19  Case Study in Parametric Survival Modeling and Model Approximation

Data source: Random sample of 1000 patients from Phases I & II of SUPPORT (Study to Understand Prognoses Preferences Outcomes and Risks of Treatment, funded by the Robert Wood Johnson Foundation). See Knaus et al. (1995). The dataset is available from hbiostat.org/data.

A

19.1 Descriptive Statistics

Create a variable acute to flag categories of interest; print univariable descriptive statistics.

Code 
require(rms)
options(prType='html')     # for print, summary, anova
getHdata(support)          # Get data frame from web site
acute <- support$dzclass %in% c('ARF/MOSF','Coma')
des <- describe(support[acute,])
sparkline::sparkline(0)    # load sparkline dependencies
Code 
maketabs(print(des, 'both'), wide=TRUE, initblank=TRUE)
support[acute, ] Descriptives
24 Continous Variables of 35 Variables, 537 Observations
Variable Label n Missing Distinct Info Mean pMedian Gini |Δ| Quantiles
.05 .10 .25 .50 .75 .90 .95
age Age 537 0 529 1.000 60.7 61.44 19.98 28.49 35.22 47.93 63.67 74.49 81.54 85.56
slos Days from Study Entry to Discharge 537 0 85 0.999 23.44 17.5 22.24 4.0 5.0 9.0 15.0 27.0 47.4 68.2
d.time Days of Follow-Up 537 0 340 1.000 446.1 362.5 566.1 4 6 16 182 724 1421 1742
edu Years of Education 411 126 22 0.957 12.03 12 3.581 7 8 10 12 14 16 17
scoma SUPPORT Coma Score based on Glasgow D3 537 0 11 0.822 19.24 13 27.87 0 0 0 0 37 55 100
charges Hospital Charges 517 20 516 1.000 86652 62842 90079 11075 15180 27389 51079 100904 205562 283411
totcst Total RCC cost 471 66 471 1.000 46360 35732 46195 6359 8449 15412 29308 57028 108927 141569
totmcst Total micro-cost 331 206 328 1.000 39022 32370 36200 6131 8283 14415 26323 54102 87495 111920
avtisst Average TISS, Days 3-25 536 1 205 1.000 29.83 29.5 14.19 12.46 14.50 19.62 28.00 39.00 47.17 50.37
meanbp Mean Arterial Blood Pressure Day 3 537 0 109 1.000 83.28 84 35 41.8 49.0 59.0 73.0 111.0 124.4 135.0
wblc White Blood Cell Count Day 3 532 5 241 1.000 14.1 13 9.984 0.8999 4.5000 7.9749 12.3984 18.1992 25.1891 30.1873
hrt Heart Rate Day 3 537 0 111 0.999 105 106 38.59 51 60 75 111 126 140 155
resp Respiration Rate Day 3 537 0 45 0.997 23.72 24 12.65 8 10 12 24 32 39 40
temp Temperature (celcius) Day 3 537 0 61 0.999 37.52 37.5 1.505 35.50 35.80 36.40 37.80 38.50 39.09 39.50
pafi PaO2/(.01*FiO2) Day 3 500 37 357 1.000 227.2 217.5 125 86.99 105.08 137.88 202.56 290.00 390.49 433.31
alb Serum Albumin Day 3 346 191 34 0.997 2.668 2.65 0.7219 1.700 1.900 2.225 2.600 3.100 3.400 3.800
bili Bilirubin Day 3 386 151 88 0.997 2.678 1.2 3.507 0.3000 0.4000 0.6000 0.8999 2.0000 6.5996 13.1743
crea Serum creatinine Day 3 537 0 84 0.998 2.232 1.7 1.997 0.6000 0.7000 0.8999 1.3999 2.5996 5.2395 7.3197
sod Serum sodium Day 3 537 0 38 0.997 138.1 137.5 7.471 129 131 134 137 142 147 150
ph Serum pH (arterial) Day 3 500 37 49 0.998 7.416 7.424 0.08775 7.270 7.319 7.380 7.420 7.470 7.510 7.529
glucose Glucose Day 3 297 240 179 1.000 167.7 153 92.13 76.0 89.0 106.0 141.0 200.0 292.4 347.2
bun BUN Day 3 304 233 100 1.000 38.91 35.5 31.12 8.00 11.00 16.75 30.00 56.00 79.70 100.70
urine Urine Output Day 3 303 234 262 1.000 2095 1957 1579 20.3 364.0 1156.5 1870.0 2795.0 4008.6 4817.5
adlsc Imputed ADL Calibrated to Surrogate 537 0 144 0.956 2.119 1.962 2.386 0.000 0.000 0.000 1.839 3.375 6.000 6.000
support[acute, ] Descriptives
11 Categorical Variables of 35 Variables, 537 Observations
Variable Label n Missing Distinct Info Sum Mean pMedian Gini |Δ|
death Death at any time up to NDI date:31DEC94 537 0 2 0.670 356 0.6629

