7 Building Cox Proportional Hazards models

Published

Last modified: 2024-05-16: 19:13:41 (PM)

Configuring R

Functions from these packages will be used throughout this document:

Show R code

library(conflicted) # check for conflicting function definitions
# library(printr) # inserts help-file output into markdown output
library(rmarkdown) # Convert R Markdown documents into a variety of formats.
library(pander) # format tables for markdown
library(ggplot2) # graphics
library(ggeasy) # help with graphics
library(ggfortify) # help with graphics
library(dplyr) # manipulate data
library(tibble) # `tibble`s extend `data.frame`s
library(magrittr) # `%>%` and other additional piping tools
library(haven) # import Stata files
library(knitr) # format R output for markdown
library(tidyr) # Tools to help to create tidy data
library(plotly) # interactive graphics
library(dobson) # datasets from Dobson and Barnett 2018
library(parameters) # format model output tables for markdown
library(haven) # import Stata files
library(latex2exp) # use LaTeX in R code (for figures and tables)
library(fs) # filesystem path manipulations
library(survival) # survival analysis
library(survminer) # survival analysis graphics
library(KMsurv) # datasets from Klein and Moeschberger
library(parameters) # format model output tables for
library(webshot2) # convert interactive content to static for pdf
library(forcats) # functions for categorical variables ("factors")
library(stringr) # functions for dealing with strings
library(lubridate) # functions for dealing with dates and times

Here are some R settings I use in this document:

Show R code

rm(list = ls()) # delete any data that's already loaded into R

conflicts_prefer(dplyr::filter)
ggplot2::theme_set(
  ggplot2::theme_bw() + 
        # ggplot2::labs(col = "") +
    ggplot2::theme(
      legend.position = "bottom",
      text = ggplot2::element_text(size = 12, family = "serif")))

knitr::opts_chunk$set(message = FALSE)
options('digits' = 4)

panderOptions("big.mark", ",")
pander::panderOptions("table.emphasize.rownames", FALSE)
pander::panderOptions("table.split.table", Inf)
conflicts_prefer(dplyr::filter) # use the `filter()` function from dplyr() by default
legend_text_size = 9

7.1 Building Cox Proportional Hazards models

7.1.1 `hodg` Lymphoma Data Set from `KMsurv`

Participants

43 bone marrow transplant patients at Ohio State University (Avalos 1993)

Variables

dtype: Disease type (Hodgkin’s or non-Hodgkins lymphoma)
gtype: Bone marrow graft type:
allogeneic: from HLA-matched sibling
autologous: from self (prior to chemo)
time: time to study exit
delta: study exit reason (death/relapse vs censored)
wtime: waiting time to transplant (in months)
score: Karnofsky score:
80–100: Able to carry on normal activity and to work; no special care needed.
50–70: Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed.
10–60: Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.

Data

Show R code

data(hodg, package = "KMsurv")
hodg2 = hodg |> 
  as_tibble() |> 
  mutate(
    # We add factor labels to the categorical variables:
    gtype = gtype |> 
      case_match(
        1 ~ "Allogenic",
        2 ~ "Autologous"),
    dtype = dtype |> 
      case_match(
        1 ~ "Non-Hodgkins",
        2 ~ "Hodgkins") |> 
      factor() |> 
      relevel(ref = "Non-Hodgkins"), 
    delta = delta |> 
      case_match(
        1 ~ "dead",
        0 ~ "alive"),
    surv = Surv(
      time = time, 
      event = delta == "dead")
  )
hodg2 |> print()
#> # A tibble: 43 × 7
#>    gtype     dtype         time delta score wtime   surv
#>    <chr>     <fct>        <int> <chr> <int> <int> <Surv>
#>  1 Allogenic Non-Hodgkins    28 dead     90    24    28 
#>  2 Allogenic Non-Hodgkins    32 dead     30     7    32 
#>  3 Allogenic Non-Hodgkins    49 dead     40     8    49 
#>  4 Allogenic Non-Hodgkins    84 dead     60    10    84 
#>  5 Allogenic Non-Hodgkins   357 dead     70    42   357 
#>  6 Allogenic Non-Hodgkins   933 alive    90     9   933+
#>  7 Allogenic Non-Hodgkins  1078 alive   100    16  1078+
#>  8 Allogenic Non-Hodgkins  1183 alive    90    16  1183+
#>  9 Allogenic Non-Hodgkins  1560 alive    80    20  1560+
#> 10 Allogenic Non-Hodgkins  2114 alive    80    27  2114+
#> # ℹ 33 more rows

7.1.2 Proportional hazards model

Show R code


hodg.cox1 = coxph(
  formula = surv ~ gtype * dtype + score + wtime, 
  data = hodg2)

summary(hodg.cox1)
#> Call:
#> coxph(formula = surv ~ gtype * dtype + score + wtime, data = hodg2)
#> 
#>   n= 43, number of events= 26 
#> 
#>                                  coef exp(coef) se(coef)     z Pr(>|z|)    
#> gtypeAutologous                0.6394    1.8953   0.5937  1.08   0.2815    
#> dtypeHodgkins                  2.7603   15.8050   0.9474  2.91   0.0036 ** 
#> score                         -0.0495    0.9517   0.0124 -3.98  6.8e-05 ***
#> wtime                         -0.0166    0.9836   0.0102 -1.62   0.1046    
#> gtypeAutologous:dtypeHodgkins -2.3709    0.0934   1.0355 -2.29   0.0220 *  
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                               exp(coef) exp(-coef) lower .95 upper .95
#> gtypeAutologous                  1.8953     0.5276    0.5920     6.068
#> dtypeHodgkins                   15.8050     0.0633    2.4682   101.207
#> score                            0.9517     1.0507    0.9288     0.975
#> wtime                            0.9836     1.0167    0.9641     1.003
#> gtypeAutologous:dtypeHodgkins    0.0934    10.7074    0.0123     0.711
#> 
#> Concordance= 0.776  (se = 0.059 )
#> Likelihood ratio test= 32.1  on 5 df,   p=6e-06
#> Wald test            = 27.2  on 5 df,   p=5e-05
#> Score (logrank) test = 37.7  on 5 df,   p=4e-07

7.2 Diagnostic graphs for proportional hazards assumption

7.2.1 Analysis plan

survival function for the four combinations of disease type and graft type.
observed (nonparametric) vs. expected (semiparametric) survival functions.
complementary log-log survival for the four groups.

7.2.2 Kaplan-Meier survival functions

Show R code

km_model = survfit(
  formula = surv ~ dtype + gtype,
  data = hodg2)

km_model |> 
  autoplot(conf.int = FALSE) +
  theme_bw() +
  theme(
    legend.position="bottom",
    legend.title = element_blank(),
    legend.text = element_text(size = legend_text_size)
  ) +
  guides(col=guide_legend(ncol=2)) +
  ylab('Survival probability, S(t)') +
  xlab("Time since transplant (days)")

Kaplan-Meier Survival Curves for HOD/NHL and Allo/Auto Grafts

7.2.3 Observed and expected survival curves

Show R code

# we need to create a tibble of covariate patterns;
# we will set score and wtime to mean values for disease and graft types:
means = hodg2 |> 
  summarize(
    .by = c(dtype, gtype), 
    score = mean(score), 
    wtime = mean(wtime)) |> 
  arrange(dtype, gtype) |> 
  mutate(strata = paste(dtype, gtype, sep = ",")) |> 
  as.data.frame() 

# survfit.coxph() will use the rownames of its `newdata`
# argument to label its output:
rownames(means) = means$strata

cox_model = 
  hodg.cox1 |> 
  survfit(
    data = hodg2, # ggsurvplot() will need this
    newdata = means)

Show R code

# I couldn't find a good function to reformat `cox_model` for ggplot, 
# so I made my own:
stack_surv_ph = function(cox_model)
{
  cox_model$surv |> 
    as_tibble() |> 
    mutate(time = cox_model$time) |> 
    pivot_longer(
      cols = -time,
      names_to = "strata",
      values_to = "surv") |> 
    mutate(
      cumhaz = -log(surv),
      model = "Cox PH")
}

km_and_cph =
  km_model |> 
  fortify(surv.connect = TRUE) |> 
  mutate(
    strata = trimws(strata),
    model = "Kaplan-Meier",
    cumhaz = -log(surv)) |>
  bind_rows(stack_surv_ph(cox_model))

Show R code

km_and_cph |> 
  ggplot(aes(x = time, y = surv, col = model)) +
  geom_step() +
  facet_wrap(~strata) +
  theme_bw() + 
  ylab("S(t) = P(T>=t)") +
  xlab("Survival time (t, days)") +
  theme(legend.position = "bottom")

Observed and expected survival curves for `bmt` data

7.2.4 Cumulative hazard (log-scale) curves

Also known as “complementary log-log (clog-log) survival curves”.

