21 Case Study in Cox Regression

Note that all the analyses presented here may be done in a more general context - see Chapter 25

21.1 Choosing the Number of Parameters and Fitting the Model

Clinical trial of estrogen for prostate cancer
Response is time to death, all causes
Base analysis on Cox proportional hazards model (Cox, 1972)
$S(t | X)$ = probability of surviving at least to time $t$ given set of predictor values $X$
$S(t | X) = S_{0}(t)^{\exp(X\beta)}$
Censor time to death at time of last follow-up for patients still alive at end of study (treat survival time for pt.
censored at 24m as 24m+)
Use simple, partial approaches to data reduction
Use transcan for single imputation
Again combine last 2 categories for ekg,pf
See if we can use a full additive model (4 knots for continuous $X$)

Predictor	Name	d.f.	Original Levels
Dose of estrogen	`rx`	3	placebo, 0.2, 1.0, 5.0 mg estrogen
Age in years	`age`	3
Weight index: wt(kg)-ht(cm)+200	`wt`	3
Performance rating	`pf`	2	normal, in bed <50% of time, in bed >50%, in bed always
History of cardiovascular disease	`hx`	1	present/absent
Systolic blood pressure/10	`sbp`	3
Diastolic blood pressure/10	`dbp`	3
Electrocardiogram code	`ekg`	5	normal, benign, rhythm disturb., block, strain, old myocardial infarction, new MI
Serum hemoglobin (g/100ml)	`hg`	3
Tumor size (cm$^2$)	`sz`	3
Stage/histologic grade combination	`sg`	3
Serum prostatic acid phosphatase	`ap`	3
Bone metastasis	`bm`	1	present/absent

Total of 36 candidate d.f.
Impute missings and estimate shrinkage

Code

require(rms)
options(prType='html')    # for print, summary, anova, validate
getHdata(prostate)
levels(prostate$ekg)[levels(prostate$ekg) %in%
                     c('old MI','recent MI')] <- 'MI'
# combines last 2 levels and uses a new name, MI

prostate$pf.coded <- as.integer(prostate$pf)
# save original pf, re-code to 1-4
levels(prostate$pf)  <- c(levels(prostate$pf)[1:3],
                          levels(prostate$pf)[3])
# combine last 2 levels

w <- transcan(~ sz + sg + ap + sbp + dbp + age +
              wt + hg + ekg + pf + bm + hx,
              imputed=TRUE, data=prostate, pl=FALSE, pr=FALSE)

attach(prostate)
sz  <- impute(w, sz, data=prostate)
sg  <- impute(w, sg, data=prostate)
age <- impute(w, age,data=prostate)
wt  <- impute(w, wt, data=prostate)
ekg <- impute(w, ekg,data=prostate)

dd <- datadist(prostate)
options(datadist='dd')

units(dtime) <- 'Month'
S <- Surv(dtime, status!='alive')

f <- cph(S ~ rx + rcs(age,4) + rcs(wt,4) + pf + hx +
         rcs(sbp,4) + rcs(dbp,4) + ekg + rcs(hg,4) +
         rcs(sg,4) + rcs(sz,4) + rcs(log(ap),4) + bm)
print(f, coefs=FALSE)

Cox Proportional Hazards Model

cph(formula = S ~ rx + rcs(age, 4) + rcs(wt, 4) + pf + hx + rcs(sbp, 
    4) + rcs(dbp, 4) + ekg + rcs(hg, 4) + rcs(sg, 4) + rcs(sz, 
    4) + rcs(log(ap), 4) + bm)

	Model Tests	Discrimination Indexes
Obs 502	LR χ² 136.22	R² 0.238
Events 354	d.f. 36	R²_36,502 0.181
Center -2.9933	Pr(>χ²) 0.0000	R²_36,354 0.247
	Score χ² 143.62	D_xy 0.333
	Pr(>χ²) 0.0000

Global LR $\chi^2$ is 135 and very significant $\rightarrow$ modeling warranted
AIC on $\chi^2$ scale = $136.2 - 2 \times 36 = 64.2$
Rough shrinkage: 0.74 ($\frac{136.2 - 36}{136.2}$)
Informal data reduction (increase for ap)

Data reduction strategy
Variables	Reductions	d.f. Saved
`wt`	Assume variable not important enough for 4 knots; use 3	1
`pf`	Assume linearity	1
`hx,ekg`	Make new 0,1,2 variable and assume linearity: 2=`hx` and `ekg` not normal or benign, 1=either, 0=none	5
`sbp,dbp`	Combine into mean arterial bp and use 3 knots: map=$\frac{2}{3}$ `dbp` $+ \frac{1}{3}$ `sbp`	4
`sg`	Use 3 knots	1
`sz`	Use 3 knots	1
`ap`	Look at shape of effect of `ap` in detail, and take log before expanding as spline to achieve stability: add 1 knot	-1