sex 537 0 2




hospdead Death in Hospital 537 0 2 0.703 201 0.3743

dzgroup 537 0 3




dzclass 537 0 2




num.co number of comorbidities 537 0 7 0.926
1.525 1.5 1.346
income 335 202 4




race 535 2 5




adlp ADL Patient Day 3 104 433 8 0.875
1.577 1 2.152
adls ADL Surrogate Day 3 392 145 8 0.888
1.86 1.5 2.466
sfdm2 468 69 5




B
Code 
spar(ps=11)
# Show patterns of missing data
plot(naclus(support[acute,]))
Figure 19.1: Cluster analysis showing which predictors tend to be missing on the same patients

Show associations between predictors using a general non-monotonic measure of dependence (Hoeffding \(D\)).

C
Code 
ac <- support[acute,]
ac$dzgroup <- ac$dzgroup[drop=TRUE]    # Remove unused levels
vc <- varclus(~ age+sex+dzgroup+num.co+edu+income+scoma+race+
              meanbp+wblc+hrt+resp+temp+pafi+alb+bili+crea+sod+
              ph+glucose+bun+urine+adlsc, data=ac, sim='hoeffding')
plot(vc)
Figure 19.2: Hierarchical clustering of potential predictors using Hoeffding \(D\) as a similarity measure. Categorical predictors are automatically expanded into dummy variables.

19.2 Checking Adequacy of Log-Normal Accelerated Failure Time Model

Code 
dd <- datadist(ac)
# describe distributions of variables to rms
options(datadist='dd')

# Generate right-censored survival time variable
ac <- upData(ac, print=FALSE,
  years = d.time/365.25,
  units = c(years = 'Year'),
  S     = Surv(years, death))

# Show normal inverse Kaplan-Meier estimates
# stratified by dzgroup
survplot(npsurv(S ~ dzgroup, data=ac), conf='none',
         fun=qnorm,logt=TRUE)
Figure 19.3: \(\Phi^{-1}(S_{ ext{KM}}(t))\) stratified by dzgroup. Linearity and semi-parallelism indicate a reasonable fit to the log-normal accelerated failure time model with respect to one predictor.

More stringent assessment of log-normal assumptions: check distribution of residuals from an adjusted model:

D
Code 
spar(mfrow=c(2,2), ps=8, top=1, lwd=1)
f <- psm(S ~ dzgroup + rcs(age,5) + rcs(meanbp,5),
               dist='lognormal', y=TRUE, data=ac)
r <- resid(f)
with(ac, {
  survplot(r, dzgroup, label.curve=FALSE)
  survplot(r, age,     label.curve=FALSE)
  survplot(r, meanbp,  label.curve=FALSE)
  survplot(r, runif(length(age)), label.curve=FALSE)
} )
Figure 19.4: Kaplan-Meier estimates of distributions of normalized, right-censored residuals from the fitted log-normal survival model. Residuals are stratified by important variables in the model (by quartiles of continuous variables), plus a random variable to depict the natural variability (in the lower right plot). Theoretical standard Gaussian distributions of residuals are shown with a thick solid line. The upper left plot is with respect to disease group.

The fit for dzgroup is not great but overall fit is good.

Remove from consideration predictors that are missing in \(> 0.2\) of the patients. Many of these were only collected for the second phase of SUPPORT.