Show R code

na_model = survfit(
  formula = surv ~ dtype + gtype,
  data = hodg2,
  type = "fleming")

na_model |> 
  survminer::ggsurvplot(
  legend = "bottom", 
  legend.title = "",
  ylab = "log(Cumulative Hazard)",
  xlab = "Time since transplant (days, log-scale)",
  fun = 'cloglog', 
  size = .5,
  ggtheme = theme_bw(),
  conf.int = FALSE, 
  censor = TRUE) |>  
  magrittr::extract2("plot") +
  guides(
    col = 
      guide_legend(
        ncol = 2,
        label.theme = 
          element_text(
            size = legend_text_size)))

Figure 7.1: Complementary log-log survival curves - Nelson-Aalen estimates

Let’s compare these empirical (i.e., non-parametric) curves with the fitted curves from our coxph() model:

Show R code

cox_model |> 
  survminer::ggsurvplot(
    facet_by = "",
    legend = "bottom", 
    legend.title = "",
    ylab = "log(Cumulative Hazard)",
    xlab = "Time since transplant (days, log-scale)",
    fun = 'cloglog', 
    size = .5,
    ggtheme = theme_bw(),
    censor = FALSE, # doesn't make sense for cox model
    conf.int = FALSE) |>  
  magrittr::extract2("plot") +
  guides(
    col = 
      guide_legend(
        ncol = 2,
        label.theme = 
          element_text(
            size = legend_text_size)))

Figure 7.2: Complementary log-log survival curves - PH estimates

Now let’s overlay these cumulative hazard curves:

Show R code

na_and_cph = 
  na_model |> 
  fortify(fun = "cumhaz") |> 
  # `fortify.survfit()` doesn't name cumhaz correctly:
  rename(cumhaz = surv) |>  
  mutate(
    surv = exp(-cumhaz),
    strata = trimws(strata)) |> 
  mutate(model = "Nelson-Aalen") |> 
  bind_rows(stack_surv_ph(cox_model))

na_and_cph |> 
  ggplot(
    aes(
      x = time, 
      y = cumhaz, 
      col = model)) +
  geom_step() +
  facet_wrap(~strata) +
  theme_bw() + 
  scale_y_continuous(
    trans = "log10",
    name = "Cumulative hazard H(t) (log-scale)") +
  scale_x_continuous(
    trans = "log10",
    name = "Survival time (t, days, log-scale)") +
  theme(legend.position = "bottom")

Figure 7.3: Observed and expected cumulative hazard curves for `bmt` data (cloglog format)

7.3 Predictions and Residuals

7.3.1 Review: Predictions in Linear Regression

In linear regression, we have a linear predictor for each data point \(i\)

\[ \begin{aligned} \eta_i &= \beta_0+\beta_1x_{1i}+\cdots+\beta_px_{pi}\\ \hat y_i &=\hat\eta_i = \hat\beta_0+\hat\beta_1x_{1i}+\cdots+\hat\beta_px_{pi}\\ y_i &\sim N(\eta_i,\sigma^2) \end{aligned} \]

\(\hat y_i\) estimates the conditional mean of \(y_i\) given the covariate values \(\tilde{x}_i\). This together with the prediction error says that we are predicting the distribution of values of \(y\).

7.3.2 Review: Residuals in Linear Regression

The usual residual is \(r_i=y_i-\hat y_i\), the difference between the actual value of \(y\) and a prediction of its mean.
The residuals are also the quantities the sum of whose squares is being minimized by the least squares/MLE estimation.

7.3.3 Predictions and Residuals in survival models

In survival analysis, the equivalent of \(y_i\) is the event time \(t_i\), which is unknown for the censored observations.
The expected event time can be tricky to calculate:

\[ \hat{\text{E}}[T|X=x] = \int_{t=0}^{\infty} \hat S(t)dt \]

7.3.4 Wide prediction intervals

The nature of time-to-event data results in very wide prediction intervals:

Suppose a cancer patient is predicted to have a mean lifetime of 5 years after diagnosis and suppose the distribution is exponential.
If we want a 95% interval for survival, the lower end is at the 0.025 percentage point of the exponential which is qexp(.025, rate = 1/5) = 0.12658904 years, or 1/40 of the mean lifetime.
The upper end is at the 0.975 point which is qexp(.975, rate = 1/5) = 18.44439727 years, or 3.7 times the mean lifetime.
Saying that the survival time is somewhere between 6 weeks and 18 years does not seem very useful, but it may be the best we can do.
For survival analysis, something is like a residual if it is small when the model is accurate or if the accumulation of them is in some way minimized by the estimation algorithm, but there is no exact equivalence to linear regression residuals.
And if there is, they are mostly quite large!

7.3.5 Types of Residuals in Time-to-Event Models

It is often hard to make a decision from graph appearances, though the process can reveal much.
Some diagnostic tests are based on residuals as with other regression methods:
Schoenfeld residuals (via cox.zph) for proportionality.
Cox-Snell residuals for goodness of fit.
martingale residuals for non-linearity.
dfbeta for influence.

7.3.6 Schoenfeld residuals

There is a Schoenfeld residual for each subject \(i\) with an event (not censored) and for each predictor \(x_{k}\).
At the event time \(t\) for that subject, there is a risk set \(R\), and each subject \(j\) in the risk set has a risk coefficient \(\theta_j\) and also a value \(x_{jk}\) of the predictor.
The Schoenfeld residual is the difference between \(x_{ik}\) and the risk-weighted average of all the \(x_{jk}\) over the risk set.

\[ r^S_{ik} = x_{ik}-\frac{\sum_{k\in R}x_{jk}\theta_k}{\sum_{k\in R}\theta_k} \]

This residual measures how typical the individual subject is with respect to the covariate at the time of the event. Since subjects should fail more or less uniformly according to risk, the Schoenfeld residuals should be approximately level over time, not increasing or decreasing.

We can test this with the correlation with time on some scale, which could be the time itself, the log time, or the rank in the set of failure times.

The default is to use the KM curve as a transform, which is similar to the rank but deals better with censoring.

The cox.zph() function implements a score test proposed in Grambsch and Therneau (1994).

Show R code

hodg.zph = cox.zph(hodg.cox1)
print(hodg.zph)
#>               chisq df     p
#> gtype        0.5400  1 0.462
#> dtype        1.8012  1 0.180
#> score        3.8805  1 0.049
#> wtime        0.0173  1 0.895
#> gtype:dtype  4.0474  1 0.044
#> GLOBAL      13.7573  5 0.017

`gtype`

Show R code

ggcoxzph(hodg.zph, var = "gtype")

`dtype`

Show R code

ggcoxzph(hodg.zph, var = "dtype")

`score`

Show R code

ggcoxzph(hodg.zph, var = "score")

`wtime`

Show R code

ggcoxzph(hodg.zph, var = "wtime")

`gtype:dtype`

Show R code

ggcoxzph(hodg.zph, var = "gtype:dtype")

Conclusions

From the correlation test, the Karnofsky score and the interaction with graft type disease type induce modest but statistically significant non-proportionality.
The sample size here is relatively small (26 events in 43 subjects). If the sample size is large, very small amounts of non-proportionality can induce a significant result.
As time goes on, autologous grafts are over-represented at their own event times, but those from HOD patients become less represented.
Both the statistical tests and the plots are useful.

7.4 Goodness of Fit using the Cox-Snell Residuals

(references: Klein & Moeschberger textbook, §11.2, and Dobson & Barnett textbook, §10.6)

Suppose that an individual has a survival time \(T\) which has survival function \(S(t)\), meaning that \(\Pr(T> t) = S(t)\). Then \(S(T)\) has a uniform distribution on \((0,1)\).

\[ \begin{aligned} \Pr(S(T_i) \le u) &= \Pr(T_i > S_i^{-1}(u))\\ &= S_i(S_i^{-1}(u))\\ &= u \end{aligned} \]

Also, if \(U\) has a uniform distribution on \((0,1)\), then what is the distribution of \(-\ln(U)\)?

\[ \begin{aligned} \Pr(-\ln(U) < x) &= \Pr(U>\text{exp}\left\{-x\right\})\\ &= 1-e^{-x} \end{aligned} \]

which is the CDF of an exponential distribution with parameter \(\lambda=1\).

