects.
The non-linearity is not very large, as compared to the linear portion,
but still may be important.

We would like to go forward and fit separate age curves for the males and
the females, since the above fit makes an untested
assumption that the male/female
ratio of death rates will be the same at all ages. 
The primary problem is that a formula of 
\texttt{sex * pspline(age)} does not work;
the coxph routine is not clever enough to do the right thing automatically
for \code{pspline} interactions.
(Perhaps some future version will be sufficiently intelligent, but don't hold
your breath).

As a first solution we will use regression splines, i.e., splines
that can be represented using a basis matrix.

<<nfit>>=
options(show.signif.stars=FALSE)  # display statistical intellegence
require(splines, quietly=TRUE)
nfit1 <- coxph(Surv(futime, death) ~ sex + age, flchain)
nfit2 <- coxph(Surv(futime, death) ~ sex + ns(age, df=3), flchain)
nfit3 <- coxph(Surv(futime, death) ~ sex * ns(age, df=3), flchain)
anova(nfit1, nfit2, nfit3)
@ 
The nonlinear term is significant but the interaction is not.
Nevertheless we would like to plot the two estimated curves for 
\code{nfit3}, expecting that they will be approximately parallel.
The \code{termplot} routine is not able to deal with models that
have an interaction and will bow out with a warning message;
we use explicit prediction instead, which is nearly as easy.
<<nfit2, fig=TRUE>>=
pdata <- expand.grid(age= 50:99, sex=c("F", "M"))
pdata[1:5,]

ypred <- predict(nfit3, newdata=pdata, se=TRUE)
yy <- ypred$fit + outer(ypred$se, c(0, -1.96, 1.96), '*')
matplot(50:99, exp(matrix(yy, ncol=6)), type='l', lty=c(1,1,2,2,2,2),
        lwd=2, col=1:2, log='y',
        xlab="Age", ylab="Relative risk")
legend(55, 20, c("Female", "Male"), lty=1, lwd=2, col=1:2, bty='n')
abline(h=1)
@
The \code{ns} function generates a basis of dummy variables to represent
the spline, which will work automatically in interactions. 
The coefficients that result are not very interpretable, but the result of
predict is invariant to this.  
The issues as compared to using \code{termplot} are
\begin{enumerate}
  \item We need to provide our own set of predictor values for the plot,
    whereas \code{termplot} would automatically use the set of unique
    age and sex values.  
  \item Keeping track of the indexing.  The predict function produces
    two vectors each of length \code{nrow(pdata)} with a predicted
    value and its standard error, one value for each row of 
    \code{pdata}.  The data set is in order of females, then males.
    We fold it into an appropriate matrix for use with matplot.
  \item The vertical centering of the curves corresponds to an average
    population predictor of $\eta = X\beta =0$; i.e., the average over the
    subjects in the data set.  This is a consequence of the
    variable centering that \code{coxph} does for numerical stability.
    To center at some particular (age, sex) pair obtain the predicted
    value for that fictional subject and subtract the resulting
    value from \code{yy}.
\end{enumerate}   

To create the same figure with \code{pspline} curves it is necessary
to code the males and females as two separate terms.
To do this create our own dummy variables to handle the interaction.

<<fit2>>=
agem <- with(flchain, ifelse(sex=="M", age, 60))
agef <- with(flchain, ifelse(sex=="F", age, 60))
fit2 <- coxph(Surv(futime, death) ~ sex + pspline(agef, df=3)
              + pspline(agem, df=3), data=flchain)
anova(fit2, fit1)
@ 
You might well ask why we used 60 as a dummy value of \texttt{agem} for
the females instead of 0?
If a value of 0 is used it forces the pspline function to create a basis
set that includes all the empty space between 0 and 50, and do predictions
at 0; these last can become numerically unstable leading to errors or
incorrect values.
Best is to pick a value close to the mean, though any value within the
range will do.  For this plot we will use a 65 year old female as the
reference.

<<plot2, fig=TRUE>>=
# predictions
pdata2 <- pdata
pdata2$agem <- with(pdata2, ifelse(sex=="M", age, 60))
pdata2$agef <- with(pdata2, ifelse(sex=="F", age, 60))
ypred2 <- predict(fit2, pdata2, se=TRUE)
yy <- ypred2$fit + outer(ypred2$se, c(0, -1.96, 1.96), '*')

# reference
refdata <- data.frame(sex='F', agef=65, agem=60)
ref <- predict(fit2, newdata=refdata, type="lp")

# plot
matplot(50:99, exp(matrix(yy-ref, ncol=6)), type='l', lty=c(1,1,2,2,2,2),
        lwd=2, col=1:2, log='y',
        xlab="Age", ylab="Relative risk")
legend(55, 20, c("Female", "Male"), lty=1, lwd=2, col=1:2, bty='n')
abline(h=1)
@ 

The final curves for males and female are not quite parallel,
most of the difference is at the highest ages, however, where there
are very few subjects.
One thing the plot does not display is that the spacing between the
male and female points also has a standard error.
This moves the entire bundle of three red curves up and down.  It is not
clear how best to add this information into the plot.
For questions of parallelism and shape, as here, it seemed best to
ignore it, which is what the termplot function also does.
If someone were reading individual male/female differences off the plot
a different choice would be appropriate.
\end{document}