Of those variables to be included in the model, find which ones have enough potential predictive power to justify allowing for nonlinear relationships or multiple categories, which spend more d.f. For each variable compute Spearman \(\rho^2\) based on multiple linear regression of rank(\(x\)), rank(\(x\))\(^2\) and the survival time, truncating survival time at the shortest follow-up for survivors (356 days). This rids the data of censoring but creates many ties at 356 days.

Code 
spar(top=1, ps=10, rt=3)
ac <- upData(ac, print=FALSE,
  shortest.follow.up = min(d.time[death==0], na.rm=TRUE),
  d.timet            = pmin(d.time, shortest.follow.up))

w <- spearman2(d.timet ~ age + num.co + scoma + meanbp +
             hrt + resp + temp + crea + sod + adlsc +
             wblc + pafi + ph + dzgroup + race, p=2, data=ac)
plot(w, main='')
Figure 19.5: Generalized Spearman \(\rho^2\) rank correlation between predictors and truncated survival time

A better approach is to use the complete information in the failure and censoring times by computing Somers’ \(D_{xy}\) rank correlation allowing for censoring.

E
Code 
spar(top=1, ps=10, rt=3)
w <- rcorrcens(S ~ age + num.co + scoma + meanbp + hrt + resp +
               temp + crea + sod + adlsc + wblc + pafi + ph +
               dzgroup + race, data=ac)
plot(w, main='')
Figure 19.6: Somers’ \(D_{xy}\) rank correlation between predictors and original survival time. For dzgroup or race, the correlation coefficient is the maximum correlation from using a dummy variable to represent the most frequent or one to represent the second most frequent category.
Code 
# Compute number of missing values per variable
sapply(ac[.q(age,num.co,scoma,meanbp,hrt,resp,temp,crea,sod,adlsc,
             wblc,pafi,ph)], function(x) sum(is.na(x)))
   age num.co  scoma meanbp    hrt   resp   temp   crea    sod  adlsc   wblc 
     0      0      0      0      0      0      0      0      0      0      5 
  pafi     ph 
    37     37
Code 
# Can also do naplot(naclus(support[acute,]))
# Can also use the Hmisc naclus and naplot functions to do this
# Impute missing values with normal or modal values
ac <- upData(ac, print=FALSE,
  wblc.i = impute(wblc, 9),
  pafi.i = impute(pafi, 333.3),
  ph.i   = impute(ph,   7.4),
  race2  = ifelse(is.na(race), 'white',
                  ifelse(race != 'white', 'other', 'white')) )
dd <- datadist(ac)

Do a formal redundancy analysis using more than pairwise associations, and allow for non-monotonic transformations in predicting each predictor from all other predictors. This analysis requires missing values to be imputed so as to not greatly reduce the sample size.

F
Code 
r <- redun(~ crea + age + sex + dzgroup + num.co + scoma + adlsc + race2 +
           meanbp + hrt + resp + temp + sod + wblc.i + pafi.i + ph.i,
           data=ac, nk=4)
r

Redundancy Analysis

~crea + age + sex + dzgroup + num.co + scoma + adlsc + race2 + 
    meanbp + hrt + resp + temp + sod + wblc.i + pafi.i + ph.i

n: 537  p: 16   nk: 4 

Number of NAs:   0 

Transformation of target variables forced to be linear

R-squared cutoff: 0.9   Type: ordinary 

R^2 with which each variable can be predicted from all other variables:

   crea     age     sex dzgroup  num.co   scoma   adlsc   race2  meanbp     hrt 
  0.133   0.246   0.132   0.451   0.147   0.418   0.153   0.151   0.178   0.258 
   resp    temp     sod  wblc.i  pafi.i    ph.i 
  0.131   0.197   0.135   0.093   0.143   0.171 

No redundant variables
Code 
r2describe(r$scores, nvmax=4)   # show top 4 strongest predictors of each var.