So,

\[ \begin{aligned} r^{CS}_i& \stackrel{\text{def}}{=}-\ln[\hat S(t_i|x_i)] = \hat H(t_i|\tilde{x}_i) \end{aligned} \]

should have an exponential distribution with constant hazard \(\lambda=1\) if the estimate \(\hat S_i\) is accurate, which means that these values should look like a censored sample from this exponential distribution. These values are called generalized residuals or Cox-Snell residuals.

Show R code

hodg2 = hodg2 |> 
  mutate(cs = predict(hodg.cox1, type = "expected"))

surv.csr = survfit(
  data = hodg2,
  formula = Surv(time = cs, event = delta == "dead") ~ 1,
  type = "fleming-harrington")

autoplot(surv.csr, fun = "cumhaz") + 
  geom_abline(aes(intercept = 0, slope = 1), col = "red") +
  theme_bw()

Cumulative Hazard of Cox-Snell Residuals

The line with slope 1 and intercept 0 fits the curve relatively well, so we don’t see lack of fit using this procedure.

7.5 Martingale Residuals

The martingale residuals are a slight modification of the Cox-Snell residuals. If the censoring indicator is \(\delta_i\), then \[r^M_i=\delta_i-r^{CS}_i\] These residuals can be interpreted as an estimate of the excess number of events seen in the data but not predicted by the model. We will use these to examine the functional forms of continuous covariates.

7.5.1 Using Martingale Residuals

Martingale residuals can be used to examine the functional form of a numeric variable.

We fit the model without that variable and compute the martingale residuals.
We then plot these martingale residuals against the values of the variable.
We can see curvature, or a possible suggestion that the variable can be discretized.

Let’s use this to examine the score and wtime variables in the wtime data set.

Karnofsky score

Show R code

hodg2 = hodg2 |> 
  mutate(
    mres = 
      hodg.cox1 |> 
      update(. ~ . - score) |> 
      residuals(type="martingale"))

hodg2 |> 
  ggplot(aes(x = score, y = mres)) +
  geom_point() +
  geom_smooth(method = "loess", aes(col = "loess")) +
  geom_smooth(method = 'lm', aes(col = "lm")) +
  theme_classic() +
  xlab("Karnofsky Score") +
  ylab("Martingale Residuals") +
  guides(col=guide_legend(title = ""))

Martingale Residuals vs. Karnofsky Score

The line is almost straight. It could be some modest transformation of the Karnofsky score would help, but it might not make much difference.

Waiting time

Show R code

hodg2$mres = 
  hodg.cox1 |> 
  update(. ~ . - wtime) |> 
  residuals(type="martingale")

hodg2 |> 
  ggplot(aes(x = wtime, y = mres)) +
  geom_point() +
  geom_smooth(method = "loess", aes(col = "loess")) +
  geom_smooth(method = 'lm', aes(col = "lm")) +
  theme_classic() +
  xlab("Waiting Time") +
  ylab("Martingale Residuals") +
  guides(col=guide_legend(title = ""))

The line could suggest a step function. To see where the drop is, we can look at the largest waiting times and the associated martingale residual.

The martingale residuals are all negative for wtime >83 and positive for the next smallest value. A reasonable cut-point is 80 days.

Updating the model

Let’s reformulate the model with dichotomized wtime.

Show R code

hodg2 = 
  hodg2 |> 
  mutate(
    wt2 = cut(
      wtime,c(0, 80, 200),
      labels=c("short","long")))

hodg.cox2 =
  coxph(
    formula = 
      Surv(time, event = delta == "dead") ~ 
      gtype*dtype + score + wt2,
    data = hodg2)

Show R code

hodg.cox1 |> drop1(test="Chisq")

Model summary table with waiting time on continuous scale

Show R code

hodg.cox2 |> drop1(test="Chisq")

Model summary table with dichotomized waiting time

The new model has better (lower) AIC.

7.6 Checking for Outliers and Influential Observations

We will check for outliers using the deviance residuals. The martingale residuals show excess events or the opposite, but highly skewed, with the maximum possible value being 1, but the smallest value can be very large negative. Martingale residuals can detect unexpectedly long-lived patients, but patients who die unexpectedly early show up only in the deviance residual. Influence will be examined using dfbeta in a similar way to linear regression, logistic regression, or Poisson regression.

7.6.1 Deviance Residuals

\[ \begin{aligned} r_i^D &= \textrm{sign}(r_i^M)\sqrt{-2\left[ r_i^M+\delta_i\ln(\delta_i-r_i^M) \right]}\\ r_i^D &= \textrm{sign}(r_i^M)\sqrt{-2\left[ r_i^M+\delta_i\ln(r_i^{CS}) \right]} \end{aligned} \]

Roughly centered on 0 with approximate standard deviation 1.

7.6.2

Show R code

hodg.mart = residuals(hodg.cox2,type="martingale")
hodg.dev = residuals(hodg.cox2,type="deviance")
hodg.dfb = residuals(hodg.cox2,type="dfbeta")
hodg.preds = predict(hodg.cox2)                   #linear predictor

Show R code

plot(hodg.preds,
     hodg.mart,
     xlab="Linear Predictor",
     ylab="Martingale Residual")

Martingale Residuals vs. Linear Predictor

The smallest three martingale residuals in order are observations 1, 29, and 18.

Show R code

plot(hodg.preds,hodg.dev,xlab="Linear Predictor",ylab="Deviance Residual")

The two largest deviance residuals are observations 1 and 29. Worth examining.

7.6.3 dfbeta

dfbeta is the approximate change in the coefficient vector if that observation were dropped
dfbetas is the approximate change in the coefficients, scaled by the standard error for the coefficients.

Graft type

Show R code

plot(hodg.dfb[,1],xlab="Observation Order",ylab="dfbeta for Graft Type")

dfbeta Values by Observation Order for Graft Type

The smallest dfbeta for graft type is observation 1.

Disease type

Show R code

plot(hodg.dfb[,2],
     xlab="Observation Order",
     ylab="dfbeta for Disease Type")

dfbeta Values by Observation Order for Disease Type

The smallest two dfbeta values for disease type are observations 1 and 16.

Karnofsky score

Show R code

plot(hodg.dfb[,3],
     xlab="Observation Order",
     ylab="dfbeta for Karnofsky Score")

dfbeta Values by Observation Order for Karnofsky Score

The two highest dfbeta values for score are observations 1 and 18. The next three are observations 17, 29, and 19. The smallest value is observation 2.

Waiting time (dichotomized)

Show R code

plot(
  hodg.dfb[,4],
  xlab="Observation Order",
  ylab="dfbeta for `Waiting Time < 80`")

dfbeta Values by Observation Order for Waiting Time (dichotomized)

The two large values of dfbeta for dichotomized waiting time are observations 15 and 16. This may have to do with the discretization of waiting time.

Interaction: graft type and disease type

Show R code

plot(hodg.dfb[,5],
     xlab="Observation Order",
     ylab="dfbeta for dtype:gtype")

dfbeta Values by Observation Order for dtype:gtype

The two largest values are observations 1 and 16. The smallest value is observation 35.

Table 7.1: Observations to Examine by Residuals and Influence

Diagnostic	Observations to Examine
Martingale Residuals	1, 29, 18
Deviance Residuals	1, 29
Graft Type Influence	1
Disease Type Influence	1, 16
Karnofsky Score Influence	1, 18 (17, 29, 19)
Waiting Time Influence	15, 16
Graft by Disease Influence	1, 16, 35

The most important observations to examine seem to be 1, 15, 16, 18, and 29.

