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@ 

\title{Populations, Cox models, and ``type III'' tests}
\author{Terry M Therneau \\ \emph{Mayo Clinic}}
\newcommand{\code}[1]{\texttt{#1}}
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                        {tests-#1.pdf}}

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\begin{document}
  \maketitle
  \tableofcontents

\section{Introduction}
This note started with an interchange on the R-help.
A user asked ``how do I do a type III test using the Cox model'', and I
replied that this was not a well defined question.
If he/she could define exactly what it was that they were after, then
I would look into it.
To which the response was that ``SAS does it''.
A grant deadline was looming so the discussion did not get any further
at that point, but it eventually led to a much longer investigation
on my part, which is summarized in this note.  
There are three central ideas as it turns out: populations, computation,
and the mapping linear models ideas onto the Cox model.

The first idea, and perhaps the central one, is using the model fit from 
a current data set to predict for a new population.  
This plays an important role in predicted survival curves, see for instance
the vignette on that topic or chapter 10 of our book \cite{Therneau00};
recognizing that ``type 3'' tests are simply another variant on that theme was
a pivotal step in my understanding.  
This immediately leads to the important subtopic of ``prediction for
\emph{which} population''.  The SAS type 3 computations corresponds to a very 
particular and inflexible choice.

The second theme is computational: given some summary measure and a population
for which you wish to predict it, the result will be some sort of weighted
average.  There are two primary ways to set up this computation.  In a linear
model one of them can be reduced to a particular contrast 
$C \hat\beta$ in the fitted coefficients $\hat\beta$, which is an appealing
choice since follow-up computations such as the variance of the estimate
become particularly simple.  A common, simple, but unreliable algorithm
for creating $C$ has been a major source of confusion (hereafter referred to
as the NSTT: not safe type three).

The last theme is how the linear models formulae map to the Cox model case.
In particular, there is a strong temptation to use $C \hat\beta$ with
$C$ taken from linear models machinery and $\hat\beta$ from a fitted
Cox model.  The problem is that this implicitly requires a replacement
of $E[\exp(X)]$ with $\exp(E[X])$.
For a Cox model $C \beta$ is certainly a valid statistic for any $C$,
we just have no clear idea of what it is testing.

For the impatient readers among you I'll list the main conclusions
of this report at the start.
\begin{itemize}
  \item SAS type 3 predicts for a population with a uniform distribution
    across all categorical predictors.
    Scholarly papers discussing fundamental issues with using
        such an approach as a default analysis method
        have appeared almost biannually in the statistics
        literature, with little apparent effect on the usage of the 
        method. 
    SAS documentation of type 3 is almost entirely focused on the
    algorithm they use for computing $C$ and ignores the population issue.
  \item Population predictions very often make sense, including the
    question the type 3 approach is attempting to address.  There are
    valid ways to compute these estimates for a Cox model, they are
    closely related the inverse probability weight (IPW) methods used
    in propensity scores and marginal structural models.
  \item The algorithm used to compute $C$ by the SAS glm procedure is 
    sophisticated and reliable. 
    The SAS phreg procedure uses the linear models approach
    of $C \hat\beta$ to compute a ``type 3'' contrast, 
    with $C$ computed via the NSTT.
    The combination is a statistical disaster.     
    (This is true for SAS version 9.4; I will update this note if 
    things change.)
\end{itemize} 
    
\section{Linear approximations and the Cox model}
\label{sect:transfer}
One foundation of my concern has to do with the relationship between
linear models and coxph.
The solution to the Cox model equations
can be represented as an iteratively reweighted least-squares problem, with
an updated weight matrix and adjusted dependent variable at each iteration,
rather like a GLM model.
This fact has been rediscovered multiple times, and leads to the notion
that since the last iteration of the fit \emph{looks} 
just like a set of least-squares
equations, then various least squares ideas could be carried over to the
proportional hazards model by simply writing them out using these final terms.

In practice, sometimes this works and sometimes it doesn't.  
The Wald statistic is one example of the former type, which
is completely reliable as long as the coefficients $\beta$ are not too  
large\footnote{
  In practice failure only occurs in the rare case that one of the coefficients 
is tending to infinity.  However, in that case the failure is complete: 
the likelihood
ratio and score tests behave perfectly well but the Wald test is worthless.}.
A counter example is found in two ideas used to examine model
adequacy: adjusted variable plots and constructed variable plots, each
of which was carried over to the Cox model case by reprising the 
linear-model equations.
After a fair bit of exploring I found neither is worth doing
\cite{Therneau00}.
Copying over a linear models formula simply did not work in this case.

\begin{figure}
  \myfig{data}
  \caption{Average free light chain for males and females.  The figure
    shows both a smooth and the means within deciles of age.}
  \label{fig:data}
  \end{figure}

\section{Data set}
We will motivate our discussion with the simple case of a two-way
analysis.
The \code{flchain} data frame contains the results of a small number
of laboratory tests done on a large fraction of the 1995
population of Olmsted County, Minnesota aged 50 or older
\cite{Kyle06, Dispenzieri12}.
The R data set contains a 50\% random sample of this larger study
and is included as a part of the survival package.
The primary purpose of the study was to measure the amount of
plasma immunoglobulins and its components.  
Intact immunoglobulins are composed of a heavy chain and light chain
portion.  In normal subjects there is overproduction of the light chain 
component by the immune cells leading to a small amount of 
\emph{free light chain}  in the circulation.
Excessive amounts of free light chain (FLC) are thought to be a marker of
disregulation in the immune system.
Free light chains have two major forms denoted as kappa and lambda,
we will use the sum of the two.

An important medical question is whether high levels of FLC have an
impact on survival, which will be explored using a Cox model.  
To explore linear models we will compare FLC values between males
and females.
A confounding factor is that free light chain values rise with age, in
part because it is eliminated by the kidneys and renal function
declines with age.
The age distribution of males and females differs, so we
will need to adjust our simple comparison between the sexes
for age effects.
The impact of age on mortality is of course even greater
and so correction for the age imbalance is is critical when exploring
the impact of FLC on survival.

Figure \ref{fig:data} shows the trend in free light chain values
as a function of age.
For illustration of linear models using factors, we have also
created a categorical age value using deciles of age.
The table of counts shows that the sex distribution becomes increasingly
unbalanced at the older ages, from about 1/2 females in the youngest
group to a 4:1 ratio in the oldest.
<<data, fig=TRUE, include=FALSE>>=
library(survival)
library(splines)
age2 <- cut(flchain$age, c(49, 59, 69, 79, 89, 120),                   
            labels=c("50-59", "60-69", "70-79", "80-89", "90+"))
counts <- with(flchain, table(sex, age2))
counts
#
flchain$flc <- flchain$kappa + flchain$lambda                    
male <- (flchain$sex=='M')
mlow <- with(flchain[male,],  smooth.spline(age, flc))
flow <- with(flchain[!male,], smooth.spline(age, flc))
plot(flow, type='l', ylim=range(flow$y, mlow$y),
     xlab="Age", ylab="FLC")
lines(mlow, col=2)
cellmean <- with(flchain, tapply(flc, list(sex, age2), mean, na.rm=T))
matpoints(c(55,65,75, 85, 95), t(cellmean), pch='fm', col=1:2)

round(cellmean, 2)
@
Notice that the male/female difference in FLC varies with age, 
\Sexpr{round(cellmean[1,1],1)} versus \Sexpr{round(cellmean[2,1],1)}
at age 50--59 and \Sexpr{round(cellmean[1,5],1)} versus
 \Sexpr{round(cellmean[2,5],1)} at age 90.
The data does not fit a simple additive model; there are ``interactions''
to use statistical parlance.
An excess of free light chain is thought to be at least partly a reflection of 
immune senescence, and due to our hormonal backgrounds men and women simply
do not age in quite the same way.

\section{Population averages}
The question of how to test for a main effect in the presence of interaction
is an old one.
At one time this author considered the phrase ``main effect in the presence
of interaction'' to be an oxymoron, but long experience with clinical
data sets has led me to the opposite conclusion.
Real data always has interactions.  
The treatment effect of a drug will not be
exactly the same for old and young, thin and obese, physically active and
sedentary, etc.  
Explicit recognition of this is
an underlying rationale of the current drive towards ``personalized medicine'',
though that buzzword often focuses only on genetic differences.
Any given data set may often be too small to explore these variations and
our statistical models will of necessity smooth over the complexity,
but interactions are nevertheless still present.

Consider the data shown in figure \ref{fig1} below, which shows a particular
laboratory test value by age and sex.  
We see that the sex effect varies by age.  
Given this, what could be meant by a ``main effect'' of sex? 
One sensible approach is to select a fixed \emph{population} for the
ages, and then compute the
average sex effect over that population.
Indeed this is precisely what many computations do behind the scenes,
e.g. the ``type 3'' estimates found in linear models.

There are three essential components to the calculation: a reference
population for the confounders, a summary measure of interest, and
a computational algorithm.  
To understand how linear models methods may (or may not) extend to the
proportional hazards model it is useful consider all three facets;
each is revealing.

Four possible choices for a target population of ages are given below.
\begin{enumerate}
  \item Empirical: the age distribution of the sample at hand, also called
    the data distribution. In our sample this would be the age distribution
    of all \Sexpr{nrow(flchain)} subjects, ignoring sex.
  \item SAS: a uniform distribution is assumed over all categorical
    adjusters, and the data distribution for continuous ones.
  \item External reference: a fixed external population, e.g. the age 
    distribution of the US 2010 census.  
  \item MVUE: minimum variance unbiased; the implicit population corresponding
    to a multivariate least squares fit.
\end{enumerate}
Method 3 is common in epidemiology, method 1 is found in traditional
survey sampling and in other common cases as we will see below.
The type 3 estimates of SAS correspond to population 2.
If there an interaction between two categorical variables x1 and x2, then
the uniform distribution is taken to be over all combinations 
formed by the pair, and similarly for higher order interactions.