Strongest Predictors of Each Variable With Cumulative R^2

crea
ph.i (0.038) + num.co (0.05) + resp (0.062) + sex (0.071)

age
hrt (0.04) + race2 (0.071) + num.co (0.084) + wblc.i (0.097)

sex
sod (0.012) + pafi.i (0.02) + crea (0.026) + ph.i (0.034)

dzgroup
scoma (0.307) + hrt (0.32) + meanbp (0.333) + pafi.i (0.341)

num.co
adlsc (0.039) + temp (0.052) + crea (0.064) + age (0.071)

scoma
dzgroup (0.307) + adlsc (0.32) + meanbp (0.333) + sod (0.343)

adlsc
num.co (0.039) + scoma (0.055) + temp (0.065) + hrt (0.073)

race2
age (0.034) + temp (0.044) + dzgroup (0.052) + sex (0.06)

meanbp
pafi.i (0.015) + ph.i (0.028) + num.co (0.036) + hrt (0.044)

hrt
resp (0.053) + temp (0.098) + age (0.125) + dzgroup (0.145)

resp
hrt (0.053) + crea (0.067) + temp (0.07) + meanbp (0.072)

temp
hrt (0.044) + sod (0.063) + num.co (0.082) + pafi.i (0.093)

sod
temp (0.02) + scoma (0.036) + sex (0.044) + num.co (0.05)

wblc.i
age (0.013) + hrt (0.02) + dzgroup (0.025) + pafi.i (0.03)

pafi.i
dzgroup (0.02) + temp (0.034) + meanbp (0.046) + wblc.i (0.052)

ph.i
crea (0.038) + meanbp (0.048) + sex (0.056) + temp (0.06)

Better approach to gauging predictive potential and allocating d.f.:

  • Allow all continuous variables to have a the maximum number of knots entertained, in a log-normal survival model
  • Must use imputation to avoid losing data
  • Fit a “saturated” main effects model
  • Makes full use of censored data
  • Had to limit to 4 knots, force scoma to be linear, and omit ph.i to avoid singularity
G
Code 
k <- 4
f <- psm(S ~ rcs(age,k)+sex+dzgroup+pol(num.co,2)+scoma+
         pol(adlsc,2)+race+rcs(meanbp,k)+rcs(hrt,k)+rcs(resp,k)+
         rcs(temp,k)+rcs(crea,k)+rcs(sod,k)+rcs(wblc.i,k)+
         rcs(pafi.i,k), dist='lognormal', data=ac, x=TRUE, y=TRUE)
plot(anova(f, test='LR'))
Figure 19.7: Partial likelihood ratio \(\chi^{2}\) statistics for association of each predictor with response from saturated main effects model, penalized for d.f.
  • This figure properly blinds the analyst to the form of effects (tests of linearity).
  • Fit a log-normal survival model with number of parameters corresponding to nonlinear effects determined from Figure 19.7. For the most promising predictors, five knots can be allocated, as there are fewer singularity problems once less promising predictors are simplified.
HI

Note: Since the audio was recorded, a bug in psm was fixed on 2017-03-12. Discrimination indexes shown in the table below are correct but the audio is incorrect for \(g\) and \(g_{r}\).

Code 
f <- psm(S ~ rcs(age,5) + sex + dzgroup + num.co +
             scoma + pol(adlsc,2) + race2 + rcs(meanbp,5) +
             rcs(hrt,3) + rcs(resp,3) + temp +
             rcs(crea,4) + sod + rcs(wblc.i,3) + rcs(pafi.i,4),
         dist='lognormal', data=ac, x=TRUE, y=TRUE)
f