7.6.4

Show R code

with(hodg,summary(time[delta==1]))
#>    Min. 1st Qu.  Median    Mean 3rd Qu.    Max. 
#>     2.0    41.2    62.5    97.6    83.2   524.0

Show R code

with(hodg,summary(wtime))
#>    Min. 1st Qu.  Median    Mean 3rd Qu.    Max. 
#>     5.0    16.0    24.0    37.7    55.5   171.0

Show R code

with(hodg,summary(score))
#>    Min. 1st Qu.  Median    Mean 3rd Qu.    Max. 
#>    20.0    60.0    80.0    76.3    90.0   100.0

Show R code

hodg.cox2
#> Call:
#> coxph(formula = Surv(time, event = delta == "dead") ~ gtype * 
#>     dtype + score + wt2, data = hodg2)
#> 
#>                                coef exp(coef) se(coef)  z     p
#> gtypeAutologous                0.67      1.94     0.59  1 0.263
#> dtypeHodgkins                  2.33     10.25     0.73  3 0.002
#> score                         -0.06      0.95     0.01 -4 8e-06
#> wt2long                       -2.06      0.13     1.05 -2 0.050
#> gtypeAutologous:dtypeHodgkins -2.07      0.13     0.93 -2 0.026
#> 
#> Likelihood ratio test=35  on 5 df, p=1e-06
#> n= 43, number of events= 26

Show R code

hodg2[c(1,15,16,18,29),] |> 
  select(gtype, dtype, time, delta, score, wtime) |> 
  mutate(
    comment = 
      c(
        "early death, good score, low risk",
        "high risk grp, long wait, poor score",
        "high risk grp, short wait, poor score",
        "early death, good score, med risk grp",
        "early death, good score, med risk grp"
      ))

7.6.5 Action Items

Unusual points may need checking, particularly if the data are not completely cleaned. In this case, observations 15 and 16 may show some trouble with the dichotomization of waiting time, but it still may be useful.
The two largest residuals seem to be due to unexpectedly early deaths, but unfortunately this can occur.
If hazards don’t look proportional, then we may need to use strata, between which the base hazards are permitted to be different. For this problem, the natural strata are the two diseases, because they could need to be managed differently anyway.
A main point that we want to be sure of is the relative risk difference by disease type and graft type.

Show R code

hodg.cox2 |> 
  predict(
    reference = "zero",
    newdata = means |> 
      mutate(
        wt2 = "short", 
        score = 0), 
    type = "lp") |> 
  data.frame('linear predictor' = _) |> 
  pander()

Linear Risk Predictors for Lymphoma
	linear.predictor
Non-Hodgkins,Allogenic	0
Non-Hodgkins,Autologous	0.6651
Hodgkins,Allogenic	2.327
Hodgkins,Autologous	0.9256

For Non-Hodgkin’s, the allogenic graft is better. For Hodgkin’s, the autologous graft is much better.

7.7 Stratified survival models

7.7.1 Revisiting the leukemia dataset (`anderson`)

We will analyze remission survival times on 42 leukemia patients, half on new treatment, half on standard treatment.

This is the same data as the drug6mp data from KMsurv, but with two other variables and without the pairing. This version comes from the Kleinbaum and Klein survival textbook (e.g., p281):

Show R code


anderson = 
  paste0(
    "http://web1.sph.emory.edu/dkleinb/allDatasets/",
    "surv2datasets/anderson.dta") |> 
  haven::read_dta() |> 
  mutate(
    status = status |> 
      case_match(
        1 ~ "relapse",
        0 ~ "censored"
      ),
    
    sex = sex |> 
      case_match(
        0 ~ "female",
        1 ~ "male"
      ) |> 
      factor() |> 
      relevel(ref = "female"),
    
    rx = rx |> 
      case_match(
        0 ~ "new",
        1 ~ "standard"
      ) |> 
      factor() |> relevel(ref = "standard"),
    
    surv = Surv(
      time = survt, 
      event = (status == "relapse"))
  )

print(anderson)

7.7.2 Cox semi-parametric proportional hazards model

Show R code


anderson.cox1 = coxph(
  formula = surv ~ rx + sex + logwbc,
  data = anderson)

summary(anderson.cox1)
#> Call:
#> coxph(formula = surv ~ rx + sex + logwbc, data = anderson)
#> 
#>   n= 42, number of events= 30 
#> 
#>           coef exp(coef) se(coef)     z Pr(>|z|)    
#> rxnew   -1.504     0.222    0.462 -3.26   0.0011 ** 
#> sexmale  0.315     1.370    0.455  0.69   0.4887    
#> logwbc   1.682     5.376    0.337  5.00  5.8e-07 ***
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>         exp(coef) exp(-coef) lower .95 upper .95
#> rxnew       0.222      4.498     0.090     0.549
#> sexmale     1.370      0.730     0.562     3.338
#> logwbc      5.376      0.186     2.779    10.398
#> 
#> Concordance= 0.851  (se = 0.041 )
#> Likelihood ratio test= 47.2  on 3 df,   p=3e-10
#> Wald test            = 33.5  on 3 df,   p=2e-07
#> Score (logrank) test = 48  on 3 df,   p=2e-10

Test the proportional hazards assumption

Show R code

cox.zph(anderson.cox1)
#>        chisq df    p
#> rx     0.036  1 0.85
#> sex    5.420  1 0.02
#> logwbc 0.142  1 0.71
#> GLOBAL 5.879  3 0.12

Graph the K-M survival curves

Show R code


anderson_km_model = survfit(
  formula = surv ~ sex,
  data = anderson)

anderson_km_model |> 
  autoplot(conf.int = FALSE) +
  theme_bw() +
  theme(legend.position="bottom")

The survival curves cross, which indicates a problem in the proportionality assumption by sex.

7.7.3 Graph the Nelson-Aalen cumulative hazard

We can also look at the log-hazard (“cloglog survival”) plots:

Show R code

anderson_na_model = survfit(
  formula = surv ~ sex,
  data = anderson,
  type = "fleming")

anderson_na_model |> 
  autoplot(
    fun = "cumhaz",
    conf.int = FALSE) +
  theme_classic() +
  theme(legend.position="bottom") +
  ylab("log(Cumulative Hazard)") +
  scale_y_continuous(
    trans = "log10",
    name = "Cumulative hazard (H(t), log scale)") +
  scale_x_continuous(
    breaks = c(1,2,5,10,20,50),
    trans = "log"
  )

Cumulative hazard (cloglog scale) for `anderson` data

This can be fixed by using strata or possibly by other model alterations.

7.7.4 The Stratified Cox Model

In a stratified Cox model, each stratum, defined by one or more factors, has its own base survival function \(h_0(t)\).
But the coefficients for each variable not used in the strata definitions are assumed to be the same across strata.
To check if this assumption is reasonable one can include interactions with strata and see if they are significant (this may generate a warning and NA lines but these can be ignored).
Since the sex variable shows possible non-proportionality, we try stratifying on sex.

Show R code


anderson.coxph.strat = 
  coxph(
    formula = 
      surv ~ rx + logwbc + strata(sex),
    data = anderson)

summary(anderson.coxph.strat)
#> Call:
#> coxph(formula = surv ~ rx + logwbc + strata(sex), data = anderson)
#> 
#>   n= 42, number of events= 30 
#> 
#>          coef exp(coef) se(coef)     z Pr(>|z|)    
#> rxnew  -0.998     0.369    0.474 -2.11    0.035 *  
#> logwbc  1.454     4.279    0.344  4.22  2.4e-05 ***
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>        exp(coef) exp(-coef) lower .95 upper .95
#> rxnew      0.369      2.713     0.146     0.932
#> logwbc     4.279      0.234     2.180     8.398
#> 
#> Concordance= 0.812  (se = 0.059 )
#> Likelihood ratio test= 32.1  on 2 df,   p=1e-07
#> Wald test            = 22.8  on 2 df,   p=1e-05
#> Score (logrank) test = 30.8  on 2 df,   p=2e-07

Let’s compare this to a model fit only on the subset of males:

Show R code


anderson.coxph.male = 
  coxph(
    formula = surv ~ rx + logwbc,
    subset = sex == "male",
    data = anderson)

summary(anderson.coxph.male)
#> Call:
#> coxph(formula = surv ~ rx + logwbc, data = anderson, subset = sex == 
#>     "male")
#> 
#>   n= 20, number of events= 14 
#> 
#>          coef exp(coef) se(coef)     z Pr(>|z|)   
#> rxnew  -1.978     0.138    0.739 -2.68   0.0075 **
#> logwbc  1.743     5.713    0.536  3.25   0.0011 **
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>        exp(coef) exp(-coef) lower .95 upper .95
#> rxnew      0.138      7.227    0.0325     0.589
#> logwbc     5.713      0.175    1.9991    16.328
#> 
#> Concordance= 0.905  (se = 0.043 )
#> Likelihood ratio test= 29.2  on 2 df,   p=5e-07
#> Wald test            = 15.3  on 2 df,   p=5e-04
#> Score (logrank) test = 26.4  on 2 df,   p=2e-06

Show R code

anderson.coxph.female = 
  coxph(
    formula = 
      surv ~ rx + logwbc,
    subset = sex == "female",
    data = anderson)

summary(anderson.coxph.female)
#> Call:
#> coxph(formula = surv ~ rx + logwbc, data = anderson, subset = sex == 
#>     "female")
#> 
#>   n= 22, number of events= 16 
#> 
#>          coef exp(coef) se(coef)     z Pr(>|z|)  
#> rxnew  -0.311     0.733    0.564 -0.55    0.581  
#> logwbc  1.206     3.341    0.503  2.40    0.017 *
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>        exp(coef) exp(-coef) lower .95 upper .95
#> rxnew      0.733      1.365     0.243      2.21
#> logwbc     3.341      0.299     1.245      8.96
#> 
#> Concordance= 0.692  (se = 0.085 )
#> Likelihood ratio test= 6.65  on 2 df,   p=0.04
#> Wald test            = 6.36  on 2 df,   p=0.04
#> Score (logrank) test = 6.74  on 2 df,   p=0.03

The coefficients of treatment look different. Are they statistically different?