\section{Linear models and populations}
If we ignore the age effect, then everyone agrees on the best estimate
of mean FLC: the simple average of FLC values
within each sex.
The male-female difference is estimated as the difference of these means.
This is what is obtained from a simple linear regression of FLC on sex.
Once we step beyond this and adjust for age, 
the relevant linear models can be looked
at in several ways; we will explore three of them below:
contrasts, case weights, and nesting.
This ``all roads lead to Rome'' property of linear models is one of their
fascinating aspects, at least mathematically.

\subsection{Case weights}
\begin{figure}
  \myfig{pop}
  \caption{Three possible adjusting populations for the FLC data
    set, a empirical reference in black, least squares based
  one in red, and the US 2000 reference population as `u'.}
  \label{fig:pop}
\end{figure}

How do we form a single number summary of 
``the effect of sex on FLC''?
Here are four common choices.
\begin{enumerate}
  \item Unadjusted.  The mean for males minus the mean for females.
    The major problem with this is that a difference in age distributions
    will bias the result.  Looking at figure \ref{fig:data} imagine that
    this were two treatments A and B rather than male/female, and that
    the upper one had been given to predominantly 50-65 year olds and the 
    lower predominantly to subjects over 80.  An unadjusted difference
    would actually reverse the true ordering of the curves.
  \item Population adjusted.  An average difference between the curves,
    weighted by age. Three common weightings are
    \begin{enumerate}
      \item External reference.  It is common practice in epidemiology
        to use an external population as the reference age distribution,
        for instance the US 2000 census distribution.  This aids in 
        comparing results between studies.
      \item Empirical population.  The overall population structure of the 
        observed data.
      \item Least squares.  The population structure that minimizes the
        variance of the estimated female-male difference.
    \end{enumerate}
\end{enumerate}
The principle idea behind case weights is to reweight the data such that
confounders become balanced, i.e., ages are balanced when examining the
sex effect and sex is balanced when examining age.
Any fitted least squares estimate
can be rewritten as a weighted sum of the data points with weight
matrix $W= (X'X)^{-1}X'$. $W$ has $p$ rows, one per coefficient,
each row is the weight vector for
the corresponding element of $\hat\beta$.  So we can backtrack and
see what population assumption was underneath any given fit
by looking at the weights for the relevant coefficient(s).
Consider the two fits below. 
In both the second coefficient is an estimate of the overall 
difference in FLC values between the sexes.  
(The relationship in figure \ref{fig:data} is clearly curved so we have
foregone the use of a simple linear term for age; there is no point
in fitting an obviously incorrect model.)
Since $\beta_2$ is a contrast the underlying weight vectors have
negative values for the females and positive for the males.
<<>>=
us2000 <- rowSums(uspop2[51:101,,'2000'])

fit1 <- lm(flc ~ sex, flchain, x=TRUE)
fit2 <- lm(flc ~ sex + ns(age,4), flchain, x=TRUE)
c(fit1$coef[2], fit2$coef[2])

wt1  <- solve(t(fit1$x)%*%fit1$x, t(fit1$x))[2,] # unadjusted
wt2 <-  solve(t(fit2$x)%*%fit2$x, t(fit2$x))[2,] # age-adjusted
table(wt1, flchain$sex)
@ 

To reconstruct the implied population density, one can
use the density function with \code{wt1} or \code{wt2} as
the case weights.
Examination of \code{wt1} immediately shows that the values
are $-1/n_f$ for females and $1/n_m$ for males where
$n_f$ and $n_m$ are number of males and females, respectively.
The linear model \code{fit1} is the simple difference in male
and female means; the implied population structure for
males and females is the unweighted density of each.

Because this data set is very large and age is coded in years
we can get a density estimate for fit2 by simple counting.
The result is coded below and shown in figure \ref{fig:pop}.
The empirical reference and least squares reference are nearly
identical.  This is not a surprise.
Least squares fits produce minimum variance unbiased estimates (MVUE),
and the variance of a weighted average is minimized by using weights
proportional to the sample size, thus the MVUE estimate will give highest
weights to those ages with a lot of people.
The weights are not \emph{exactly} proportional to sample size for
each age.
As we all know, for a given sample size $n$ a study comparing two groups 
will have
the most power with equal allocation between the groups.  
Because the M/F ratio is more unbalanced at the right edge of the age
distribution the MVUE estimate gives just a little less weight there,
but the difference between it and the overall data set population
will be slight for all but those pathological
cases where there is minimal overlap between M/F age distributions.
(And in that case the entire discussion about what ``adjustment'' can or
should mean is much more difficult.)
<<pop, fig=TRUE, include=FALSE>>=
us2000 <- rowSums(uspop2[51:101,,'2000'])
tab0 <- table(flchain$age)
tab2 <- tapply(abs(wt2), flchain$age, sum)
matplot(50:100, cbind(tab0/sum(tab0), tab2/sum(tab2)),
        type='l', lty=1,
        xlab="Age", ylab="Density")

us2000 <- rowSums(uspop2[51:101,,'2000'])
matpoints(50:100, us2000/sum(us2000), pch='u')
legend(60, .02, c("Empirical reference", "LS reference"),
       lty=1, col=1:2, bty='n')
@ 
The LS calculation does a population adjustment automatically
for us behind the scenes via the matrix algebra of linear models.
If we try to apply population reference adjustment directly
a problem immediately arises: in the US reference 
\Sexpr{round(100*us2000[46]/sum(us2000),2)}\% of the population is
aged 95 years, and our sample has no 95 year old males; it is
not possible to re weight the sample so as to exactly match the
US population reference.
This occurs in any data set that is divided into small strata.
The traditional epidemiology approach to this is to use wider
age intervals of 5 or 10 years.
Weights are chosen for each
age/sex strata such that the
sum of weights for females = sum of weights for males within each age
group (balance), and the total sum of weights in an age group is 
equal to the reference population.  The next section goes into this further.
An increasingly popular approach for producing results that are standardized
to the empirical reference population (i.e. the data distribution)
is to use a smoothed age effect, obtained through 
inverse probability weights which are based on logistic regression,
e.g. in the causal models literature and propensity score literature.
This approach is illustrated in a vignette on adjusted survival
curves which is also in the survival package.

\subsection{Categorical predictors and contrasts}
When the adjusting variable or variables are categorical --- a factor in R or a 
class variable in SAS --- then two more aspects come into play.
The first is that any estimate of interest can be written in terms
of the cell means. 
Formally, the cell means are a \emph{sufficient statistic} for the data.
For our data set and using the categorized variable \code{age2}
let $\theta_{ij}$ parameterize these means.
$$
  \begin{tabular}{cccccc}
    &50--59 & 60--69 & 70-79 & 80-89 & 90+ \\ \hline
 Female & $\theta_{11}$ & $\theta_{12}$ & $\theta_{13}$& $\theta_{14}$& 
                    $\theta_{15}$ \\
 Male & $\theta_{21}$ & $\theta_{22}$ & $\theta_{23}$& $\theta_{24}$ &
                    $\theta_{25}$ \\
\end{tabular}
  $$
For a design with three factors we will have $\theta_{ijk}$, etc.
Because it is a sufficient statistic, 
any estimate or contrast of interest can be written as a weighted sum of the
$\theta$s. 
Formulas for the resulting estimates along with their variances and
tests were worked out by Yates in 1934 \cite{Yates34} and are often referred
to as a Yates weighted means estimates.  
For higher order designs the computations can be rearranged in a form that
is manageable on a desk calculator, and this is in fact the primary point of
that paper.  
(Interestingly, his computational process turns out to be closely 
related to the fast Fourier transform.)

The second facet of categorical variables is that another adjustment 
is added to the list of common estimates:
\begin{enumerate}
  \item Unadjusted 
  \item Population adjusted
    \begin{enumerate}
      \item External reference
      \item Empirical (data set) reference
      \item Least squares
      \item Uniform. A population in which each combination of the
        factors has the same frequency of occurrence.
    \end{enumerate}
\end{enumerate}

The uniform population plays a special role in the case of designed
experiments, where equal allocation corresponds to the optimal study
design.  The Yates estimates are particularly simple in this
case.  For a hypothetical population with equal numbers in each
age category the estimated average FLC for females turns out to be
$\mu_f = \sum_j \theta_{1j} /5$ 
and the male - female contrast is $\sum_j(\theta_{2j}-\theta_{1j})/5$.
We will refer to these as the ``Yates'' estimates and contrast for
an effect.
Conversely, the estimated age effects, treating sex as a confounding
effect and assuming an equal distribution of females and males as the
reference population, gives 
an estimated average FLC for the 60-69 year olds of
$\mu_{60-69}= (\theta_{12} + \theta_{22})/2$, and etc for the other age
groups.