Parametric Survival Model: Log Normal Distribution

psm(formula = S ~ rcs(age, 5) + sex + dzgroup + num.co + scoma + 
    pol(adlsc, 2) + race2 + rcs(meanbp, 5) + rcs(hrt, 3) + rcs(resp, 
    3) + temp + rcs(crea, 4) + sod + rcs(wblc.i, 3) + rcs(pafi.i, 
    4), data = ac, dist = "lognormal", x = TRUE, y = TRUE)
Model Likelihood
Ratio Test		 Discrimination
Indexes
Obs 537 LR χ2 236.83 R2 0.594
Events 356 d.f. 30 R230,537 0.320
σ 2.2308 Pr(>χ2) <0.0001 R230,356 0.441
Dxy 8.891
β S.E. Wald Z Pr(>|Z|)
(Intercept)   -5.3904   3.7603 -1.43 0.1517
age   -0.0148   0.0309 -0.48 0.6322
age'   -0.0412   0.1078 -0.38 0.7024
age''   0.1670   0.5594 0.30 0.7653
age'''   -0.2099   1.3707 -0.15 0.8783
sex=male   -0.0737   0.2181 -0.34 0.7354
dzgroup=Coma   -2.0676   0.4062 -5.09 <0.0001
dzgroup=MOSF w/Malig   -1.4664   0.3112 -4.71 <0.0001
num.co   -0.1917   0.0858 -2.23 0.0255
scoma   -0.0142   0.0044 -3.25 0.0011
adlsc   -0.3735   0.1520 -2.46 0.0140
adlsc2   0.0442   0.0243 1.82 0.0691
race2=white   -0.2979   0.2658 -1.12 0.2624
meanbp   0.0702   0.0210 3.34 0.0008
meanbp'   -0.3080   0.2261 -1.36 0.1732
meanbp''   0.8438   0.8556 0.99 0.3241
meanbp'''   -0.5715   0.7707 -0.74 0.4584
hrt   -0.0171   0.0069 -2.46 0.0140
hrt'   0.0064   0.0063 1.02 0.3090
resp   0.0454   0.0230 1.97 0.0483
resp'   -0.0851   0.0291 -2.93 0.0034
temp   0.0523   0.0834 0.63 0.5308
crea   -0.4585   0.6727 -0.68 0.4955
crea'  -11.5176  19.0027 -0.61 0.5444
crea''   21.9840  31.0113 0.71 0.4784
sod   0.0044   0.0157 0.28 0.7792
wblc.i   0.0746   0.0331 2.25 0.0242
wblc.i'   -0.0880   0.0377 -2.34 0.0195
pafi.i   0.0169   0.0055 3.07 0.0021
pafi.i'   -0.0569   0.0239 -2.38 0.0173
pafi.i''   0.1088   0.0482 2.26 0.0239
Log(scale)   0.8024   0.0401 19.99 <0.0001
Code 
a <- anova(f, test='LR')

19.3 Summarizing the Fitted Model

  • Plot the shape of the effect of each predictor on log survival time.
  • All effects centered: can be placed on common scale
  • LR \(\chi^2\) statistics, penalized for d.f., plotted in descending order
J
Code 
ggplot(Predict(f, ref.zero=TRUE), vnames='names',
       sepdiscrete='vertical', anova=a)
Figure 19.8: Effect of each predictor on log survival time. Predicted values have been centered so that predictions at predictor reference values are zero. Pointwise 0.95 confidence bands are also shown. As all \(Y\)-axes have the same scale, it is easy to see which predictors are strongest.

K
Code 
a
Likelihood Ratio Statistics for S
χ2 d.f. P
age 16.10 4 0.0029
 Nonlinear 0.23 3 0.9722
sex 0.11 1 0.7354
dzgroup 45.11 2 <0.0001
num.co 5.00 1 0.0253
scoma 10.44 1 0.0012
adlsc 8.24 2 0.0162
 Nonlinear 3.30 1 0.0694
race2 1.26 1 0.2618
meanbp 26.99 4 <0.0001
 Nonlinear 10.38 3 0.0156
hrt 11.82 2 0.0027
 Nonlinear 1.04 1 0.3079
resp 10.94 2 0.0042
 Nonlinear 8.49 1 0.0036
temp 0.39 1 0.5309
crea 33.14 3 <0.0001
 Nonlinear 21.05 2 <0.0001
sod 0.08 1 0.7792
wblc.i 5.44 2 0.0659
 Nonlinear 5.43 1 0.0198
pafi.i 15.13 3 0.0017
 Nonlinear 6.93 2 0.0312
TOTAL NONLINEAR 58.28 14 <0.0001
TOTAL 236.83 30 <0.0001
Code 
plot(a)
Figure 19.9: Contribution of variables in predicting survival time in log-normal model

L
Code 
spar(top=1, ps=11)
options(digits=3)
plot(summary(f), log=TRUE, main='')
Figure 19.10: Estimated survival time ratios for default settings of predictors. For example, when age changes from its lower quartile to the upper quartile (47.9y to 74.5y), median survival time decreases by more than half. Different shaded areas of bars indicate different confidence levels (0.9, 0.95, 0.99).