Code

heart <- hx + ekg %nin% c('normal','benign')
label(heart) <- 'Heart Disease Code'
map   <- (2*dbp + sbp)/3
label(map) <- 'Mean Arterial Pressure/10'
dd <- datadist(dd, heart, map)

f <- cph(S ~ rx + rcs(age,4) + rcs(wt,3) + pf.coded +
         heart + rcs(map,3) + rcs(hg,4) +
         rcs(sg,3) + rcs(sz,3) + rcs(log(ap),5) + bm,
         x=TRUE, y=TRUE, surv=TRUE, time.inc=5*12)
print(f, coefs=FALSE)

Cox Proportional Hazards Model

cph(formula = S ~ rx + rcs(age, 4) + rcs(wt, 3) + pf.coded + 
    heart + rcs(map, 3) + rcs(hg, 4) + rcs(sg, 3) + rcs(sz, 3) + 
    rcs(log(ap), 5) + bm, x = TRUE, y = TRUE, surv = TRUE, time.inc = 5 * 
    12)

	Model Tests	Discrimination Indexes
Obs 502	LR χ² 118.37	R² 0.210
Events 354	d.f. 24	R²_24,502 0.171
Center -2.4307	Pr(>χ²) 0.0000	R²_24,354 0.234
	Score χ² 125.58	D_xy 0.321
	Pr(>χ²) 0.0000

Code

# x, y for anova LR, predict, validate, calibrate;
# surv, time.inc for calibrate
anova(f, test='LR')

Likelihood Ratio Statistics for `S`
	χ²	d.f.	P
rx	8.46	3	0.0373
age	11.98	3	0.0074
Nonlinear	8.31	2	0.0157
wt	7.80	2	0.0202
Nonlinear	2.45	1	0.1176
pf.coded	3.49	1	0.0616
heart	23.82	1	<0.0001
map	0.05	2	0.9777
Nonlinear	0.04	1	0.8339
hg	11.44	3	0.0095
Nonlinear	7.53	2	0.0231
sg	1.65	2	0.4386
Nonlinear	0.05	1	0.8295
sz	11.81	2	0.0027
Nonlinear	0.06	1	0.7998
ap	6.22	4	0.1836
Nonlinear	5.82	3	0.1208
bm	0.03	1	0.8674
TOTAL NONLINEAR	22.73	11	0.0193
TOTAL	118.37	24	<0.0001

Savings of 12 d.f.
AIC=70, shrinkage 0.80

21.2 Checking Proportional Hazards

This is our tentative model
Examine distributional assumptions using scaled Schoenfeld residuals
Complication arising from predictors using multiple d.f.
Transform to 1 d.f. empirically using $X\hat{\beta}$
cox.zph does this automatically
Following analysis approx. since internal coefficients estimated

Code

z <- predict(f, type='terms')
# required x=T above to store design matrix
f.short <- cph(S ~ z, x=TRUE, y=TRUE)
# store raw x, y so can get residuals

Fit f.short has same LR $\chi^2$ of 118 as the fit f, but with falsely low d.f.
All $\beta=1$

Code

require(survival)   # or use survival::cox.zph(...)
phtest <- cox.zph(f, transform='identity')
phtest

                   chisq df    p
rx              4.07e+00  3 0.25
rcs(age, 4)     4.27e+00  3 0.23
rcs(wt, 3)      2.22e-01  2 0.89
pf.coded        5.34e-02  1 0.82
heart           4.95e-01  1 0.48
rcs(map, 3)     3.20e+00  2 0.20
rcs(hg, 4)      5.26e+00  3 0.15
rcs(sg, 3)      1.01e+00  2 0.60
rcs(sz, 3)      3.07e-01  2 0.86
rcs(log(ap), 5) 3.59e+00  4 0.47
bm              2.11e-06  1 1.00
GLOBAL          2.30e+01 24 0.52

Code

plot(phtest[1])  # plot only the first variable

None of the effects significantly change over time
Global test of PH $P=0.52$

21.3 Testing Interactions

Will ignore non-PH for dose even though it makes sense
More accurate predictions could be obtained using stratification or time dep. cov.
Test all interactions with dose
Reduce to 1 d.f. as before