We can obtain the building blocks for Yates estimates by using the
interaction function and omitting the intercept.
<<yfit>>=
yatesfit <- lm(flc ~ interaction(sex, age2) -1, data=flchain)
theta <- matrix(coef(yatesfit), nrow=2)
dimnames(theta) <- dimnames(counts)
round(theta,2)
@ 
For a linear model fit,
any particular weighted average of the coefficients along with its
variance and the corresponding sums of squares can be computed using
the \code{contrast} function given below.
Let $C$ be a contrast matrix with $k$ rows, each containing
one column per coefficient.
Then $C\theta$ is a vector of length $k$ containing the weighted
averages and
$V = \hat\sigma^2 C (X'X)^{-1}C'$ is its variance matrix.
The sums of squares is the increase in the sum of squared residuals if the
fit were restricted to the subspace $C\theta =0$.
Formulas are from chapter 5 of Searle \cite{Searle71}.
Some authors reserve the word \emph{contrast} for the case where each
row of $C$ sums to zero and use \emph{estimate} for all others;
I am being less restrictive since the same computation serves for
both.
<<>>=
qform <- function(beta, var) # quadratic form b' (V-inverse) b
    sum(beta * solve(var, beta))
contrast <- function(cmat, fit) {
    varmat <- vcov(fit)
    if (class(fit) == "lm") sigma2 <- summary(fit)$sigma^2              
    else sigma2 <- 1   # for the Cox model case

    beta <- coef(fit)
    if (!is.matrix(cmat)) cmat <- matrix(cmat, nrow=1)
    if (ncol(cmat) != length(beta)) stop("wrong dimension for contrast")

    estimate <- drop(cmat %*% beta)  #vector of contrasts
    ss <- qform(estimate, cmat %*% varmat %*% t(cmat)) *sigma2
    list(estimate=estimate, ss=ss, var=drop(cmat %*% varmat %*% t(cmat)))
    }

yates.sex <- matrix(0, 2, 10)
yates.sex[1, c(1,3,5,7,9)] <-  1/5    #females
yates.sex[2, c(2,4,6,8,10)] <- 1/5    #males

contrast(yates.sex, yatesfit)$estimate  # the estimated "average" FLC for F/M
contrast(yates.sex[2,]-yates.sex[,1], yatesfit) # male - female contrast
@

<<echo=FALSE>>=
# Create the estimates table -- lots of fits
emat <- matrix(0., 6, 3)
dimnames(emat) <- list(c("Unadjusted", "MVUE: continuous age", 
                         "MVUE: categorical age", "Empirical (data) reference",
                         "US200 reference", "Uniform (Yates)"),
                       c("est", "se", "SS"))

#unadjusted
emat[1,] <- c(summary(fit1)$coef[2,1:2], anova(fit1)["sex", "Sum Sq"])
# MVUE -- do the two fits
fit2 <- lm(flc ~ ns(age,4) + sex, flchain)
emat[2,] <- c(summary(fit2)$coef[6, 1:2], anova(fit2)["sex", "Sum Sq"])
fit2 <- lm(flc ~ age2 + sex, flchain)
emat[3,] <- c(summary(fit2)$coef[6, 1:2], anova(fit2)["sex", "Sum Sq"])

#Remainder, use contrasts
tfun <- function(wt) {
    cvec <- c(matrix(c(-wt, wt), nrow=2, byrow=TRUE))
    temp <- contrast(cvec, yatesfit)
    c(temp$est, sqrt(temp$var), temp$ss)
}
emat[4,] <- tfun(colSums(counts)/sum(counts))

usgroup <- tapply(us2000, rep(1:5, c(10,10,10,10,11)), sum)/sum(us2000)
emat[5,]<- tfun(usgroup)
emat[6,] <- tfun(rep(1/5,5))
@ 
\begin{table} \centering
  \begin{tabular}{l|ccc}
    & estimate & sd & SS \\ \hline
<<echo=FALSE, results=tex>>=
temp <- dimnames(emat)[[1]]
for (i in 1:nrow(emat))
   cat(temp[i], sprintf(" &%5.3f", emat[i,1]),sprintf(" &%6.5f", emat[i,2]), 
       sprintf(" & %6.1f", emat[i,3]), "\\\\ \n")
@ 
\end{tabular}
  \caption{Estimates of the male-female difference along with their
    standard errors.  The last 4 rows are based on categorized age.}
  \label{tab:allest}
\end{table}
Table \ref{tab:est} shows all of the estimates of the male/female
difference we have considered so far along with their standard errors.
Because it gives a much larger weight to the 90+ age group than any of
the other estimates, and that group has the largest M-F difference,
the projected difference for a uniform population (Yates estimate)
yields the largest contrast.
It pays a large price for this in terms of standard error, however, and is
over twice the value of the other approaches.
As stated earlier, any least squares parameter estimate can be written
as a weighted sum of the y values.
Weighted averages have 
minimal variance when all of the weights are close to 1.  
The unadjusted estimate adheres to this precisely and the data-reference
and MVUE stay as close as possible to constant weights, subject to balancing the
population.  The Yates estimate, by treating every cell equally,
implicitly gives much larger weights to the oldest ages.
Table \ref{tab:est} shows the effective observation weights used for each of the
age categories.

<<weights>>=
casewt <- array(1, dim=c(2,5,4)) # case weights by sex, age group, estimator
csum <- colSums(counts)
casewt[,,2] <- counts[2:1,] / rep(csum, each=2)
casewt[,,3] <- rep(csum, each=2)/counts
casewt[,,4] <- 1/counts
#renorm each so that the mean weight is 1
for (i in 1:4) {
    for (j in 1:2) {
        meanwt <- sum(casewt[j,,i]*counts[j,])/ sum(counts[j,])
        casewt[j,,i] <- casewt[j,,i]/ meanwt
    }
}
@ 

\begin{table} \centering
  \begin{tabular}{rlrrrrr}
    &&50--59& 60--69 & 70--79 & 80--89 & 90+ \\ \hline
<<echo=FALSE, results=tex>>=
tname <- c("Unadjusted", "Min var", "Empirical", "Yates")
for (i in 1:2) {
    for (j in 1:4) {
        cat("&",tname[j], " & ",
            paste(sprintf("%4.2f", casewt[i,,j]), collapse= " & "),
             "\\\\\n")
       if (j==1) cat(c("Female", "Male")[i])
    }
    if (i==1) cat("\\hline ")
}
@     
  \end{tabular}
  \caption{Observation weights for each data point
    corresponding to four basic approaches. 
    All weights are normed so as to have an average value of 1.}
  \label{tab:est}
\end{table}

Looking at table \ref{tab:est} notice the per observation weights for 
the $\ge 90$ age group, 
which is the one with the greatest female/male imbalance in the
population.  
For all but the unbalanced estimate (which ignores age) the males are
given a weight that is approximately 3 times that for females
in order to re balance the shortage of males in that category.
However, the
absolute values of the weights differ considerably.

\subsection{Different codings}
Because the cell means are a sufficient statistic, all of the estimates based
on categorical age can be written in terms of the cell means $\hat\theta$.
The Yates contrast is the simplest to write down:
$$ \begin{tabular} {rrrrrr}
  & 50--59 & 60--69 & 70--79 & 80--89 & 90+ \\ \hline
  Female & -1/5 & -1/5 & -1/5 & -1/5 & -1/5 \\
  Male & 1/5 & 1/5 & 1/5 & 1/5 & 1/5
\end{tabular}
$$
%(Note that for calculating a sum of squares we will get the exact same
%result from a matrix using $\pm 1$ rather than $\pm 1/5$;
%the Yates contrast is often written this way.)
For the data set weighting the values of 1/5 are replaced by
$n_{+j}/n_{++}$, the overall frequency of each age group, where a $+$
in the subscript stands for addition over that subscript in the table
of counts.  
The US population weights use the population frequency of each age group.
The MVUE contrast has weights of
$w_j/\sum w_j$ where $w_j = 1/(1/n_{1j} + 1/n_{2j})$, which are admittedly
not very intuitive.
$$
\begin{tabular}{rrrrrr}
  & 50--59 & 60--69 & 70--79 & 80--89 & 90+ \\ \hline
<<echo=FALSE, results=tex>>=
temp <- 1/colSums(1/counts)
temp <- temp/sum(temp)
cat("Female", sprintf(" & %5.3f", -temp), "\\\\ \n")
cat("Male",   sprintf(" & %5.3f", temp), "\\\\ \n")
@ 
\end{tabular}
$$
In the alternate model \code{y \textasciitilde sex + age2} 
the MVUE contrast is much
simpler, namely (0, 1, 0,0,0,0,0), and can be read directly off the
printout as $\beta/se(\beta)$.  
The computer's calculation of $(X'X)^{-1}$ has derived the ``complex''
MVUE weights for us without needing to lift a pencil.
The Yates contrast, however, cannot be created from the coefficients of the
simpler model at all.
This observation holds in general: a contrast that is simple to write down
in one coding may appear complicated in another, or not even be possible.

The usual and more familiar coding for a two way model is
\begin{equation}
  y_{ij} = \mu + \alpha_i + \beta_j + \gamma_{ij} \label{std}
\end{equation}
What do the Yates' estimates look like in this form?  Let $e_i$ be the
Yates estimate for row $i$ and $k$ the number of columns in the two way table
of $\theta$ values.  Then
\begin{align*}
  e_i &= (1/k)\sum_{j=1}^k \theta_{ij} \\
      &= \mu + \alpha_i + \sum_j \left(\beta_j + \gamma_{ij}\right)/k 
\end{align*}
and the Yates test for row effect is
\begin{align}
  0 &= e_i - e_{i'} \quad \forall i,i' \nonumber \\
    &= (\alpha_i - \alpha_{i'}) + (1/k)\sum_j(\gamma_{ij} - \gamma_{i'j})
             \label{ycont}
\end{align}