Show R code


anderson.coxph.strat.intxn = 
  coxph(
    formula = surv ~ strata(sex) * (rx + logwbc),
    data = anderson)

anderson.coxph.strat.intxn |> summary()
#> Call:
#> coxph(formula = surv ~ strata(sex) * (rx + logwbc), data = anderson)
#> 
#>   n= 42, number of events= 30 
#> 
#>                          coef exp(coef) se(coef)     z Pr(>|z|)  
#> rxnew                  -0.311     0.733    0.564 -0.55    0.581  
#> logwbc                  1.206     3.341    0.503  2.40    0.017 *
#> strata(sex)male:rxnew  -1.667     0.189    0.930 -1.79    0.073 .
#> strata(sex)male:logwbc  0.537     1.710    0.735  0.73    0.465  
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                        exp(coef) exp(-coef) lower .95 upper .95
#> rxnew                      0.733      1.365    0.2427      2.21
#> logwbc                     3.341      0.299    1.2452      8.96
#> strata(sex)male:rxnew      0.189      5.294    0.0305      1.17
#> strata(sex)male:logwbc     1.710      0.585    0.4048      7.23
#> 
#> Concordance= 0.797  (se = 0.058 )
#> Likelihood ratio test= 35.8  on 4 df,   p=3e-07
#> Wald test            = 21.7  on 4 df,   p=2e-04
#> Score (logrank) test = 33.1  on 4 df,   p=1e-06

Show R code

anova(
  anderson.coxph.strat.intxn,
  anderson.coxph.strat)

We don’t have enough evidence to tell the difference between these two models.

7.7.5 Conclusions

We chose to use a stratified model because of the apparent non-proportionality of the hazard for the sex variable.
When we fit interactions with the strata variable, we did not get an improved model (via the likelihood ratio test).
So we use the stratifed model with coefficients that are the same across strata.

7.7.6 Another Modeling Approach

We used an additive model without interactions and saw that we might need to stratify by sex.
Instead, we could try to improve the model’s functional form - maybe the interaction of treatment and sex is real, and after fitting that we might not need separate hazard functions.
Either approach may work.

Show R code


anderson.coxph.intxn = 
  coxph(
    formula = surv ~ (rx + logwbc) * sex,
    data = anderson)

anderson.coxph.intxn |> summary()
#> Call:
#> coxph(formula = surv ~ (rx + logwbc) * sex, data = anderson)
#> 
#>   n= 42, number of events= 30 
#> 
#>                   coef exp(coef) se(coef)     z Pr(>|z|)  
#> rxnew          -0.3748    0.6874   0.5545 -0.68    0.499  
#> logwbc          1.0637    2.8971   0.4726  2.25    0.024 *
#> sexmale        -2.8052    0.0605   2.0323 -1.38    0.167  
#> rxnew:sexmale  -2.1782    0.1132   0.9109 -2.39    0.017 *
#> logwbc:sexmale  1.2303    3.4223   0.6301  1.95    0.051 .
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                exp(coef) exp(-coef) lower .95 upper .95
#> rxnew             0.6874      1.455   0.23185     2.038
#> logwbc            2.8971      0.345   1.14730     7.315
#> sexmale           0.0605     16.531   0.00113     3.248
#> rxnew:sexmale     0.1132      8.830   0.01899     0.675
#> logwbc:sexmale    3.4223      0.292   0.99539    11.766
#> 
#> Concordance= 0.861  (se = 0.036 )
#> Likelihood ratio test= 57  on 5 df,   p=5e-11
#> Wald test            = 35.6  on 5 df,   p=1e-06
#> Score (logrank) test = 57.1  on 5 df,   p=5e-11

Show R code

cox.zph(anderson.coxph.intxn)
#>            chisq df    p
#> rx         0.136  1 0.71
#> logwbc     1.652  1 0.20
#> sex        1.266  1 0.26
#> rx:sex     0.149  1 0.70
#> logwbc:sex 0.102  1 0.75
#> GLOBAL     3.747  5 0.59

7.8 Time-varying covariates

(adapted from Klein, Moeschberger, et al. (2003), §9.2)

7.8.1 Motivating example: back to the leukemia dataset

# load the data:
data(bmt, package = 'KMsurv')
bmt |> as_tibble() |> print(n = 5)
#> # A tibble: 137 × 22
#>   group    t1    t2    d1    d2    d3    ta    da    tc    dc    tp    dp    z1
#>   <int> <int> <int> <int> <int> <int> <int> <int> <int> <int> <int> <int> <int>
#> 1     1  2081  2081     0     0     0    67     1   121     1    13     1    26
#> 2     1  1602  1602     0     0     0  1602     0   139     1    18     1    21
#> 3     1  1496  1496     0     0     0  1496     0   307     1    12     1    26
#> 4     1  1462  1462     0     0     0    70     1    95     1    13     1    17
#> 5     1  1433  1433     0     0     0  1433     0   236     1    12     1    32
#> # ℹ 132 more rows
#> # ℹ 9 more variables: z2 <int>, z3 <int>, z4 <int>, z5 <int>, z6 <int>,
#> #   z7 <int>, z8 <int>, z9 <int>, z10 <int>

This dataset comes from the Copelan et al. (1991) study of allogenic bone marrow transplant therapy for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Outcomes (endpoints)

The main endpoint is disease-free survival (t2 and d3) for the three risk groups, “ALL”, “AML Low Risk”, and “AML High Risk”.

Possible intermediate events

graft vs. host disease (GVHD), an immunological rejection response to the transplant (bad)
acute (AGVHD)
chronic (CGVHD)
platelet recovery, a return of platelet count to normal levels (good)

One or the other, both in either order, or neither may occur.

Covariates

We are interested in possibly using the covariates z1-z10 to adjust for other factors.
In addition, the time-varying covariates for acute GVHD, chronic GVHD, and platelet recovery may be useful.

Preprocessing

We reformat the data before analysis:

Show R code

# reformat the data:
bmt1 = 
  bmt |> 
  as_tibble() |> 
  mutate(
    id = 1:n(), # will be used to connect multiple records for the same individual
    
    group =  group |> 
      case_match(
        1 ~ "ALL",
        2 ~ "Low Risk AML",
        3 ~ "High Risk AML") |> 
      factor(levels = c("ALL", "Low Risk AML", "High Risk AML")),
    
    `patient age` = z1,
    
    `donor age` = z2,
    
    `patient sex` = z3 |> 
      case_match(
        0 ~ "Female",
        1 ~ "Male"),
    
    `donor sex` = z4 |> 
      case_match(
        0 ~ "Female",
        1 ~ "Male"),
    
    `Patient CMV Status` = z5 |> 
      case_match(
        0 ~ "CMV Negative",
        1 ~ "CMV Positive"),
    
    `Donor CMV Status` = z6 |> 
      case_match(
        0 ~ "CMV Negative",
        1 ~ "CMV Positive"),
    
    `Waiting Time to Transplant` = z7,
    
    FAB = z8 |> 
      case_match(
        1 ~ "Grade 4 Or 5 (AML only)",
        0 ~ "Other") |> 
      factor() |> 
      relevel(ref = "Other"),
    
    hospital = z9 |>  # `z9` is hospital
      case_match(
        1 ~ "Ohio State University",
        2 ~ "Alferd",
        3 ~ "St. Vincent",
        4 ~ "Hahnemann") |> 
      factor() |> 
      relevel(ref = "Ohio State University"),
    
    MTX = (z10 == 1) # a prophylatic treatment for GVHD
    
  ) |> 
  select(-(z1:z10)) # don't need these anymore

bmt1 |> 
  select(group, id:MTX) |> 
  print(n = 10)
#> # A tibble: 137 × 12
#>    group    id `patient age` `donor age` `patient sex` `donor sex`
#>    <fct> <int>         <int>       <int> <chr>         <chr>      
#>  1 ALL       1            26          33 Male          Female     
#>  2 ALL       2            21          37 Male          Male       
#>  3 ALL       3            26          35 Male          Male       
#>  4 ALL       4            17          21 Female        Male       
#>  5 ALL       5            32          36 Male          Male       
#>  6 ALL       6            22          31 Male          Male       
#>  7 ALL       7            20          17 Male          Female     
#>  8 ALL       8            22          24 Male          Female     
#>  9 ALL       9            18          21 Female        Male       
#> 10 ALL      10            24          40 Male          Male       
#> # ℹ 127 more rows
#> # ℹ 6 more variables: `Patient CMV Status` <chr>, `Donor CMV Status` <chr>,
#> #   `Waiting Time to Transplant` <int>, FAB <fct>, hospital <fct>, MTX <lgl>

7.8.2 Time-Dependent Covariates

A time-dependent covariate (“TDC”) is a covariate whose value changes during the course of the study.
For variables like age that change in a linear manner with time, we can just use the value at the start.
But it may be plausible that when and if GVHD occurs, the risk of relapse or death increases, and when and if platelet recovery occurs, the risk decreases.