Code

z.dose <- z[,"rx"]  # same as saying z[,1] - get first column
z.other <- z[,-1]   # all but the first column of z
f.ia <- cph(S ~ z.dose * z.other, x=TRUE, y=TRUE)
anova(f.ia, test='LR')

Likelihood Ratio Statistics for `S`
	χ²	d.f.	P
z.dose (Factor+Higher Order Factors)	20.65	11	0.0371
All Interactions	11.89	10	0.2926
z.other (Factor+Higher Order Factors)	121.19	20	<0.0001
All Interactions	11.89	10	0.2926
z.dose × z.other (Factor+Higher Order Factors)	11.89	10	0.2926
TOTAL	130.26	21	<0.0001

21.4 Describing Predictor Effects

Plot relationship between each predictor and $\log \lambda$

Code

ggplot(Predict(f), sepdiscrete='vertical', nlevels=4,
       vnames='names')

Figure 21.2: Shape of each predictor on log hazard of death. $Y$-axis shows $X\hat{\beta}$, but the predictors not plotted are set to reference values. Note the highly non-monotonic relationship with `ap`, and the increased slope after age 70 which has been found in outcome models for various diseases.

21.5 Validating the Model

Validate for $D_{xy}$ and slope shrinkage

Code

set.seed(1)  # so can reproduce results
v <- validate(f, B=300)
v

Index	Original Sample	Training Sample	Test Sample	Optimism	Corrected Index	Successful Resamples
D_xy	0.3208	0.3494	0.2953	0.0541	0.2667	300
R²	0.2101	0.2481	0.1756	0.0724	0.1377	300
Slope	1	1	0.7863	0.2137	0.7863	300
D	0.0292	0.0354	0.0239	0.0116	0.0176	300
U	-5e-04	-5e-04	0.0024	-0.0029	0.0024	300
Q	0.0297	0.0359	0.0215	0.0144	0.0153	300
g	0.7174	0.7999	0.629	0.1708	0.5466	300

Shrinkage surprisingly close to heuristic estimate of 0.79
Now validate 5-year survival probability estimates

Code

cal <- calibrate(f, B=300, u=5*12, maxdim=3)

Using Cox survival estimates at 60 Months

Code

plot(cal)

Figure 21.3: Bootstrap estimate of calibration accuracy for 5-year estimates from the final Cox model, using adaptive linear spline hazard regression. Line nearer the ideal line corresponds to apparent predictive accuracy. The blue curve corresponds to bootstrap-corrected estimates.

21.6 Presenting the Model

Display hazard ratios, overriding default for ap

Code

spar(top=1)
plot(summary(f, ap=c(1,20)), log=TRUE, main='')

Figure 21.4: Hazard ratios and multi-level confidence bars for effects of predictors in model, using default ranges except for `ap`

Draw nomogram, with predictions stated 4 ways

Code

spar(ps=8)
surv  <- Survival(f)
surv3 <- function(x) surv(3*12,lp=x)
surv5 <- function(x) surv(5*12,lp=x)
quan  <- Quantile(f)
med   <- function(x) quan(lp=x)/12
ss    <- c(.05,.1,.2,.3,.4,.5,.6,.7,.8,.9,.95)

nom <- nomogram(f, ap=c(.1,.5,1,2,3,4,5,10,20,30,40),
                fun=list(surv3, surv5, med),
                funlabel=c('3-year Survival','5-year Survival',
                  'Median Survival Time (years)'),
                fun.at=list(ss, ss, c(.5,1:6)))
plot(nom, xfrac=.65, lmgp=.35)