Equation \eqref{std} is over determined and all computer
programs add constraints in order to guarantee a unique solution.
However those constraints are applied, however, equation \eqref{ycont}
holds.
The default in R is treatment contrasts, which use the first level
of any factor as a reference level.
Under this constraint the reference coefficients are set to zero, i.e., all
coefficients of equations \eqref{std} and \eqref{ycont} 
above where $i=1$ or $j=1$.
We have been computing the male - female contrast,
corresponding to $i=2$ and $i'=1$
in equation \eqref{ycont}, and the Yates contrast for sex becomes
$\alpha_2 + 1/5(\gamma_{22} +\gamma_{23} +\gamma_{24} +\gamma_{25})$.
The code below verifies that this contrast plus the usual R fit replicates
the results in table \ref{tab:allest}.
<<treatment>>=
fit3 <- lm(flc ~ sex * age2, flchain)
coef(fit3)
contrast(c(0,1, 0,0,0,0, .2,.2,.2,.2), fit3) #Yates
@ 
The usual constraint is SAS is to use the last level of any class 
variable as the reference group,
i.e., all coefficients with $i=2$ or $j=5$ in equations 
\eqref{std} and \eqref{ycont} are set to zero.
<<SAS>>=
options(contrasts=c("contr.SAS", "contr.poly"))
sfit1 <- lm(flc ~ sex, flchain)
sfit2 <- lm(flc ~ sex + age2, flchain)
sfit3 <- lm(flc ~ sex * age2, flchain)
contrast(c(0,-1, 0,0,0,0, -.2,-.2,-.2,-.2), sfit3) # Yates for SAS coding
@
The appendix contains SAS code and output for the three models
\code{sfit1, sfit2} and \code{sfit3} above.
The \code{E3} option was added to the SAS model statements, which causes
a symbolic form of the contrasts that were used for 
``type III'' results to be included in the printout.
Look down the column labeled ``SEX'' and you will see exactly the
coefficients used just above, after a bit of
SAS to English translation.
\begin{itemize}
  \item The SAS printout is labeled per equation \eqref{std}, so
    L1= column 1 of the full $X$ matrix = intercept.  L2 = column 2
    = females, L3 = column 3 = males, L4= column 4 = age 50--59, etc.
   \item In the symbolic printout they act as though sum constraints were
     in force: the last column of age is labeled with a symbolic value that
     would cause the age coefficients to sum to zero.  
     However, in actuality these coefficients are set to zero.  The table of
     parameter estimates at the end of the printout reveals this; forced
     zeros have a blank for their standard error.
  \item When calculating the contrast one can of course skip over the 
    zero coefficients, and the R functions do not include them in the
    coefficient vector.  
    Remove all of these aliased rows from the SAS symbolic printout to get
    the actual contrast that is used; this will agree with my notation.
  \item The SAS printout corresponds to a female-male contrast and I have
    been using male-female for illustration.  
    This changes the signs of the contrast coefficients
    but not the result.
\end{itemize}
The \code{estimate} statement in the SAS code required that all of
the coefficients be listed, even the aliased ones
(someone more proficient in SAS may
know a way to avoid this and enter only the non-aliased values.)

%A general principle is that a given hypothesis may be represented as
%a simple contrast in one coding but be complex in another.  
%The unadjusted test is a trivial contrast in the sfit1 coding, but a 
%complex one in the sfit3 coding.
%The Yates test cannot be expressed as a contrast using the sfit1 or sfit2
%coding, is simple and obvious in the cell means coding, and has
%simple but non obvious coefficients in the sfit3 coding.
%Que sera sera.

So, how do we actually compute the Yates contrast in a computer program?
We will take it as a give that no one wants to memorize contrast formulas.
Appendix \ref{sect:coding} describes three algorithms for the computation.

One of these three (NSTT) is completely unreliable, but is included because
it is so often found in code.
If one uses the sum constraints commonly found in textbooks,
which corresponds to the \code{contr.sum} constraint in R and to \code{effect}
constraints in SAS, and there are no missing cells, then the last term
in equation \eqref{ycont} is zero and the simple 
contrast $\alpha_i =0$ will be equal to the Yates contrast for sex. 
I often see this method recommended on R help in response to
the question of ``how to obtain type III'', computed either by use of the 
\code{drop1} command or the \code{Anova} function found within the car
package, but said advice almost never mentions the need for this particular
non-default setting of the contrasts option\footnote{The Companion to Applied
Regression (car) package is designed to be used with the book of the same
name by John Fox, and the book does clarify the need for sum constraints.}.
When applied to other codings the results of this procedure can be 
surprising.
<<nstt>>=
options(contrasts = c("contr.treatment", "contr.poly")) #R default
fit3a <- lm(flc ~ sex * age2, flchain)
options(contrasts = c("contr.SAS", "contr.poly"))
fit3b <- lm(flc~ sex * age2, flchain)
options(contrasts=c("contr.sum", "contr.poly"))
fit3c <- lm(flc ~ sex * age2, flchain)
#
nstt <- c(0,1, rep(0,8))  #test only the sex coef = the NSTT method
temp <- rbind(unlist(contrast(nstt, fit3a)),
              unlist(contrast(nstt, fit3b)),
              unlist(contrast(nstt, fit3c)))[,1:2]
dimnames(temp) <- list(c("R", "SAS", "sum"), c("effect", "SS"))
print(temp)
#
drop1(fit3a, .~.)
@ 
For the case of a two level effect such as sex, the 
NSTT contrast under the default R coding is a comparison of males to
females in the first age group \textbf{only},
and under the default SAS coding it is a comparison of males to females
within the \textbf{last} age group.
Due to this easy creation of a test statistic which has no relation to
the global comparison one expects from the ``type 3'' label the acronym
\emph{not safe type three}(NSTT) was chosen, ``not SAS'' and ``nonsense''
are alternate mnemonics.

\subsection{Sums of squares and projections}
\label{sect:anova}
The most classic exposition of least squares is as a set of
projections, each on to a smaller space.
Computationally we represent this as a series of model fits,
each fit summarized by the change from the prior fit 
in terms of residual sum of squares.
<<anova>>=
options(show.signif.stars = FALSE) #exhibit intelligence
sfit0  <- lm(flc ~ 1, flchain)
sfit1b <- lm(flc ~ age2, flchain)
anova(sfit0, sfit1b, sfit2, sfit3)
@ 
The second row is a test for the age effect.
The third row of the above table summarizes the improvement in
fit for the model with sex + age2 over the model with just age2,
a test of ``sex, adjusted for age''.
This test is completely identical to the minimum variance contrast,
and is in fact the way in which that SS is normally obtained.
The test for a sex effect, unadjusted for age, 
is identical to an anova table that compares
the intercept-only fit to one with sex, i.e., the second line from
a call to \code{anova(sfit0, sfit1)}.

The anova table for a nested sequence of models $A$, $A+B$, $A + B +C$, \ldots
has a simple interpretation, outside of contrasts or populations,
as an improvement in fit.  Did the variable(s) $B$ add significantly 
to the goodness of fit for a model with just $A$, was $C$ an important
addition to a model that already includes $A$ and $B$?  
The assessment of improvement is based on the likelihood ratio test (LRT),
and extends naturally to all other models based on likelihoods.
The tests based on a target population (external, data population,
or Yates) do not fit naturally into this approach, however.

%Obtaining the Yates contrast using a sequential sums of squares approach
%is possible but a bit contrived.
%Our final fit in the table will be \code{sfit3}, but
%the one prior to it needs to be from a constrained version of \code{sfit3},
%whose solution lies in the space spanned by  the Yates contrast 
%$\beta_2 + \beta_7/5 + \beta_8/5 + \beta_9/5 + \beta_{10}/5 = 0$. 
%There is no simple way to write down an ordinary LS model equation that
%will do this, and instead one must use one a program for constrained
%linear regression; these are far less familiar.
%There are many algorithms to fit a constrained linear regression, one is
%to transform the problem as $X\beta = (XQ)(Q'\beta) = Z \phi$
%where $Q$ is an orthogonal transformation matrix.
%If the first column of $Q$ is chosen as a scaled version of the Yates
%contrast, then setting that contrast equal to zero is the same as
%the constraint $\phi_1 =0$; it suffices to fit a model using all but the
%first column of $Z$. 

\subsection{What is SAS type 3?}
We are now in a position to fully describe the SAS sums of squares.
\begin{itemize}
  \item Type 1 is the output of the ANOVA table, where terms are entered
    in the order specified in the model.
  \item Type 2 is the result of a two stage process
    \begin{enumerate}
      \item Order the terms by level: 0= intercept, 1= main effects, 
        2= 2 way interactions, \ldots.
      \item For terms of level k, print the MVUE contrast from a model
        that includes all terms of levels $0-k$.
        Each of these will be equivalent to the corresponding line of
        a sequential ANOVA table where the term in question was entered
        as the last one of its level.
    \end{enumerate}
  \item Type 3 and 4 are also a 2 stage process
    \begin{enumerate}
      \item Segregate the terms into those for which a Yates contrast
        can be formed versus those for which it can not.  The second group
        includes the intercept, any continuous variables, and any factor
        (class) variables that do not participate in interactions with
        other class variables.
      \item For variables in the first group compute Yates contrasts. For
        those in the second group compute the type 2 results.
    \end{enumerate}
\end{itemize}

SAS has two different algorithms for computing the Yates contrast, which
correspond to the \code{ATT} and \code{STT} options of the \code{yates}
function.
SAS describes the two contrast algorithms
in their document 
``The four types of estimable functions'' \cite{SASguide}, 
one of which defines type 3 and the other type 4.
I found it very challenging to recreate their algorithm from this document.
Historical knowledge of the underlying linear model algorithms used by
SAS is a useful
and almost necessary adjunct, as many of the steps in the document are side
effects of their calculation.

When there are missing cells, then it is not possible to compute a 
contrast that corresponds to a uniform
distribution over the cells, and thus the standard Yates contrast is 
also not defined.
The SAS type 3 and 4 algorithms still produce a value, however. 
What exactly this result ``means'' and whether it is a good idea has
been the subject of lengthy debates which I will not explore here. Sometimes
the type 3 and type 4 algorithms will agree but often do not when there
are missing cells, which further muddies the waters.

Thus we have 3 different tests: the MVUE comparison which will be close
but not exactly equal to the data set population, Yates comparisons which
correspond to a uniform reference population, and the SAS type 3 (STT) which
prints out a chimeric blend of uniform population weighting for 
those factor variables that participate in
interactions and the MVUE weighting for all the other terms.  


\subsection{Which estimate is best?}
Deciding which estimate is the best is complicated.
Unfortunately a lot of statistical textbooks emphasize the peculiar
situation of balanced data with exactly the same number of subjects 
in each cell.
Such data is \emph{extremely} peculiar if you work in medicine;
in 30 years work and several hundred studies I have seen 2 instances.
In this peculiar case the unadjusted, MVUE, empirical reference and Yates
populations are all correspond to a uniform population and 
so give identical results.
No thinking about which estimate is best is required.
This has led many to avoid the above question, instead pining for that
distant Eden where the meaning of ``row effect'' is perfectly unambiguous.
But we are faced with real data and need to make a choice.