19.4 Internal Validation of the Fitted Model Using the Bootstrap

Validate indexes describing the fitted model.

Code 
# First add data to model fit so bootstrap can re-sample
#  from the data
g <- update(f, x=TRUE, y=TRUE)
set.seed(717)
validate(g, B=300, dxy=TRUE)
Index Original
Sample		 Training
Sample		 Test
Sample		 Optimism Corrected
Index		 Successful
Resamples
Dxy 0.4852 0.5099 0.4593 0.0506 0.4346 300
R2 0.594 0.6582 0.5383 0.1199 0.4741 300
Intercept 0 0 -0.0454 0.0454 -0.0454 300
Slope 1 1 0.9057 0.0943 0.9057 300
D 0.4788 0.5488 0.4237 0.1251 0.3537 300
U -0.0041 -0.0041 -0.0097 0.0056 -0.0096 300
Q 0.4829 0.553 0.4334 0.1196 0.3633 300
g 1.9593 2.0516 1.8684 0.1832 1.7761 300
  • From \(D_{xy}\) and \(R^2\) there is a moderate amount of overfitting.
  • Slope shrinkage factor (0.90) is not troublesome
  • Almost unbiased estimate of future predictive discrimination on similar patients is the corrected \(D_{xy}\) of 0.43.
M

Validate predicted 1-year survival probabilities. Use a smooth approach that does not require binning (Kooperberg et al., 1995) and use less precise Kaplan-Meier estimates obtained by stratifying patients by the predicted probability, with at least 60 patients per group.

N
Code 
set.seed(717)
cal <- calibrate(g, u=1, B=300)
plot(cal, subtitles=FALSE)
cal <- calibrate(g, cmethod='KM', u=1, m=60, B=300, pr=FALSE)
plot(cal, add=TRUE)
Figure 19.11: Bootstrap validation of calibration curve. Dots represent apparent calibration accuracy; \(\times\) are bootstrap estimates corrected for overfitting, based on binning predicted survival probabilities and and computing Kaplan-Meier estimates. Black curve is the estimated observed relationship using hare and the blue curve is the overfitting-corrected hare estimate. The gray-scale line depicts the ideal relationship.

19.5 Approximating the Full Model

The fitted log-normal model is perhaps too complex for routine use and for routine data collection. Let us develop a simplified model that can predict the predicted values of the full model with high accuracy (\(R^{2} = 0.96\)). The simplification is done using a fast backward stepdown against the full model predicted values.

Code 
Z <- predict(f)    # X*beta hat
a <- ols(Z ~ rcs(age,5)+sex+dzgroup+num.co+
             scoma+pol(adlsc,2)+race2+
             rcs(meanbp,5)+rcs(hrt,3)+rcs(resp,3)+
             temp+rcs(crea,4)+sod+rcs(wblc.i,3)+
             rcs(pafi.i,4), sigma=1, data=ac)
# sigma=1 is used to prevent sigma hat from being zero when
# R2=1.0 since we start out by approximating Z with all
#  component variables
fastbw(a, aics=10000)    # fast backward stepdown

 Deleted Chi-Sq d.f. P     Residual d.f. P      AIC     R2   
 sod       0.43 1    0.512    0.43   1   0.5117   -1.57 1.000
 sex       0.57 1    0.451    1.00   2   0.6073   -3.00 0.999
 temp      2.20 1    0.138    3.20   3   0.3621   -2.80 0.998
 race2     6.81 1    0.009   10.01   4   0.0402    2.01 0.994
 wblc.i   29.52 2    0.000   39.53   6   0.0000   27.53 0.976
 num.co   30.84 1    0.000   70.36   7   0.0000   56.36 0.957
 resp     54.18 2    0.000  124.55   9   0.0000  106.55 0.924
 adlsc    52.46 2    0.000  177.00  11   0.0000  155.00 0.892
 pafi.i   66.78 3    0.000  243.79  14   0.0000  215.79 0.851
 scoma    78.07 1    0.000  321.86  15   0.0000  291.86 0.803
 hrt      83.17 2    0.000  405.02  17   0.0000  371.02 0.752
 age      68.08 4    0.000  473.10  21   0.0000  431.10 0.710
 crea    314.47 3    0.000  787.57  24   0.0000  739.57 0.517
 meanbp  403.04 4    0.000 1190.61  28   0.0000 1134.61 0.270
 dzgroup 441.28 2    0.000 1631.89  30   0.0000 1571.89 0.000

