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331–346

Printed in Great Britain

Predictive inﬂuence in the accelerated failure time

model

EDWARD J. BEDRICK

∗

Department of Mathematics and Statistics, University of New Mexico, Albuquerque,

NM 87131, USA

bedrick@stat.unm.edu

ALEX EXUZIDES

Exponent Inc., Menlo Park, CA USA

WESLEY O. JOHNSON

Department of Statistics, University of California, Davis, CA 95616, USA

MARK C. THURMOND

Department of Medicine and Epidemiology, University of California, Davis, CA, 95616, USA

SUMMARY

We develop case deletion diagnostics for prediction of future observations in the accelerated failure

time model. We view prediction to be an important inferential goal in a survival analysis and thus it is

important to identify whether particular observations may be inﬂuencing the quality of predictions. We

use the Kullback–Leibler divergence as a measure of the discrepency between the estimated probability

distributions for the full and the case-deleted samples. In particular, we focus on the effect of case deletion

on estimated survival curves but where we regard the survival curve estimate as a vehicle for prediction.

We also develop a diagnostic for assessing the effect of case deletion on inferences for the median time to

failure. The estimated median can be used with both predictive and estimative purposes in mind. We also

discuss the relationship between our suggested measures and the corresponding Cook distance measure,

which was designed with the goal of assessing estimative inﬂuence. Several applications of the proposed

diagnostics are presented.

Keywords: Case deletion; Cook’s distance; Kullback–Leibler divergence; Survival analysis.

1. INTRODUCTION

Our goal in this paper is to develop statistical methods for the detection of inﬂuential observations in

the parametric accelerated failure time (AFT) model. There has been a tremendous interest in developing

such methods in linear and nonlinear regression models, generalized linear models and, more recently,

in failure time or survival models. A standard approach considers the effect that deleting single cases

or subsets of cases has on the estimated regression coefﬁcients. This focus has led to several well known

inﬂuence measures, for example Cook’s (1977) distance and Belsley et al.’s (1980) DFBETAs. Alternative

∗

To whom correspondence should be addressed

c Oxford University Press (2002)

332 E. J. BEDRICK ET AL.

approaches, based on the notion of local inﬂuence (Cook, 1986; Lawrance, 1991), consider the impact that

perturbing cases, rather than deleting them, has on parameter estimates and inferences.

Johnson & Geisser (1983) and Johnson (1985) argued that prediction is the ultimate goal in many

statistical analyses, and thus diagnostics are needed to assess the impact that subsets of the data have on

prediction. We agree with this view, and note that cases that have a large impact on regression coefﬁcients

may have little effect on predictions, and conversely, inﬂuential cases for prediction might have little

impact on estimation (see Christensen et al. (1992) for examples in spatial data).

In this paper, we develop case deletion diagnostic measures for identifying inﬂuential cases for

prediction of future observations in the AFT model. Having identiﬁed such cases, the practical import of

case deletion is assessed by viewing estimated survival curves corresponding to covariate combinations of

interest and comparing them with the corresponding curves based on data with the candidate case having

been removed. If some of the estimated curves of interest change dramatically upon removal of a case,

prognoses based on these curves would correspondingly be affected. Such difference in prognoses should

be of interest to physicians who are informing the corresponding patients about their survival prospects.

The AFT model is often viewed as a competitor to the proportional hazards (PH) model (Cox, 1972)

when the PH model fails to ﬁt. Although the AFT model with an unspeciﬁed error distribution is a natural

analog to the PH model, there are no widely accepted methods for implementing this approach. Miller

(1976), Buckley &James (1979), Koul et al. (1981) and Christensen &Johnson (1988) developed methods

for a semi-parametric AFT model, but difﬁculties inherent in the model made their approaches somewhat

unpalatable. Kuo & Mallick (1997) and Walker & Mallick (1999) present novel Bayesian approaches but

it will take time to determine their long-term viability. We will focus our attention on the parametric AFT

model, which Aalen (2000) noted is underused in medical research and deserving of more attention.

Earlier work on diagnostics for the AFT model, for example Weissfeld & Schneider (1990a,b) and

Escobar & Meeker (1992), considered the effect of single cases and subsets of the data on parameter

estimates and functions of the parameter estimates, such as the median lifetime. We use the Kullback–

Leibler (KL) divergence as a diagnostic measure of the discrepency between estimated probability

distributions based on full and case-deleted samples. A large Kullback–Leibler number for a speciﬁc

case is an indication that substantially different predictive inferences might result if that case were

deleted. There is considerable literature in which the KL divergence is used for purposes similar to ours—

McCulloch (1989), Carlin & Polson (1991), Geisser (1993) and Sooﬁ (1994) to name a few. Although we

focus on prediction, we recognize that inference on regression coefﬁcients is an important consideration

in many studies. Consequently, we make detailed comparisons of our diagnostics with Cook’s distance,

and illustrate similarities and differences between approaches throughout the paper.