The question has long been debated in depth by wiser heads than mine.
In a companion paper to his presentation at the joint statistical meetings
in 1992, Macnaughton \cite{Macnaughton92} lists 54 references to the topic
between 1952 and 1991.  
Several discussion points recur:
\begin{enumerate}
  \item Many take the sequential ANOVA table as primary, i.e., a set of
    nested models along with likelihood ratio tests (LRT), and decry
    all comparisons of ``main effects in the presence of interaction.''
    Population weightings other than the LS one do not fit nicely into
    the nested framework.
  \item Others are distressed by the fact that the MVUE adjusting population
    is data dependent, so that one is ``never sure exactly what 
    hypothesis being tested''.  
  \item A few look at the contrast coefficients themselves, with a preference
    for simple patterns since they ``are interpretable''.
  \item No one approach works for all problems.  Any author who proposes
    a uniform rule is quickly presented with counterexamples.
\end{enumerate}
Those in group 1 argue strongly against the Yates weighting and those in group 2
argue for the Yates contrast.  
Group 3 is somewhat inexplicable to me since any
change in the choice of constraint type will change all the patterns.
I fear that an opening phrase from the 1986 overview/review of Herr
\cite{Herr86}
is still apropos, ``In an attempt to understand how we have arrived at our
present state of ignorance \ldots''.

There are some cases where the Yates approach is clearly sensible, for instance
a designed experiment which has become unbalanced due to a failed
assay or other misadventure that has caused a few data points to be missing.
There are cases such as the FLC data where the Yates contrast 
makes little sense at
all --- the hypothetical population with equal numbers of 50 and 90 year olds is
one that will never be seen--- so it is rather like speculating on the the
potential covariate effect in dryads and centaurs.
The most raucous debate has circled around the case of testing for a treatment
effect in the presence of multiple enrolling centers.  
Do we give each patient equal weight (MVUE) or each center equal weight (Yates).
A tongue-in-cheek but nevertheless excellent commentary on the subject is
given by the old curmudgeon, aka Guernsey McPearson \cite{Senn1, Senn2}.
A modern summary with focus on the clinical trials arena is found in 
chapter 14 of the textbook by  Senn \cite{Senn07}

I have found two papers particularly useful in thinking about this.
Senn \ref{Senn00} points out the strong parallels between tests for main effects
when there may be interactions and meta analyses, cross connecting these two
approaches is illuminating.
A classic reference is the 1978 paper by Aitkin \cite{Aitkin78}.
This was read before the Royal Statistical
Society and includes remarks by 10 discussants forming a who's who of
statistical theory (F Yates, J Nelder, DR Cox, DF Andrews, KR Gabriel, \ldots).
The summary of the paper states that 
``It is shown that a standard method of analysis used in many ANOVA programs,
equivalent to Yates method of weighted squares of means, may lead to 
inappropriate models''; the paper goes on to carefully show why no one
method can work in all cases.
Despite the long tradition among RSS discussants of first congratulating the 
speaker and then skewering every one their conclusions, 
not one defense of the always-Yates approach is raised!
This includes the discussion by Yates himself, who protests that his original
paper advocated the proposed approach with reservations, it's primary advantage
being that the computations could be performed on a desk calculator.

I have two primary problems with the SAS type 3 approach.
The first and greatest is that their documentation recommends the method
with no reference to this substantial and sophisticated literature
discussing strengths and weaknesses of the Yates contrast.  
This represents a level of narcissism which is completely unprofessional.
%Recommending the type III approach as best for all cases, as they do, has
%caused actual harm.
The second is that their documentation explains the method is a way that
is almost impenetrably opaque.  
If this is the only documentation one has, there will not be 1 statistician 
in 20 who would be able to
explain the actual biological hypothesis which is being addressed by 
a type 3 test.

\section{Cox models}
\subsection{Tests and contrasts}
Adapting the Yates test to a Cox model is problematic from the start.
First, what do we mean by a ``balanced population''?
In survival data, the variance of the hazard ratio for each particular
sex/age combination is proportional to the number of deaths in that
cell rather than the number of subjects.
Carrying this forward to the canonical problem of adjusting a treatment
effect for enrolling center, does this
lead to equal numbers of subjects
or equal numbers of events?
Two centers might have equal numbers of patients but different number
of events because one initiated the study at a later time (less
follow up per subject), or it might have the same follow up time but
a lower death rate.  Should we reweight in one case (which one), both,
or neither?
The second issue is that the per-cell hazard ratio estimates are no
longer a minimally sufficient statistic, so underlying arguments
about a reference population no longer directly translate into a contrast
of the parameters.  
A third but more minor issue is that the three common forms of
the test statistic ---  Wald, score, and LRT --- are identical in a linear
model but not for the Cox model, so which should we choose?

To start, take a look at the overall data and
compute the relative death rates for each age/sex cell.
<<relrate>>=
options(contrasts= c("contr.treatment", "contr.poly")) # R default
cfit0 <- coxph(Surv(futime, death) ~ interaction(sex, age2), flchain)
cmean <- matrix(c(0, coef(cfit0)), nrow=2)
cmean <- rbind(cmean, cmean[2,] - cmean[1,])
dimnames(cmean) <- list(c("F", "M", "M/F ratio"), dimnames(counts)[[2]])
signif(exp(cmean),3)
@ 
Since the Cox model is a relative risk model all of the
death rates are relative to one of the cells, in this case the
50--59 year old females has been arbitrarily chosen as the reference cell
and so has a defined rate of 1.00.  
Death rates rise dramatically with age for both males and females
(no surprise),
with males always slightly ahead in the race to a coffin.
The size of the disadvantage for males decreases in the last 2
decades, however.

The possible ways to adjust for age in comparing the two sexes
are
\begin{enumerate}
  \item The likelihood ratio test.  This is analogous to the
    sequential ANOVA table in a linear model, and has the strongest
    theoretical justification.
  \item A stratified Cox model, with age group as the stratification
    factor.  This gives a more general and rigorous adjustment for
    age.  Stratification on institution is a common approach in clinical trials.
 \item The Wald or score test for the sex coefficient, in a model that
    adjusts for age.  This is analogous to Wald tests in the linear
    model, and is asymptotically equivalent the the LRT.
  \item The test from a reweighted model, using case weights.  Results
    using this approach have been central to causal model literature,
    particularly adjustment
    for covariate imbalances in observational studies.  (Also known
    as \emph{marginal structural models}).  
    Adjustment to a uniform population is also possible.
  \item A Yates-like contrast in the Cox model coefficients.
    \begin{itemize}
      \item A reliable algorithm such as cell means coding.
      \item Unreliable approach such as the NSTT
        \end{itemize}
\end{enumerate}
I have listed these in order from the most to the least available 
justification, both in terms of practical experience and
available theory.
The two standard models are for sex alone, and sex after age.
Likelihood ratio tests for these models are the natural analog to
anova tables for the linear model, and are produced by the
same R command.  Here are results for the first three, along
with the unadjusted model that contains sex only.
<<cox anova>>=
options(contrasts=c("contr.SAS", "contr.poly"))
cfit1 <- coxph(Surv(futime, death) ~ sex, flchain)
cfit2 <- coxph(Surv(futime, death) ~ age2 + sex, flchain)
cfit3 <- coxph(Surv(futime, death) ~ sex + strata(age2), flchain)
# Unadjusted
summary(cfit1)
#
# LRT
anova(cfit2)
#
# Stratified
anova(cfit3)
summary(cfit3)
#
# Wald test
signif(summary(cfit2)$coefficients, 3)
#
anova(cfit1, cfit2)
@ 
Without adjustment for age the LRT for sex is only
\Sexpr{round(2*diff(cfit1$loglik),1)}, and after adjustment for  %$
a it increases to \Sexpr{round(anova(cfit2)[3,2],2)}.
Since females are older, not adjusting for age almost completely
erases the evidence of their actual survival advantage.
Results of the LRT
are unchanged if we change to any of the other possible codings for
the factor variables (not shown).
Adjusting for age group using a stratified model gives almost identical
results to the sequential LRT, in this case.
The Wald tests for sex are equal to $[\beta/ se(\beta)]^2$ using the
sex coefficient from the fits,
\Sexpr{round(summary(cfit1)$coef[1,4]^2,2)} and 
\Sexpr{round(summary(cfit2)$coef[5,4]^2,2)}
for the unadjusted and adjusted models, respectively.
Unlike a linear model they are not exactly equal to the 
anova table results based on the log-likelihood, but tell the same story.

Now consider weighted models, with both empirical and uniform distributions
as the target age distribution.
The fits require use of a robust variance,
since we are approaching it via a survey sampling computation.
The tapply function creates a per-subject index into the case weight
table created earlier.
<<coxfit>>=
wtindx <- with(flchain, tapply(death, list(sex, age2)))
cfitpop <- coxph(Surv(futime, death) ~ sex, flchain,
                robust=TRUE, weight = (casewt[,,3])[wtindx]) 
cfityates <- coxph(Surv(futime, death) ~ sex, flchain,
                robust=TRUE, weight = (casewt[,,4])[wtindx])
#
# Glue it into a table for viewing
#
tfun <- function(fit, indx=1) {
    c(fit$coef[indx], sqrt(fit$var[indx,indx]))
  }
coxp <- rbind(tfun(cfit1), tfun(cfit2,5), tfun(cfitpop), tfun(cfityates))
dimnames(coxp) <- list(c("Unadjusted", "Additive", "Empirical Population", 
                         "Uniform Population"),
                      c("Effect", "se(effect)"))
signif(coxp,3)
@ 
The population estimates based on reweighting lie somewhere between
the unadjusted and the sequential results.
We expect that balancing to the empirical population will give a
solution that is similar to the age + sex model, in the same
way that the close but not identical to the MVUE estimate in a linear
model. 
Balancing to a hypothetical population with equal numbers in each
age group yields a substantially smaller estimate of effect. since it gives
large weights to the oldest age group, 
where in this data set the male/female difference is smallest.