Approximate Estimates after Deleting Factors

        Coef    S.E. Wald Z P
[1,] -0.5928 0.04315 -13.74 0

Factors in Final Model

None
Code 
f.approx <- ols(Z ~ dzgroup + rcs(meanbp,5) + rcs(crea,4) + rcs(age,5) +
                rcs(hrt,3) + scoma + rcs(pafi.i,4) + pol(adlsc,2)+
                rcs(resp,3), x=TRUE, data=ac)
f.approx$stats
         n Model L.R.       d.f.         R2          g      Sigma 
   537.000   1688.225     23.000      0.957      1.915      0.370
  • Estimate variance-covariance matrix of the coefficients of reduced model
  • This covariance matrix does not include the scale parameter
O
Code 
V <- vcov(f, regcoef.only=TRUE)     # var(full model)
X <- cbind(Intercept=1, g$x)        # full model design
x <- cbind(Intercept=1, f.approx$x) # approx. model design
w <- solve(t(x) %*% x, t(x)) %*% X  # contrast matrix
v <- w %*% V %*% t(w)

Compare variance estimates (diagonals of v) with variance estimates from a reduced model that is fitted against the actual outcomes.

Code 
f.sub <- psm(S ~ dzgroup + rcs(meanbp,5) + rcs(crea,4) + rcs(age,5) +
             rcs(hrt,3) + scoma + rcs(pafi.i,4) + pol(adlsc,2)+
             rcs(resp,3), dist='lognormal', data=ac)

r <- diag(v)/diag(vcov(f.sub,regcoef.only=TRUE))
r[c(which.min(r), which.max(r))]
 hrt'   age 
0.976 0.982

P
Code 
f.approx$var <- v
anova(f.approx, test='Chisq', ss=FALSE)
Wald Statistics for Z
χ2 d.f. P
dzgroup 55.94 2 <0.0001
meanbp 29.87 4 <0.0001
 Nonlinear 9.84 3 0.0200
crea 39.04 3 <0.0001
 Nonlinear 24.37 2 <0.0001
age 18.12 4 0.0012
 Nonlinear 0.34 3 0.9517
hrt 9.87 2 0.0072
 Nonlinear 0.40 1 0.5289
scoma 9.85 1 0.0017
pafi.i 14.01 3 0.0029
 Nonlinear 6.66 2 0.0357
adlsc 9.71 2 0.0078
 Nonlinear 2.87 1 0.0904
resp 9.65 2 0.0080
 Nonlinear 7.13 1 0.0076
TOTAL NONLINEAR 58.08 13 <0.0001
TOTAL 252.32 23 <0.0001

Equation for simplified model:

Code 
# Typeset mathematical form of approximate model
latex(f.approx)
\[\mathrm{E}(\mathrm{Z}) = X\beta,~~\mathrm{where}\] \[\begin{array} \lefteqn{X\hat{\beta}=}\\ & & -2.51 \\ & & -1.94[\mathrm{Coma}]-1.75[\mathrm{MOSF\ w/Malig}] \\ & & + 0.068 \mathrm{meanbp}-3.08\!\times\!10^{-5}(\mathrm{meanbp}-41.8)_{+}^{3}+7.9\!\times\!10^{-5 }(\mathrm{meanbp}-61)_{+}^{3} \\ & & -4.91\!\times\!10^{-5}(\mathrm{meanbp}-73)_{+}^{3}+2.61\!\times\!10^{-6 }(\mathrm{meanbp}-109)_{+}^{3}-1.7\!\times\!10^{-6 }(\mathrm{meanbp}-135)_{+}^{3} \\ & & -0.553\mathrm{crea}-0.229(\mathrm{crea}-0.6)_{+}^{3}+0.45 (\mathrm{crea}-1.1)_{+}^{3}-0.233(\mathrm{crea}-1.94)_{+}^{3} \\ & & +0.0131(\mathrm{crea}-7.32)_{+}^{3} \\ & & -0.0165 \mathrm{age}-1.13\!\times\!10^{-5}(\mathrm{age}-28.5)_{+}^{3}+4.05\!\times\!10^{-5 }(\mathrm{age}-49.5)_{+}^{3} \\ & & -2.15\!\times\!10^{-5}(\mathrm{age}-63.7)_{+}^{3}-2.68\!\times\!10^{-5}(\mathrm{age}-72.7)_{+}^{3}+1.9\!\times\!10^{-5 }(\mathrm{age}-85.6)_{+}^{3} \\ & & -0.0136 \mathrm{hrt}+6.09\!\times\!10^{-7 }(\mathrm{hrt}-60)_{+}^{3}-1.68\!\times\!10^{-6}(\mathrm{hrt}-111)_{+}^{3}+1.07\!\times\!10^{-6 }(\mathrm{hrt}-140)_{+}^{3} \\ & & -0.0135\:\mathrm{scoma} \\ & & + 0.0161 \mathrm{pafi.i}-4.77\!\times\!10^{-7}(\mathrm{pafi.i}-88)_{+}^{3}+9.11\!\times\!10^{-7 }(\mathrm{pafi.i}-167)_{+}^{3} \\ & & -5.02\!\times\!10^{-7}(\mathrm{pafi.i}-276)_{+}^{3}+6.76\!\times\!10^{-8 }(\mathrm{pafi.i}-426)_{+}^{3} -0.369\:\mathrm{adlsc}+0.0409\:\mathrm{adlsc}^{2} \\ & & + 0.0394 \mathrm{resp}-9.11\!\times\!10^{-5}(\mathrm{resp}-10)_{+}^{3}+0.000176 (\mathrm{resp}-24)_{+}^{3}-8.5\!\times\!10^{-5 }(\mathrm{resp}-39)_{+}^{3} \\ \end{array}\]

\[[c]=1~\mathrm{if~subject~is~in~group}~c,~0~\mathrm{otherwise}\]\[(x)_{+}=x~\mathrm{if}~x > 0,~0~\mathrm{otherwise}\]



Nomogram for predicting median and mean survival time, based on approximate model:

Code 
# Derive R functions that express mean and quantiles
# of survival time for specific linear predictors
# analytically
expected.surv <- Mean(f)
quantile.surv <- Quantile(f)
expected.surv
function (lp = NULL, parms = 0.802352037606488) 
{
    names(parms) <- NULL
    exp(lp + exp(2 * parms)/2)
}
<environment: namespace:rms>
Code 
quantile.surv
function (q = 0.5, lp = NULL, parms = 0.802352037606488) 
{
    names(parms) <- NULL
    f <- function(lp, q, parms) lp + exp(parms) * qnorm(q)
    names(q) <- format(q)
    drop(exp(outer(lp, q, FUN = f, parms = parms)))
}
<environment: namespace:rms>
Code 
median.surv   <- function(x) quantile.surv(lp=x)
Code 
spar(ps=10)
# Improve variable labels for the nomogram
f.approx <- Newlabels(f.approx, c('Disease Group','Mean Arterial BP',
          'Creatinine','Age','Heart Rate','SUPPORT Coma Score',
          'PaO2/(.01*FiO2)','ADL','Resp. Rate'))
nom <-
  nomogram(f.approx,
           pafi.i=c(0, 50, 100, 200, 300, 500, 600, 700, 800, 900),
           fun=list('Median Survival Time'=median.surv,
                    'Mean Survival Time'  =expected.surv),
           fun.at=c(.1,.25,.5,1,2,5,10,20,40))
plot(nom, cex.var=1, cex.axis=.75, lmgp=.25)
Figure 19.12: Nomogram for predicting median and mean survival time, based on approximation of full model
R packages and functions used. All packages are available on CRAN.
Packages Purpose Functions
Hmisc Miscellaneous functions describe,ecdf,naclus,varclus,llist,spearman2,impute,latex
rms Modeling datadist,psm,rcs,ols,fastbw
Model presentation survplot,Newlabels,Function,Mean,Quantile,nomogram
Model validation validate,calibrate