7.8.3 Analysis in R

We form a variable precovery which is = 0 before platelet recovery and is = 1 after platelet recovery, if it occurs.
For each subject where platelet recovery occurs, we set up multiple records (lines in the data frame); for example one from t = 0 to the time of platelet recovery, and one from that time to relapse, recovery, or death.
We do the same for acute GVHD and chronic GVHD.
For each record, the covariates are constant.

Show R code


bmt2 = bmt1 |> 
  #set up new long-format data set:
  tmerge(bmt1, id = id, tstop = t2) |> 
  
  # the following three steps can be in any order, 
  # and will still produce the same result:
  #add aghvd as tdc:
  tmerge(bmt1, id = id, agvhd = tdc(ta)) |> 
  #add cghvd as tdc:
  tmerge(bmt1, id = id, cgvhd = tdc(tc)) |> 
  #add platelet recovery as tdc:
  tmerge(bmt1, id = id, precovery = tdc(tp))   

bmt2 = bmt2 |> 
  as_tibble() |> 
  mutate(status = as.numeric((tstop == t2) & d3))
# status only = 1 if at end of t2 and not censored

Let’s see how we’ve rearranged the first row of the data:

Show R code


bmt1 |> 
  dplyr::filter(id == 1) |> 
  dplyr::select(id, t1, d1, t2, d2, d3, ta, da, tc, dc, tp, dp)

The event times for this individual are:

t = 0 time of transplant
tp = 13 platelet recovery
ta = 67 acute GVHD onset
tc = 121 chronic GVHD onset
t2 = 2081 end of study, patient not relapsed or dead

After converting the data to long-format, we have:

Show R code

bmt2 |> 
  select(
    id,
    tstart,
    tstop,
    agvhd,
    cgvhd,
    precovery,
    status
  ) |> 
  dplyr::filter(id == 1)

Note that status could have been 1 on the last row, indicating that relapse or death occurred; since it is false, the participant must have exited the study without experiencing relapse or death (i.e., they were censored).

7.8.4 Event sequences

Let:

A = acute GVHD
C = chronic GVHD
P = platelet recovery

Each of the eight possible combinations of A or not-A, with C or not-C, with P or not-P occurs in this data set.

A always occurs before C, and P always occurs before C, if both occur.
Thus there are ten event sequences in the data set: None, A, C, P, AC, AP, PA, PC, APC, and PAC.
In general, there could be as many as \(1+3+(3)(2)+6=16\) sequences, but our domain knowledge tells us that some are missing: CA, CP, CAP, CPA, PCA, PC, PAC
Different subjects could have 1, 2, 3, or 4 intervals, depending on which of acute GVHD, chronic GVHD, and/or platelet recovery occurred.
The final interval for any subject has status = 1 if the subject relapsed or died at that time; otherwise status = 0.
Any earlier intervals have status = 0.
Even though there might be multiple lines per ID in the dataset, there is never more than one event, so no alterations need be made in the estimation procedures or in the interpretation of the output.
The function tmerge in the survival package eases the process of constructing the new long-format dataset.

7.8.5 Model with Time-Fixed Covariates

Show R code

bmt1 = 
  bmt1 |> 
  mutate(surv = Surv(t2,d3))

bmt_coxph_TF = coxph(
  formula = surv ~ group + `patient age`*`donor age` + FAB,
  data = bmt1)
summary(bmt_coxph_TF)
#> Call:
#> coxph(formula = surv ~ group + `patient age` * `donor age` + 
#>     FAB, data = bmt1)
#> 
#>   n= 137, number of events= 83 
#> 
#>                                 coef exp(coef)  se(coef)     z Pr(>|z|)    
#> groupLow Risk AML          -1.090648  0.335999  0.354279 -3.08  0.00208 ** 
#> groupHigh Risk AML         -0.403905  0.667707  0.362777 -1.11  0.26555    
#> `patient age`              -0.081639  0.921605  0.036107 -2.26  0.02376 *  
#> `donor age`                -0.084587  0.918892  0.030097 -2.81  0.00495 ** 
#> FABGrade 4 Or 5 (AML only)  0.837416  2.310388  0.278464  3.01  0.00264 ** 
#> `patient age`:`donor age`   0.003159  1.003164  0.000951  3.32  0.00089 ***
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                            exp(coef) exp(-coef) lower .95 upper .95
#> groupLow Risk AML              0.336      2.976     0.168     0.673
#> groupHigh Risk AML             0.668      1.498     0.328     1.360
#> `patient age`                  0.922      1.085     0.859     0.989
#> `donor age`                    0.919      1.088     0.866     0.975
#> FABGrade 4 Or 5 (AML only)     2.310      0.433     1.339     3.988
#> `patient age`:`donor age`      1.003      0.997     1.001     1.005
#> 
#> Concordance= 0.665  (se = 0.033 )
#> Likelihood ratio test= 32.8  on 6 df,   p=1e-05
#> Wald test            = 33  on 6 df,   p=1e-05
#> Score (logrank) test = 35.8  on 6 df,   p=3e-06
drop1(bmt_coxph_TF, test = "Chisq")

Show R code

bmt1$mres = 
  bmt_coxph_TF |> 
  update(. ~ . - `donor age`) |> 
  residuals(type="martingale")

bmt1 |> 
  ggplot(aes(x = `donor age`, y = mres)) +
  geom_point() +
  geom_smooth(method = "loess", aes(col = "loess")) +
  geom_smooth(method = 'lm', aes(col = "lm")) +
  theme_classic() +
  xlab("Donor age") +
  ylab("Martingale Residuals") +
  guides(col=guide_legend(title = ""))

A more complex functional form for donor age seems warranted; left as an exercise for the reader.

Now we will add the time-varying covariates:

Show R code


# add counting process formulation of Surv():
bmt2 = 
  bmt2 |> 
  mutate(
    surv = 
      Surv(
        time = tstart,
        time2 = tstop,
        event = status,
        type = "counting"))

Let’s see how the data looks for patient 15:

Show R code

bmt1 |> dplyr::filter(id == 15) |> dplyr::select(tp, dp, tc,dc, ta, da, FAB, surv, t1, d1, t2, d2, d3)

Show R code

bmt2 |> dplyr::filter(id == 15) |> dplyr::select(id, agvhd, cgvhd, precovery, surv)

7.8.6 Model with Time-Dependent Covariates

Show R code

bmt_coxph_TV = coxph(
  formula = 
    surv ~ 
    group + `patient age`*`donor age` + FAB + agvhd + cgvhd + precovery,
  data = bmt2)

summary(bmt_coxph_TV)
#> Call:
#> coxph(formula = surv ~ group + `patient age` * `donor age` + 
#>     FAB + agvhd + cgvhd + precovery, data = bmt2)
#> 
#>   n= 341, number of events= 83 
#> 
#>                                 coef exp(coef)  se(coef)     z Pr(>|z|)   
#> groupLow Risk AML          -1.038514  0.353980  0.358220 -2.90   0.0037 **
#> groupHigh Risk AML         -0.380481  0.683533  0.374867 -1.01   0.3101   
#> `patient age`              -0.073351  0.929275  0.035956 -2.04   0.0413 * 
#> `donor age`                -0.076406  0.926440  0.030196 -2.53   0.0114 * 
#> FABGrade 4 Or 5 (AML only)  0.805700  2.238263  0.284273  2.83   0.0046 **
#> agvhd                       0.150565  1.162491  0.306848  0.49   0.6237   
#> cgvhd                      -0.116136  0.890354  0.289046 -0.40   0.6878   
#> precovery                  -0.941123  0.390190  0.347861 -2.71   0.0068 **
#> `patient age`:`donor age`   0.002895  1.002899  0.000944  3.07   0.0022 **
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                            exp(coef) exp(-coef) lower .95 upper .95
#> groupLow Risk AML              0.354      2.825     0.175     0.714
#> groupHigh Risk AML             0.684      1.463     0.328     1.425
#> `patient age`                  0.929      1.076     0.866     0.997
#> `donor age`                    0.926      1.079     0.873     0.983
#> FABGrade 4 Or 5 (AML only)     2.238      0.447     1.282     3.907
#> agvhd                          1.162      0.860     0.637     2.121
#> cgvhd                          0.890      1.123     0.505     1.569
#> precovery                      0.390      2.563     0.197     0.772
#> `patient age`:`donor age`      1.003      0.997     1.001     1.005
#> 
#> Concordance= 0.702  (se = 0.028 )
#> Likelihood ratio test= 40.3  on 9 df,   p=7e-06
#> Wald test            = 42.4  on 9 df,   p=3e-06
#> Score (logrank) test = 47.2  on 9 df,   p=4e-07

Platelet recovery is highly significant.