Last, look at constructed contrasts from a cell means model.  We
can either fit this using the interaction, or apply the previous
contrast matrix to the coefficients found above.
Since the ``intercept'' of a Cox model is absorbed into the baseline
hazard our contrast matrix will have one less column.
<<>>=
cfit4 <- coxph(Surv(futime, death) ~ sex * age2, flchain)
# Uniform population contrast
ysex <- c(0,-1, 0,0,0,0, -.2,-.2,-.2,-.2) #Yates for sex, SAS coding
contrast(ysex[-1], cfit4) 
# Verify using cell means coding
cfit4b <- coxph(Surv(futime, death) ~ interaction(sex, age2), flchain)
temp <- matrix(c(0, coef(cfit4b)),2)  # the female 50-59 is reference
diff(rowMeans(temp)) #direct estimate of the Yates
#
temp2 <- rbind(temp, temp[2,] - temp[1,])
dimnames(temp2) <- list(c('female', 'male', 'difference'), levels(age2))
round(temp2, 3)
#                        
#
# NSTT contrast
contrast(c(1,0,0,0,0,0,0,0,0), cfit4)
@ 
In the case of a two level covariate such as sex, the NSTT algorithm 
plus the SAS coding yields an estimate and test for a difference in
sex for the \emph{first} age group;
the proper contrast is an average.
Since it gives more weight to the larger ages, where the sex effect
is smallest, the Yates-like contrast is smaller than the result from an
additive model \code{cfit2}.
Nevertheless, this contrast and
the sequential test are more similar for the survival 
outcome than for the linear models.
This is due to the fact that the variances of the individual hazards
for each sex/age combination are proportional to the number of
deaths in that cell rather than the number of subjects per cell.
A table of the number of deaths is not as imbalanced as the
table of subject counts, and so the Yates and MLE ``populations''
are not as far apart as they were for the linear regression.
There are fewer subjects at the higher ages but they die more
frequently.
 
Why is the Yates-like contrast so different than the result of 
creating a uniform age distribution using case weights followed
by an MLE estimate?  Again, the MLE estimate has death counts as
the effective weights; the case-weighted uniform population
has smaller weights for the youngest age group and that group also
has the lowest death rate, resulting in lower influence for that group
and an estimate shrunken towards the 90+ difference of
\Sexpr{round(temp2[3,5], 3)}.
All told, for survival models 
adjustment to a uniform population is a slippery target.

\subsection{SAS phreg results}
Now for the main event: what does SAS do?
First, for the simple case of an additive model
the SAS results are identical to those shown above.
The coefficients, variances and log-likelihoods for cfit2
are identical to the phreg output for an additive model, as
found in the appendix.
As would be expected from the linear models case, 
the ``type III'' results for the additive model
are simply the Wald tests for the fit, repackaged with a new label.

Now look at the model that contains interactions.
We originally surmised that a contrast calculation would be the
most likely
way in which the phreg code would implement type 3, as it is the
easiest to integrate with existing code. 
Results are shown in the last SAS fit of the appendix.
Comparing these results of the SAS printout labeled as ``Type III Wald''
to the contrasts calculated above shows that phreg is using the NSTT method.
This is a bit of a shock.
All of the SAS literature on type III emphasizes the care with which 
they form the calculation so as to always produce a Yates contrast
(or in the case of missing cells a Yates-like one),
and there was no hint in the documentation that phreg does anything different.
As a double check direct contrast statements
corresponding to the Yates and NSTT contrasts were added to the SAS code,
and give confirmatory results.  
A further run which forced sum constraints by adding
\code{'/ effect'} to the SAS class statement (not shown) restored the
correct Yates contrast, as expected.
As a final check, look at the NSTT version of the LRT, which corresponds
to simply dropping the sex column from the $X$ matrix.
<<nstt-lrt>>=
xmat4 <- model.matrix(cfit4)
cfit4b <- coxph(Surv(futime, death) ~ xmat4[,-1], flchain)
anova(cfit4b, cfit4)
@ 
This agrees with the LR ``type 3'' test of the phreg printout.

\subsection{Conclusion}
Overall, both rebalanced estimates and coefficient contrasts are 
interesting exercises for the Cox model, but their actual utility
is unclear.  
It is difficult to make a global optimality argument for
either one, particularly in comparison to the sequential tests
which have the entire weight of likelihood theory as a justification.
Case reweighted estimates do play a key role when attempting to 
adjust for non-random treatment assignment, as found in the
literature for causal analysis and marginal structural models;
a topic and literature far too extensive and nuanced for discussion
in this note.

No special role is apparent, at least to this author, for regular or even
sporadic use of a Yates contrast in survival models.  
The addition of such a feature and label to the SAS phreg package is
a statistical calamity, one that knowledgeable and conscientious
statistical practitioners will likely have to fight for the rest of their
careers.
In the common case of a treatment comparison, adjusted for enrolling center,
the default ``type III'' printout from phreg corresponds to a comparison
of treatments within the last center;
the only contribution of the remainder of the data set is to help define
the baseline hazard function and the effect of any continuous adjusters that
happen to be in the model.
The quadruple whammy of a third rate implementation (the NSTT),
defaults that lead to a useless and misleading result,
no documentation of the actual computation that is being done,
and irrational reverence for the type III label conspire
to make this a particularly unfortunate event.

\appendix
\section{Computing the Yates estimate}
\label{sect:coding}
We will take it as a given that no one wants to memorize contrast formulas,
and so we need a way to compute Yates contrasts automatically in a computer
program.  
The most direct method is to encode the original fit in terms of the 
cell means, as has been done throughout this report.  
The Yates contrast is then simply an average of estimates across the
appropriate margin.
However, we normally will want to solve the linear or Cox model fit in
a more standard coding and then compute the Yates contrast after the fact.
Note that any population re norming requires estimates of the cell means, 
whether
they were explicit parameters or not, i.e., the model fit must include
interaction terms.

Here are three algorithms for this post-hoc computation.
All of them depend, directly or indirectly, on the breakdown found earlier
in equation \eqref{std}.
\begin{align}
  y_{ij} &= \mu + \alpha_i + \beta_j + \gamma_{ij} + \epsilon \label{a1} \\
         &= \theta_{ij} + \epsilon \label{a2}\\
  \theta_{ij} &=  \mu + \alpha_i + \beta_j + \gamma_{ij} \label{a3} \\
\end{align}
Equation \eqref{a1} is the standard form from our linear models textbooks,
equation \eqref{a2} is the cell means form, and \eqref{a3} is the
result of matching them together.
Using this equivalence a Yates test for row effects will be
\begin{align}
  0 &= e_i - e_{i'} \quad \forall i,i' \nonumber \\
    &= (\alpha_i - \alpha_{i'}) + (1/k)\sum_j(\gamma_{ij} - \gamma_{i'j})
             \label{ycont2}
\end{align}
where the subscripts $i$ and $i'$ range over the rows and $k$ is the
number of columns.

To illustrate the methods we will use 3 small data sets defined below.
All are unbalanced.  The second data set removes the aD observation and
so has a zero cell, the third removes the diagonal and has 3 missing
cells.

<<ydata>>= 
data1 <- data.frame(y = rep(1:6, length=20),
                    x1 = factor(letters[rep(1:3, length=20)]),
                    x2 = factor(LETTERS[rep(1:4, length=10)]),
		    x3 = 1:20)
data1$x1[19] <- 'c'
data1 <- data1[order(data1$x1, data1$x2),]
row.names(data1) <- NULL
with(data1, table(x1,x2))
     
# data2 -- single missing cell
indx <- with(data1, x1=='a' & x2=='D')
data2 <- data1[!indx,]

#data3 -- missing the diagonal
data3 <- data1[as.numeric(data1$x1) != as.numeric(data1$x2),]
@

\subsection{NSTT method}
The first calculation method is based on a simple observation.  
If we impose the standard sums constraint on equation \eqref{a1}
which is often found in textbooks (but nowhere else) of
$\sum_i \alpha_i = \sum_j \beta_j = 0$, $\sum_i\gamma_{ij} =0 \; \forall j$ 
and $\sum_j \gamma_{ij} = 0 \; \forall i$,
then the last term in equation \eqref{ycont2} is identically 0.
Thus the Yates contrast corresponds exactly to a test of $\alpha=0$.
In R we can choose this coding by using the \code{contr.sum} option.
This approach has the appearance of simplicity: we can do an ordinary
test for row effects within an interaction model.
Here is R code that is often proposed for ``type III'' computation, 
which is based on the same process.

<<>>=
options(contrasts=c("contr.sum", "contr.poly"))
fit1 <- lm(y ~ x1*x2, data1)
drop1(fit1, .~.)
@ 

The problem with this approach is that it depends critically on use of
the sum constraints.  If we apply the same code after fitting the data
set under the more usual constraints a completely different value 
ensues.
<<>>=
options(contrasts=c("contr.SAS", "contr.poly"))
fit2 <- lm(y ~ x1*x2, data1)
drop1(fit2, .~.)
options(contrasts=c("contr.treatment", "contr.poly"))
fit3 <- lm(y ~ x1*x2, data1)
drop1(fit3, .~.)
@ 
Both common choices of contrasts give a different answer than contr.sum,
and both are useless.
I thus refer to this as the Not Safe Type Three (NSTT) algorithm,
``not SAS type three'' and ``nonsense type three'' are two other sensible
expansions.
This approach should NEVER be used in practice.

\subsection{ATT}
The key idea of the averaging approach (Averaged Type Three)
is to directly evaluate equation \eqref{ycont2}.
The first step of the computation is shown below
<<att>>=
X <- model.matrix(fit2)
ux <- unique(X)
ux
indx <- rep(1:3, c(4,4,4))
effects <- t(rowsum(ux, indx)/4)  # turn sideways to fit the paper better
effects
yates <- effects[,-1] - effects[,1]
yates
@ 
The data set ux has 12 rows, one for each of the 12 unique x*x2 combinations.
Because data1 was sorted, the first 4 rows correspond to x=1, the next 4
to x=2 and the next to x=3 which is useful for illustration but has no
impact on the computation.
The average of rows 1-4 (column 1 of \code{effects} above) is the estimated
average response for subjects with x1=a, assuming a uniform distribution over
the 12 cells.  
Any two differences between the three effects is an equivalent basis for
computing the Yates contrast.