Figure 21.5: Nomogram for predicting death in prostate cancer trial

```{r include=FALSE} require(Hmisc) options(qproject='rms', prType='html') require(qreport) getRs('qbookfun.r') hookaddcap() knitr::set_alias(w = 'fig.width', h = 'fig.height', cap = 'fig.cap', scap ='fig.scap') ``` # Case Study in Cox Regression {#sec-coxcase} Note that all the analyses presented here may be done in a more general context - see @sec-ordsurv ## Choosing the Number of Parameters and Fitting the Model `r mrg(sound("cox-case-1"))` * Clinical trial of estrogen for prostate cancer * Response is time to death, all causes * Base analysis on Cox proportional hazards model [@cox72] * $S(t | X)$ = probability of surviving at least to time $t$ given set of predictor values $X$ * $S(t | X) = S_{0}(t)^{\exp(X\beta)}$ * Censor time to death at time of last follow-up for patients still alive at end of study (treat survival time for pt.\ censored at 24m as 24m+) * Use simple, partial approaches to data reduction * Use `transcan` for single imputation * Again combine last 2 categories for `ekg,pf` * See if we can use a full additive model (4 knots for continuous $X$) `r ipacue()` | Predictor | Name | d.f. | Original Levels | |---|---|---|---| Dose of estrogen | `rx` | 3 | placebo, 0.2, 1.0, 5.0 mg estrogen | Age in years | `age` | 3 | | Weight index: wt(kg)-ht(cm)+200 | `wt` | 3 | | Performance rating | `pf` | 2 | normal, in bed <50% of time, in bed >50%, in bed always | History of cardiovascular disease | `hx` | 1 |present/absent | Systolic blood pressure/10 | `sbp` | 3 | | Diastolic blood pressure/10 | `dbp` | 3 | | Electrocardiogram code | `ekg` | 5 | normal, benign, rhythm disturb., block, strain, old myocardial infarction, new MI | Serum hemoglobin (g/100ml) | `hg` | 3 | | Tumor size (cm$^2$) | `sz` | 3 | | Stage/histologic grade combination | `sg` | 3 | | Serum prostatic acid phosphatase | `ap` | 3 | | Bone metastasis | `bm` | 1 | present/absent | * Total of 36 candidate d.f. * Impute missings and estimate shrinkage `r ipacue()` ```{r} require(rms) options(prType='html') # for print, summary, anova, validate getHdata(prostate) levels(prostate$ekg)[levels(prostate$ekg) %in% c('old MI','recent MI')] <- 'MI' # combines last 2 levels and uses a new name, MI prostate$pf.coded <- as.integer(prostate$pf) # save original pf, re-code to 1-4 levels(prostate$pf) <- c(levels(prostate$pf)[1:3], levels(prostate$pf)[3]) # combine last 2 levels w <- transcan(~ sz + sg + ap + sbp + dbp + age + wt + hg + ekg + pf + bm + hx, imputed=TRUE, data=prostate, pl=FALSE, pr=FALSE) attach(prostate) sz <- impute(w, sz, data=prostate) sg <- impute(w, sg, data=prostate) age <- impute(w, age,data=prostate) wt <- impute(w, wt, data=prostate) ekg <- impute(w, ekg,data=prostate) dd <- datadist(prostate) options(datadist='dd') units(dtime) <- 'Month' S <- Surv(dtime, status!='alive') f <- cph(S ~ rx + rcs(age,4) + rcs(wt,4) + pf + hx + rcs(sbp,4) + rcs(dbp,4) + ekg + rcs(hg,4) + rcs(sg,4) + rcs(sz,4) + rcs(log(ap),4) + bm) print(f, coefs=FALSE) ``` * Global LR $\chi^2$ is 135 and very significant $\rightarrow$ modeling warranted `r ipacue()` * AIC on $\chi^2$ scale = $136.2 - 2 \times 36 = 64.2$ * Rough shrinkage: 0.74 ($\frac{136.2 - 36}{136.2}$) * Informal data reduction (increase for `ap`) `r ipacue()` | Variables | Reductions | d.f. Saved | |-----------|------------|------------| | `wt` | Assume variable not important enough for 4 knots; use 3 | 1 | | `pf` | Assume linearity | 1 | | `hx,ekg` | Make new 0,1,2 variable and assume linearity: 2=`hx` and `ekg` not normal or benign, 1=either, 0=none | 5 | | `sbp,dbp` | Combine into mean arterial bp and use 3 knots: map=$\frac{2}{3}$ `dbp` $+ \frac{1}{3}$ `sbp` | 4 | | `sg` | Use 3 knots | 1 | | `sz` | Use 3 knots | 1 | | `ap` | Look at shape of effect of `ap` in detail, and take log before expanding as spline to achieve stability: add 1 knot | -1 | : Data reduction strategy ```{r} heart <- hx + ekg %nin% c('normal','benign') label(heart) <- 'Heart Disease Code' map <- (2*dbp + sbp)/3 label(map) <- 'Mean Arterial Pressure/10' dd <- datadist(dd, heart, map) f <- cph(S ~ rx + rcs(age,4) + rcs(wt,3) + pf.coded + heart + rcs(map,3) + rcs(hg,4) + rcs(sg,3) + rcs(sz,3) + rcs(log(ap),5) + bm, x=TRUE, y=TRUE, surv=TRUE, time.inc=5*12) print(f, coefs=FALSE) # x, y for anova LR, predict, validate, calibrate; # surv, time.inc for calibrate anova(f, test='LR') ``` * Savings of 12 d.f. `r ipacue()` * AIC=70, shrinkage 0.80 ## Checking Proportional Hazards {#sec-coxcase-check-ph} `r mrg(sound("cox-case-2"))` * This is our tentative model * Examine distributional assumptions using scaled Schoenfeld residuals * Complication arising from predictors using multiple d.f. * Transform to 1 d.f. empirically using $X\hat{\beta}$ * `cox.zph` does this automatically * Following analysis approx. since internal coefficients estimated ```{r } z <- predict(f, type='terms') # required x=T above to store design matrix f.short <- cph(S ~ z, x=TRUE, y=TRUE) # store raw x, y so can get residuals ``` * Fit `f.short` has same LR $\chi^2$ of 118 as the fit `f`, `r ipacue()` but with falsely low d.f. * All $\beta=1$ ```{r rx-ph,cap='Raw and spline-smoothed scaled Schoenfeld residuals for dose of estrogen, nonlinearly coded from the Cox model fit, with $\\pm$ 2 standard errors.',scap='Schoenfeld residuals for dose of estrogen in Cox model'} #| label: fig-coxcase-rx-ph require(survival) # or use survival::cox.zph(...) phtest <- cox.zph(f, transform='identity') phtest plot(phtest[1]) # plot only the first variable ``` * None of the effects significantly change over time * Global test of PH $P=0.52$ ## Testing Interactions `r mrg(sound("cox-case-3"))` * Will ignore non-PH for dose even though it makes sense * More accurate predictions could be obtained using stratification or time dep. cov. * Test all interactions with dose <br> Reduce to 1 d.f. as before ```{r} z.dose <- z[,"rx"] # same as saying z[,1] - get first column z.other <- z[,-1] # all but the first column of z f.ia <- cph(S ~ z.dose * z.other, x=TRUE, y=TRUE) anova(f.ia, test='LR') ``` ## Describing Predictor Effects `r ipacue()` * Plot relationship between each predictor and $\log \lambda$ ```{r cox-shapes,h=6,w=6.75,cap='Shape of each predictor on log hazard of death. $Y$-axis shows $X\\hat{\\beta}$, but the predictors not plotted are set to reference values. Note the highly non-monotonic relationship with `ap`, and the increased slope after age 70 which has been found in outcome models for various diseases.',scap='Shapes of predictors for log hazard in prostate cancer'} #| label: fig-coxcase-shapes ggplot(Predict(f), sepdiscrete='vertical', nlevels=4, vnames='names') ``` ## Validating the Model `r ipacue()` * Validate for $D_{xy}$ and slope shrinkage ```{r} set.seed(1) # so can reproduce results v <- validate(f, B=300) v ``` * Shrinkage surprisingly close to heuristic estimate of 0.79 * Now validate 5-year survival probability estimates ```{r cal-cox,cap='Bootstrap estimate of calibration accuracy for 5-year estimates from the final Cox model, using adaptive linear spline hazard regression. Line nearer the ideal line corresponds to apparent predictive accuracy. The blue curve corresponds to bootstrap-corrected estimates.',scap='Bootstrap estimates of calibration accuracy in prostate cancer model'} #| label: fig-coxcase-cal cal <- calibrate(f, B=300, u=5*12, maxdim=3) plot(cal) ``` ## Presenting the Model `r mrg(sound("cox-case-4"))` * Display hazard ratios, overriding default for `ap` ```{r summary-cox,cap='Hazard ratios and multi-level confidence bars for effects of predictors in model, using default ranges except for `ap`',scap='Hazard ratios for prostate survival model'} #| label: fig-coxcase-summary spar(top=1) plot(summary(f, ap=c(1,20)), log=TRUE, main='') ``` * Draw nomogram, with predictions stated 4 ways ```{r cox-nomogram,w=6,h=7,cap='Nomogram for predicting death in prostate cancer trial'} #| label: fig-coxcase-nomogram spar(ps=8) surv <- Survival(f) surv3 <- function(x) surv(3*12,lp=x) surv5 <- function(x) surv(5*12,lp=x) quan <- Quantile(f) med <- function(x) quan(lp=x)/12 ss <- c(.05,.1,.2,.3,.4,.5,.6,.7,.8,.9,.95) nom <- nomogram(f, ap=c(.1,.5,1,2,3,4,5,10,20,30,40), fun=list(surv3, surv5, med), funlabel=c('3-year Survival','5-year Survival', 'Median Survival Time (years)'), fun.at=list(ss, ss, c(.5,1:6))) plot(nom, xfrac=.65, lmgp=.35) ``` ```{r echo=FALSE} saveCap('21') ```