Neither acute GVHD (agvhd) nor chronic GVHD (cgvhd) has a statistically significant effect here, nor are they significant in models with the other one removed.

Show R code


update(bmt_coxph_TV, .~.-agvhd) |> summary()
#> Call:
#> coxph(formula = surv ~ group + `patient age` + `donor age` + 
#>     FAB + cgvhd + precovery + `patient age`:`donor age`, data = bmt2)
#> 
#>   n= 341, number of events= 83 
#> 
#>                                 coef exp(coef)  se(coef)     z Pr(>|z|)   
#> groupLow Risk AML          -1.049870  0.349983  0.356727 -2.94   0.0032 **
#> groupHigh Risk AML         -0.417049  0.658988  0.365348 -1.14   0.2537   
#> `patient age`              -0.070749  0.931696  0.035477 -1.99   0.0461 * 
#> `donor age`                -0.075693  0.927101  0.030075 -2.52   0.0118 * 
#> FABGrade 4 Or 5 (AML only)  0.807035  2.241253  0.283437  2.85   0.0044 **
#> cgvhd                      -0.095393  0.909015  0.285979 -0.33   0.7387   
#> precovery                  -0.983653  0.373942  0.338170 -2.91   0.0036 **
#> `patient age`:`donor age`   0.002859  1.002863  0.000936  3.05   0.0023 **
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                            exp(coef) exp(-coef) lower .95 upper .95
#> groupLow Risk AML              0.350      2.857     0.174     0.704
#> groupHigh Risk AML             0.659      1.517     0.322     1.349
#> `patient age`                  0.932      1.073     0.869     0.999
#> `donor age`                    0.927      1.079     0.874     0.983
#> FABGrade 4 Or 5 (AML only)     2.241      0.446     1.286     3.906
#> cgvhd                          0.909      1.100     0.519     1.592
#> precovery                      0.374      2.674     0.193     0.726
#> `patient age`:`donor age`      1.003      0.997     1.001     1.005
#> 
#> Concordance= 0.701  (se = 0.027 )
#> Likelihood ratio test= 40  on 8 df,   p=3e-06
#> Wald test            = 42.4  on 8 df,   p=1e-06
#> Score (logrank) test = 47.2  on 8 df,   p=1e-07
update(bmt_coxph_TV, .~.-cgvhd) |> summary()
#> Call:
#> coxph(formula = surv ~ group + `patient age` + `donor age` + 
#>     FAB + agvhd + precovery + `patient age`:`donor age`, data = bmt2)
#> 
#>   n= 341, number of events= 83 
#> 
#>                                 coef exp(coef)  se(coef)     z Pr(>|z|)   
#> groupLow Risk AML          -1.019638  0.360725  0.355311 -2.87   0.0041 **
#> groupHigh Risk AML         -0.381356  0.682935  0.374568 -1.02   0.3086   
#> `patient age`              -0.073189  0.929426  0.035890 -2.04   0.0414 * 
#> `donor age`                -0.076753  0.926118  0.030121 -2.55   0.0108 * 
#> FABGrade 4 Or 5 (AML only)  0.811716  2.251769  0.284012  2.86   0.0043 **
#> agvhd                       0.131621  1.140676  0.302623  0.43   0.6636   
#> precovery                  -0.946697  0.388021  0.347265 -2.73   0.0064 **
#> `patient age`:`donor age`   0.002904  1.002908  0.000943  3.08   0.0021 **
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                            exp(coef) exp(-coef) lower .95 upper .95
#> groupLow Risk AML              0.361      2.772     0.180     0.724
#> groupHigh Risk AML             0.683      1.464     0.328     1.423
#> `patient age`                  0.929      1.076     0.866     0.997
#> `donor age`                    0.926      1.080     0.873     0.982
#> FABGrade 4 Or 5 (AML only)     2.252      0.444     1.291     3.929
#> agvhd                          1.141      0.877     0.630     2.064
#> precovery                      0.388      2.577     0.196     0.766
#> `patient age`:`donor age`      1.003      0.997     1.001     1.005
#> 
#> Concordance= 0.701  (se = 0.027 )
#> Likelihood ratio test= 40.1  on 8 df,   p=3e-06
#> Wald test            = 42.1  on 8 df,   p=1e-06
#> Score (logrank) test = 47.1  on 8 df,   p=1e-07

Let’s drop them both:

Show R code

bmt_coxph_TV2 = update(bmt_coxph_TV, . ~ . - agvhd -cgvhd)
bmt_coxph_TV2 |> summary()
#> Call:
#> coxph(formula = surv ~ group + `patient age` + `donor age` + 
#>     FAB + precovery + `patient age`:`donor age`, data = bmt2)
#> 
#>   n= 341, number of events= 83 
#> 
#>                                 coef exp(coef)  se(coef)     z Pr(>|z|)   
#> groupLow Risk AML          -1.032520  0.356108  0.353202 -2.92   0.0035 **
#> groupHigh Risk AML         -0.413888  0.661075  0.365209 -1.13   0.2571   
#> `patient age`              -0.070965  0.931495  0.035453 -2.00   0.0453 * 
#> `donor age`                -0.076052  0.926768  0.030007 -2.53   0.0113 * 
#> FABGrade 4 Or 5 (AML only)  0.811926  2.252242  0.283231  2.87   0.0041 **
#> precovery                  -0.983505  0.373998  0.337997 -2.91   0.0036 **
#> `patient age`:`donor age`   0.002872  1.002876  0.000936  3.07   0.0021 **
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>                            exp(coef) exp(-coef) lower .95 upper .95
#> groupLow Risk AML              0.356      2.808     0.178     0.712
#> groupHigh Risk AML             0.661      1.513     0.323     1.352
#> `patient age`                  0.931      1.074     0.869     0.999
#> `donor age`                    0.927      1.079     0.874     0.983
#> FABGrade 4 Or 5 (AML only)     2.252      0.444     1.293     3.924
#> precovery                      0.374      2.674     0.193     0.725
#> `patient age`:`donor age`      1.003      0.997     1.001     1.005
#> 
#> Concordance= 0.7  (se = 0.027 )
#> Likelihood ratio test= 39.9  on 7 df,   p=1e-06
#> Wald test            = 42.2  on 7 df,   p=5e-07
#> Score (logrank) test = 47.1  on 7 df,   p=5e-08

7.9 Recurrent Events

(Adapted from Kleinbaum and Klein, Ch 8)

Sometimes an appropriate analysis requires consideration of recurrent events.
A patient with arthritis may have more than one flareup. The same is true of many recurring-remitting diseases.
In this case, we have more than one line in the data frame, but each line may have an event.
We have to use a “robust” variance estimator to account for correlation of time-to-events within a patient.

7.9.1 Bladder Cancer Data Set

The bladder cancer dataset from Kleinbaum and Klein contains recurrent event outcome information for eighty-six cancer patients followed for the recurrence of bladder cancer tumor after transurethral surgical excision (Byar and Green 1980). The exposure of interest is the effect of the drug treatment of thiotepa. Control variables are the initial number and initial size of tumors. The data layout is suitable for a counting processes approach.

This drug is still a possible choice for some patients. Another therapeutic choice is Bacillus Calmette-Guerin (BCG), a live bacterium related to cow tuberculosis.