We can verify that the resulting estimates correspond to a uniform 
target population by directly examining the case weights for the estimate.
Each of them gives a total weight of 1/4 to each level of x2.
Each element of $\beta\beta$ is a weighted average of the data, revealed
by the rows of the matrix $(X'X)^{-1}X'$.   
The estimate are a weighted sum of the coefficients, so are also a
weighted average of the $y$ values.
<<>>=
wt <- solve(t(X) %*% X, t(X)) # twelve rows (one per coef), n columns
casewt <- t(effects) %*% wt   # case weights for the three "row efffects"
for (i in 1:3) print(tapply(casewt[i,], data1$x2, sum))
@ 

\subsection{STT}
The SAS type III method takes a different approach, based on a
a dependency matrix $D$.  Start by writing the
$X$ matrix for the problem using all of the parameters in equation \eqref{a1}.
For our flc example this will have columns for intercept (1), sex (2), age group
(5) and the age group by sex interaction (10) = 18 columns.  Now define the
lower triangular square matrix $D$ such that 
\begin{itemize}
  \item If the $i$th column of $X$ can be written as a linear combination of
    columns 1 through $i-1$, then row $i$ of $D$ contains that linear
    combination and $D_{ii}=0$.
  \item If the $i$th column is not linearly dependent on earlier ones then
    $D_{ii}=1$ and $D_{ij}=0$ for all $j \ne i$.
\end{itemize}
Columns of $D$ that correspond to linearly dependent columns of $X$ will be
identically zero and can be discarded (or not) at this point.  
The result of this operation replicates table 12.2 in the SAS reference
\cite{SASguide} labeled ``the form of estimable functions''.
To obtain the Yates contrasts for an effect replace the appropriate
columns of $D$ with the residuals from a regression on all columns to the
right of it.
Simple inspection shows that the columns of $D$ corresponding to any given
effect will already be orthogonal to other effects in $D$ \emph{except}
those for interactions that contain it; so the regression does not have
to include all columns to the right.  

It is easy to demonstrate that this gives the uniform population contrast
(Yates) for a large number of data sets, 
but I have not yet constructed a proof. 
(I suspect it could be approached using the Rao-Blackwell theorem.)  

\subsection{Bystanders}
What about a model that has a extra predictor, such as \code{x3} in
our example data and in the fit below?
<<>>=
fit4 <- lm(y ~ x1*x2 + x3, data=data1)
@ 
The standard approach is to ignore this variable when setting up
``type III'' tests: the contrast for \code{x1} will be the same as
it was in the prior model, with a 0 row in the middle for the x3
coefficient.

\subsection{Missing cells}
When there are combinations of factors with 0 subjects in that group,
it is not possible to create a uniform population via reweighting of either
subjects or parameters. 
There is thus no Yates contrast corresponding to the hypothetical
population of interest.  
For that matter, adjustment to any fixed population is no longer possible,
such as the US 2000 reference, unless groups are pooled so as to remove any
counts of zero, and even then the estimate could be problematic due to extreme
weights.

This fact does not stop each of the above 3 algorithms from 
executing and producing a number. 
This raises two further issues.
First, what does that number \emph{mean}?  Much ink has been spilled on this
subject, but I personally have never been able to come to grips with a
satisfactory explanation and so have nothing to offer on the topic.
I am  reluctant to use such estimates.
The second issue is that the computational algorithms become more fragile.
\begin{itemize}
  \item The NSTT algorithm is a disaster in waiting, 
    so no more needs to be said about situations where its behavior
    may be even worse.
  \item When fitting the original model, there will be one or more NA
    coefficients due to the linear dependencies that arise.  A natural
    extension of the ATT method is to leave these out of the sums 
    when computing each average.
    However, there are data sets for which the particular set of coefficients
    returned as missing will depend on the order in which variables 
    were listed in
    the model statement, which in turn will change the ATT result.
  \item For the STT method, our statement that certain other columns in $D$ 
    will be orthogonal to the chosen effect is no longer true.  To match
    SAS, the orthogonalization step above should include only those
    effects further to the right that contain the chosen effect (the one we
    are constructing a contrast vector for).
    As a side effect, this makes the 
    STT result invariant to the order of the variables in the
    model statement.
\end{itemize}

\section{SAS computations}
The following code was executed in version 9.3 of SAS.
\begin{verbatim}
options ls=70;
libname save "sasdata";

title "Sex only";
proc glm data=save.flc;
    class sex;
    model flc = sex;
title "Sex only";
    

proc glm data=save.flc;
    class sex age2;
    model flc = age2 sex /solution E1 E2 E3;
title "Second fit, no interaction";


proc glm data=save.flc;
    class sex age2;
    model flc = sex  age2  sex*age2/solution E1 E2 E3;

    estimate 'yates' sex 1 -1  sex*age2 .2 .2 .2 .2 .2 -.2 -.2 -.2 -.2 -.2;
    
title "Third fit, interaction";

proc phreg data=save.flc;
    class sex age2;
    model futime * death(0) = sex age2/ ties=efron;
title "Phreg fit, sex and age, additive";

proc phreg data=save.flc;
    class sex age2;
    model futime * death(0) = sex age2  sex*age2 /
          ties=efron type3(all);
    
    estimate 'Yates sex' sex 1 sex*age2  .2 .2 .2 .2;
    contrast 'NSTT sex ' sex 1 ;
    contrast 'NSTT age' age2 1 0 0 0 ,
                         age2 0 1 0 0 ,
                         age2 0 0 1 0 ,
                         age2 0 0 0 1;
title "Phreg fit, sex and age with interaction";

proc phreg data=save.flc;
    class sex age2/ param=effect;
    model futime * death(0) = sex age2  sex*age2 / ties=efron;
title "Phreg, using effect coding";
\end{verbatim}

The SAS output is voluminous, covering over a dozen pages.  
A subset is extracted below, leaving out portions that are unimportant
to our comparison.
First the GLM model for sex only.  There are no differences
between type 1 and type 3 output for this model.
\small
\begin{verbatim}
...
               Number of Observations Read        7874
               Number of Observations Used        7874
...
Dependent Variable: flc   

                                      Sum of
Source                     DF        Squares    Mean Square   F Value

Model                       1      142.19306      142.19306     42.27

Error                    7872    26481.86345        3.36406          

Corrected Total          7873    26624.05652                         
\end{verbatim}
\normalsize

The second fit with sex and then age.
\small
\begin{verbatim}
                     Type I Estimable Functions
 
                   -----------------Coefficients------------------
   Effect          age2                                        sex

   Intercept       0                                           0  

   age2      1     L2                                          0  
   age2      2     L3                                          0  
   age2      3     L4                                          0  
   age2      4     L5                                          0  
   age2      5     -L2-L3-L4-L5                                0  

   sex       F     -0.2571*L2-0.2576*L3-0.1941*L4-0.0844*L5    L7 
   sex       M     0.2571*L2+0.2576*L3+0.1941*L4+0.0844*L5     -L7



                     Type II Estimable Functions
 
                                 ---Coefficients----
                 Effect          age2            sex

                 Intercept       0               0  

                 age2      1     L2              0  
                 age2      2     L3              0  
                 age2      3     L4              0  
                 age2      4     L5              0  
                 age2      5     -L2-L3-L4-L5    0  

                 sex       F     0               L7 
                 sex       M     0               -L7



                    Type III Estimable Functions
 
                                 ---Coefficients----
                 Effect          age2            sex

                 Intercept       0               0  

                 age2      1     L2              0  
                 age2      2     L3              0  
                 age2      3     L4              0  
                 age2      4     L5              0  
                 age2      5     -L2-L3-L4-L5    0  

                 sex       F     0               L7 
                 sex       M     0               -L7

Dependent Variable: flc   

                                      Sum of
Source                     DF        Squares    Mean Square   F Value

Model                       5     2212.13649      442.42730    142.60

Error                    7868    24411.92003        3.10268          

Corrected Total          7873    26624.05652                         



Source                     DF      Type I SS    Mean Square   F Value

age2                        4    1929.642183     482.410546    155.48
sex                         1     282.494304     282.494304     91.05


Source                     DF     Type II SS    Mean Square   F Value

age2                        4    2069.943424     517.485856    166.79
sex                         1     282.494304     282.494304     91.05


Source                     DF    Type III SS    Mean Square   F Value

age2                        4    2069.943424     517.485856    166.79
sex                         1     282.494304     282.494304     91.05



                                      Standard
Parameter           Estimate             Error    t Value    Pr > |t|

Intercept        5.503757546 B      0.17553667      31.35      <.0001
age2      1     -2.587424744 B      0.17584961     -14.71      <.0001
age2      2     -2.249164537 B      0.17684133     -12.72      <.0001
age2      3     -1.770342603 B      0.17834253      -9.93      <.0001
age2      4     -1.082104827 B      0.18584656      -5.82      <.0001
age2      5      0.000000000 B                                       
sex       F     -0.383454133 B      0.04018624      -9.54      <.0001
sex       M      0.000000000 B                                       
\end{verbatim}
\normalsize

The third linear models fit, containing interactions.
For first portion I have trimmed off long printout on the right, i.e.
the estimable functions for the age2*sex effect since they are not
of interest.
\small
\begin{verbatim}
                      Type I Estimable Functions
 