Data dictionary

Variables in the `bladder` dataset
Variable	Definition
`id`	Patient unique ID
`status`	for each time interval: 1 = recurred, 0 = censored
`interval`	1 = first recurrence, etc.
`intime`	``tstop - tstart` (all times in months)
`tstart`	start of interval
`tstop`	end of interval
`tx`	treatment code, 1 = thiotepa
`num`	number of initial tumors
`size`	size of initial tumors (cm)

There are 85 patients and 190 lines in the dataset, meaning that many patients have more than one line.
Patient 1 with 0 observation time was removed.
Of the 85 patients, 47 had at least one recurrence and 38 had none.
18 patients had exactly one recurrence.
There were up to 4 recurrences in a patient.
Of the 190 intervals, 112 terminated with a recurrence and 78 were censored.

Different intervals for the same patient are correlated.

Is the effective sample size 47 or 112? This might narrow confidence intervals by as much as a factor of \(\sqrt{112/47}=1.54\)
What happens if I have 5 treatment and 5 control values and want to do a t-test and I then duplicate the 10 values as if the sample size was 20? This falsely narrows confidence intervals by a factor of \(\sqrt{2}=1.41\).

Show R code

bladder = 
  paste0(
    "http://web1.sph.emory.edu/dkleinb/allDatasets",
    "/surv2datasets/bladder.dta") |> 
  read_dta() |> 
  as_tibble()

bladder = bladder[-1,]  #remove subject with 0 observation time
print(bladder)

Show R code


bladder = 
  bladder |> 
  mutate(
    surv = 
      Surv(
        time = start,
        time2 = stop,
        event = event,
        type = "counting"))

bladder.cox1 = coxph(
  formula = surv~tx+num+size,
  data = bladder)

#results with biased variance-covariance matrix:
summary(bladder.cox1)
#> Call:
#> coxph(formula = surv ~ tx + num + size, data = bladder)
#> 
#>   n= 190, number of events= 112 
#> 
#>         coef exp(coef) se(coef)     z Pr(>|z|)    
#> tx   -0.4116    0.6626   0.1999 -2.06  0.03947 *  
#> num   0.1637    1.1778   0.0478  3.43  0.00061 ***
#> size -0.0411    0.9598   0.0703 -0.58  0.55897    
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>      exp(coef) exp(-coef) lower .95 upper .95
#> tx       0.663      1.509     0.448      0.98
#> num      1.178      0.849     1.073      1.29
#> size     0.960      1.042     0.836      1.10
#> 
#> Concordance= 0.624  (se = 0.032 )
#> Likelihood ratio test= 14.7  on 3 df,   p=0.002
#> Wald test            = 15.9  on 3 df,   p=0.001
#> Score (logrank) test = 16.2  on 3 df,   p=0.001

Note

The likelihood ratio and score tests assume independence of observations within a cluster. The Wald and robust score tests do not.

adding `cluster = id`

If we add cluster= id to the call to coxph, the coefficient estimates don’t change, but we get an additional column in the summary() output: robust se:

Show R code


bladder.cox2 = coxph(
  formula = surv ~ tx + num + size,
  cluster = id,
  data = bladder)

#unbiased though this reduces power:
summary(bladder.cox2)
#> Call:
#> coxph(formula = surv ~ tx + num + size, data = bladder, cluster = id)
#> 
#>   n= 190, number of events= 112 
#> 
#>         coef exp(coef) se(coef) robust se     z Pr(>|z|)   
#> tx   -0.4116    0.6626   0.1999    0.2488 -1.65   0.0980 . 
#> num   0.1637    1.1778   0.0478    0.0584  2.80   0.0051 **
#> size -0.0411    0.9598   0.0703    0.0742 -0.55   0.5799   
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>      exp(coef) exp(-coef) lower .95 upper .95
#> tx       0.663      1.509     0.407      1.08
#> num      1.178      0.849     1.050      1.32
#> size     0.960      1.042     0.830      1.11
#> 
#> Concordance= 0.624  (se = 0.031 )
#> Likelihood ratio test= 14.7  on 3 df,   p=0.002
#> Wald test            = 11.2  on 3 df,   p=0.01
#> Score (logrank) test = 16.2  on 3 df,   p=0.001,   Robust = 10.8  p=0.01
#> 
#>   (Note: the likelihood ratio and score tests assume independence of
#>      observations within a cluster, the Wald and robust score tests do not).

robust se is larger than se, and accounts for the repeated observations from the same individuals:

Show R code

round(bladder.cox2$naive.var, 4)
#>         [,1]    [,2]   [,3]
#> [1,]  0.0400 -0.0014 0.0000
#> [2,] -0.0014  0.0023 0.0007
#> [3,]  0.0000  0.0007 0.0049
round(bladder.cox2$var, 4)
#>         [,1]    [,2]    [,3]
#> [1,]  0.0619 -0.0026 -0.0004
#> [2,] -0.0026  0.0034  0.0013
#> [3,] -0.0004  0.0013  0.0055

These are the ratios of correct confidence intervals to naive ones:

Show R code

with(bladder.cox2, diag(var)/diag(naive.var)) |> sqrt()
#> [1] 1.244 1.223 1.056

We might try dropping the non-significant size variable:

Show R code

#remove non-significant size variable:
bladder.cox3 = bladder.cox2 |> update(. ~ . - size)
summary(bladder.cox3)
#> Call:
#> coxph(formula = surv ~ tx + num, data = bladder, cluster = id)
#> 
#>   n= 190, number of events= 112 
#> 
#>        coef exp(coef) se(coef) robust se     z Pr(>|z|)   
#> tx  -0.4117    0.6625   0.2003    0.2515 -1.64   0.1017   
#> num  0.1700    1.1853   0.0465    0.0564  3.02   0.0026 **
#> ---
#> Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
#> 
#>     exp(coef) exp(-coef) lower .95 upper .95
#> tx      0.663      1.509     0.405      1.08
#> num     1.185      0.844     1.061      1.32
#> 
#> Concordance= 0.623  (se = 0.031 )
#> Likelihood ratio test= 14.3  on 2 df,   p=8e-04
#> Wald test            = 10.2  on 2 df,   p=0.006
#> Score (logrank) test = 15.8  on 2 df,   p=4e-04,   Robust = 10.6  p=0.005
#> 
#>   (Note: the likelihood ratio and score tests assume independence of
#>      observations within a cluster, the Wald and robust score tests do not).

7.10 Age as the time scale

See Canchola et al. (2003).

Configuring R

7.1 Building Cox Proportional Hazards models

7.1.1 hodg Lymphoma Data Set from KMsurv

Participants

Variables

Data

7.1.2 Proportional hazards model

7.2 Diagnostic graphs for proportional hazards assumption

7.2.1 Analysis plan

7.2.2 Kaplan-Meier survival functions

7.2.3 Observed and expected survival curves

7.2.4 Cumulative hazard (log-scale) curves

7.3 Predictions and Residuals

7.3.1 Review: Predictions in Linear Regression

7.3.2 Review: Residuals in Linear Regression

7.3.3 Predictions and Residuals in survival models

7.3.4 Wide prediction intervals

7.3.5 Types of Residuals in Time-to-Event Models

7.3.6 Schoenfeld residuals

gtype

dtype

score

wtime

gtype:dtype

Conclusions

7.4 Goodness of Fit using the Cox-Snell Residuals

7.5 Martingale Residuals

7.5.1 Using Martingale Residuals

Karnofsky score

Waiting time

Updating the model

7.6 Checking for Outliers and Influential Observations

7.6.1 Deviance Residuals

7.6.2

7.6.3 dfbeta

Graft type

Disease type

Karnofsky score

Waiting time (dichotomized)

Interaction: graft type and disease type

7.6.4

7.6.5 Action Items

7.7 Stratified survival models

7.7.1 Revisiting the leukemia dataset (anderson)

7.7.2 Cox semi-parametric proportional hazards model

Test the proportional hazards assumption

Graph the K-M survival curves

7.7.3 Graph the Nelson-Aalen cumulative hazard

7.7.4 The Stratified Cox Model

7.7.5 Conclusions

7.7.6 Another Modeling Approach

7.8 Time-varying covariates

7.8.1 Motivating example: back to the leukemia dataset

Outcomes (endpoints)

Possible intermediate events

Covariates

Preprocessing

7.8.2 Time-Dependent Covariates

7.8.3 Analysis in R

7.8.4 Event sequences

7.8.5 Model with Time-Fixed Covariates

7.8.6 Model with Time-Dependent Covariates

7.9 Recurrent Events

7.9.1 Bladder Cancer Data Set

Data dictionary

Different intervals for the same patient are correlated.

adding cluster = id

7.10 Age as the time scale

7.1.1 `hodg` Lymphoma Data Set from `KMsurv`

`gtype`

`dtype`

`score`

`wtime`

`gtype:dtype`

7.7.1 Revisiting the leukemia dataset (`anderson`)

adding `cluster = id`