                 --------------------Coefficients--------
Effect           sex          age2

Intercept        0            0                                       

sex       F      L2           0                                       
sex       M      -L2          0                                       

age2      1      -0.0499*L2   L4                                      
age2      2      -0.0373*L2   L5                                      
age2      3      0.0269*L2    L6                                      
age2      4      0.0482*L2    L7                                      
age2      5      0.0121*L2    -L4-L5-L6-L7                            

sex*age2  F 1    0.3786*L2    0.6271*L4+0.1056*L5+0.0796*L6+0.0346*L7 
sex*age2  F 2    0.2791*L2    0.0778*L4+0.5992*L5+0.0587*L6+0.0255*L7 
sex*age2  F 3    0.2182*L2    0.0527*L4+0.0528*L5+0.6245*L6+0.0173*L7 
sex*age2  F 4    0.1055*L2    0.0188*L4+0.0188*L5+0.0142*L6+0.7006*L7 
sex*age2  F 5    0.0186*L2    -0.7764*L4-0.7764*L5-0.777*L6-0.7781*L7 
sex*age2  M 1    -0.4285*L2   0.3729*L4-0.1056*L5-0.0796*L6-0.0346*L7 
sex*age2  M 2    -0.3164*L2   -0.0778*L4+0.4008*L5-0.0587*L6-0.0255*L7
sex*age2  M 3    -0.1913*L2   -0.0527*L4-0.0528*L5+0.3755*L6-0.0173*L7
sex*age2  M 4    -0.0573*L2   -0.0188*L4-0.0188*L5-0.0142*L6+0.2994*L7
sex*age2  M 5    -0.0065*L2   -0.2236*L4-0.2236*L5-0.223*L6-0.2219*L7 

                     Type II Estimable Functions
 
                 --------------------Coefficients---------------------
Effect           sex          age2

Intercept        0            0                                       

sex       F      L2           0                                       
sex       M      -L2          0                                       

age2      1      0            L4                                      
age2      2      0            L5                                      
age2      3      0            L6                                      
age2      4      0            L7                                      
age2      5      0            -L4-L5-L6-L7                            

sex*age2  F 1    0.41*L2      0.6271*L4+0.1056*L5+0.0796*L6+0.0346*L7 
sex*age2  F 2    0.3025*L2    0.0778*L4+0.5992*L5+0.0587*L6+0.0255*L7 
sex*age2  F 3    0.2051*L2    0.0527*L4+0.0528*L5+0.6245*L6+0.0173*L7 
sex*age2  F 4    0.073*L2     0.0188*L4+0.0188*L5+0.0142*L6+0.7006*L7 
sex*age2  F 5    0.0093*L2    -0.7764*L4-0.7764*L5-0.777*L6-0.7781*L7 
sex*age2  M 1    -0.41*L2     0.3729*L4-0.1056*L5-0.0796*L6-0.0346*L7 
sex*age2  M 2    -0.3025*L2   -0.0778*L4+0.4008*L5-0.0587*L6-0.0255*L7
sex*age2  M 3    -0.2051*L2   -0.0527*L4-0.0528*L5+0.3755*L6-0.0173*L7
sex*age2  M 4    -0.073*L2    -0.0188*L4-0.0188*L5-0.0142*L6+0.2994*L7
sex*age2  M 5    -0.0093*L2   -0.2236*L4-0.2236*L5-0.223*L6-0.2219*L7 


                     Type III Estimable Functions
 
                ---------------------Coefficients---------------------
Effect          sex      age2                          sex*age2

Intercept       0        0                             0              

sex       F     L2       0                             0              
sex       M     -L2      0                             0              

age2      1     0        L4                            0              
age2      2     0        L5                            0              
age2      3     0        L6                            0              
age2      4     0        L7                            0              
age2      5     0        -L4-L5-L6-L7                  0              

sex*age2  F 1   0.2*L2   0.5*L4                        L9             
sex*age2  F 2   0.2*L2   0.5*L5                        L10            
sex*age2  F 3   0.2*L2   0.5*L6                        L11            
sex*age2  F 4   0.2*L2   0.5*L7                        L12            
sex*age2  F 5   0.2*L2   -0.5*L4-0.5*L5-0.5*L6-0.5*L7  -L9-L10-L11-L12
sex*age2  M 1   -0.2*L2  0.5*L4                        -L9            
sex*age2  M 2   -0.2*L2  0.5*L5                        -L10           
sex*age2  M 3   -0.2*L2  0.5*L6                        -L11           
sex*age2  M 4   -0.2*L2  0.5*L7                        -L12           
sex*age2  M 5   -0.2*L2  -0.5*L4-0.5*L5-0.5*L6-0.5*L7  L9+L10+L11+L12 


Source                     DF      Type I SS    Mean Square   F Value

sex                         1     142.193063     142.193063     45.97
age2                        4    2069.943424     517.485856    167.30
sex*age2                    4      87.218363      21.804591      7.05

Source                     DF     Type II SS    Mean Square   F Value

sex                         1     282.494304     282.494304     91.33
age2                        4    2069.943424     517.485856    167.30
sex*age2                    4      87.218363      21.804591      7.05


Source                     DF    Type III SS    Mean Square   F Value

sex                         1     126.961986     126.961986     41.05
age2                        4    1999.446491     499.861623    161.60
sex*age2                    4      87.218363      21.804591      7.05

                                         Standard
 Parameter                 Estimate         Error  t Value  Pr > |t|

 yates                  -0.58972607    0.09204824    -6.41    <.0001

                                       Standard
 Parameter            Estimate            Error   t Value   Pr > |t|

 Intercept         6.003043478 B     0.36672295     16.37     <.0001
 sex       F      -1.024512614 B     0.41553944     -2.47     0.0137
 sex       M       0.000000000 B                                    
 age2      1      -3.176876326 B     0.36950532     -8.60     <.0001
 age2      2      -2.787597918 B     0.37048599     -7.52     <.0001
 age2      3      -2.088127335 B     0.37292760     -5.60     <.0001
 age2      4      -1.353746449 B     0.38703805     -3.50     0.0005
 age2      5       0.000000000 B                                    
 sex*age2  F 1     0.813889663 B     0.42023749      1.94     0.0528
 sex*age2  F 2     0.716160958 B     0.42189464      1.70     0.0896
 sex*age2  F 3     0.330651265 B     0.42487846      0.78     0.4365
 sex*age2  F 4     0.313230835 B     0.44127621      0.71     0.4778
 sex*age2  F 5     0.000000000 B                                    
 sex*age2  M 1     0.000000000 B                                    
 sex*age2  M 2     0.000000000 B                                    
 sex*age2  M 3     0.000000000 B                                    
 sex*age2  M 4     0.000000000 B                                    
 sex*age2  M 5     0.000000000 B                                    
\end{verbatim}
\normalsize

The phreg printout for the additive  model with age and sex.
\small
\begin{verbatim}
                 Testing Global Null Hypothesis: BETA=0

         Test                 Chi-Square       DF     Pr > ChiSq

         Likelihood Ratio      2357.5239        5         <.0001
         Score                 3823.3905        5         <.0001
         Wald                  2374.5250        5         <.0001


                               Type 3 Tests

                                        Wald
                Effect      DF    Chi-Square    Pr > ChiSq

                sex          1       69.9646        <.0001
                age2         4     2374.5211        <.0001


            Analysis of Maximum Likelihood Estimates

                Parameter   Standard                        
Parameter   DF   Estimate      Error Chi-Square Pr > ChiSq  

sex       F  1   -0.36617    0.04378    69.9646     <.0001  
age2      1  1   -4.18209    0.12180  1179.0289     <.0001  
age2      2  1   -3.23859    0.11418   804.5068     <.0001  
age2      3  1   -2.17521    0.10963   393.6524     <.0001  
age2      4  1   -1.15226    0.11072   108.3077     <.0001  
\end{verbatim}
\normalsize

The model with age*sex interaction.
\small
\begin{verbatim}
                        Model Fit Statistics
 
                                Without           With
               Criterion     Covariates     Covariates

               -2 LOG L       37736.900      35374.050
               AIC            37736.900      35392.050
               SBC            37736.900      35443.188


               Testing Global Null Hypothesis: BETA=0
 
       Test                 Chi-Square       DF     Pr > ChiSq

       Likelihood Ratio      2362.8497        9         <.0001
       Score                 3873.5113        9         <.0001
       Wald                  2357.9498        9         <.0001


                             Type 3 Tests
 
                                   LR Statistics
             Effect        DF    Chi-Square    Pr > ChiSq

             sex            1        0.4607        0.4973
             age2           4      932.1371        <.0001
             sex*age2       4        5.3258        0.2555

 
                                 Score Statistics
             Effect        DF    Chi-Square    Pr > ChiSq

             sex            1        0.4757        0.4904
             age2           4     1506.8699        <.0001
             sex*age2       4        5.2516        0.2624

 
                                  Wald Statistics
             Effect        DF    Chi-Square    Pr > ChiSq

             sex            1        0.4833        0.4869
             age2           4      964.6007        <.0001
             sex*age2       4        5.2322        0.2643


               Analysis of Maximum Likelihood Estimates
 
                      Parameter     Standard
Parameter       DF     Estimate        Error   Chi-Square   

sex       F      1     -0.16537      0.23789       0.4833   
age2      1      1     -4.02699      0.22585     317.9171   
age2      2      1     -3.04796      0.21843     194.7187   
age2      3      1     -1.99577      0.21577      85.5504   
age2      4      1     -1.10659      0.22256      24.7216   
sex*age2  F 1    1     -0.21121      0.26896       0.6167   
sex*age2  F 2    1     -0.29334      0.25518       1.3214   
sex*age2  F 3    1     -0.25663      0.24829       1.0684   
sex*age2  F 4    1     -0.04339      0.25527       0.0289   


                 Contrast      DF    Chi-Square    Pr > ChiSq

                 NSTT sex       1        0.4833        0.4869
                 NSTT age       4      964.6007        <.0001

 
          Likelihood Ratio Statistics for Type 1 Analysis
 
                                                      LR
Source                    -2 Log L      DF    Chi-Square    Pr > ChiSq

(Without Covariates)    37736.8997                                    
sex                     37733.0932       1        3.8066        0.0511
age2                    35379.3758       4     2353.7173        <.0001
sex*age2                35374.0501       4        5.3258        0.2555

 
                              Standard
         Label    Estimate       Error    z Value    Pr > |z|

         Yates     -0.3263     0.06149      -5.31      <.0001
\end{verbatim}
\normalsize

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\end{document}