The remainder of the paper is organized as follows. Section 2 discusses the AFT model and deﬁnes the

KL divergence. Section 2 also proposes a diagnostic that measures the effect that individual cases have on

the estimated percentiles. Section 3 explores properties of the KL divergence for standard accelerated

failure models, such as the log-normal, the log-logistic, and the Weibull, and relates the divergence

to Cook’s distance. Section 4 illustrates the methods using two examples. Section 5 gives concluding

remarks. Technical results are summarized in an Appendix.

2. NOTATION

The AFT model is speciﬁed by

log(T

i

) = x

i

β + σU

i

, i = 1, . . . , n U

i

i i d

∼ S

0

(·), (1)

where the T

i

are actual, sometimes unobserved, survival times, the x

i

are ﬁxed p×1 vectors of covariates,

β is the vector of regression coefﬁcients, σ is a scale parameter, and S

0

(·) is a known baseline survivor

Predictive inﬂuence in the accelerated failure time model 333

Table 1. Baseline distributions

Baseline Distribution f

0

(u) S

0

(u)

Normal

1

√

2π

e

−0.5u

2

1 − (u)

Logistic e

u

_

(1 + e

u

)

2

(1 + e

u

)

−1

Extreme value e

(u−e

u

)

e

−e

u

function. For example, we obtain the usual log-normal survival model if the baseline is standard normal,

the log-logistic model if S

0

is logistic, and the Weibull if S

0

is the extreme-value distribution. These

baseline survival functions S

0

(u) along with their densities f

0

(u) are given in Table 1. Using the change-

of-variable formula, the density of T

i

is f

0

(z

i

)/t

i

σ, where z

i

= {log(t

i

) − x

i

β}/σ.

Exponential regression results from choosing the extreme value baseline and setting σ = 1.

Kalbﬂeisch & Prentice (1980) discuss the log F baseline which generalizes these distributions and others.

Our approach could be applied to that more general family but, for illustrative purposes, we restrict

ourselves to the three distributions in Table 1.

Consider censored survival data (t

i

, δ

i

, x

i

), i = 1, . . . , n, where t

i

is the random observed time (either

survival or censoring) and δ

i

is the random indicator of noncensoring, that is δ

i

= 0 if the i

th

observation

is censored, and 1 otherwise. We assume that the censoring mechanism is independent of the survival

times. The log-likelihood function for θ

= (β

, σ) is l(θ) ≡

n

i =1

l

i

(θ), where

l

i

(θ) ≡ l

i

(θ|t

i

, δ

i

) = δ

i

log

_

1

σt

i

f

0

(z

i

)

_

+ (1 − δ

i

)logS

0

(z

i

)

is the log-likelihood based on the i

th

observation. Let

ˆ

θ

= (

ˆ

β

**, ˆ σ) be the maximum likelihood estimate
**

(MLE) of θ, and deﬁne

ˆ

f (t ) =

1

t ˆ σ

f

0

_

log(t ) − x

ˆ

β

ˆ σ

_

to be the MLE of the density of T when the covariate vector is x.

2.1 The Kullback–Leibler divergence

Our primary goal is the assessment of the inﬂuence that individual cases have on the prediction of future

survival times, and survival probabilities associated with future subjects. For this purpose, we consider

the symmetric KL divergence (Johnson, 1985), which measures the discrepency between two probability

distributions with densities g

1

and g

2

as follows: J(g

1

, g

2

) = I (g

1

, g

2

) + I (g

2

, g

1

), where

I (g

i

, g

j

) =

_

g

i

(t )log

_

g

i

(t )

g

j

(t )

_

dt.

Note that J(g

1

, g

2

) 0 with J(g

1

, g

2

) = 0 if and only if the densities are identical. In particular, we

propose the symmetric divergence J(

ˆ

f ,

ˆ

f

(i )

) to measure the discrepency between the full data estimative

density

ˆ

f and the estimative density

ˆ

f

(i )

(t ) =

1

t ˆ σ

(i )

f

0

_

log(t ) − x

ˆ

β

(i )

ˆ σ

(i )

_

,

334 E. J. BEDRICK ET AL.

where

ˆ

θ

(i )

= (

ˆ

β

(i )

, ˆ σ

(i )

) is the MLE when the i th case in the sample is held out. More generally, the

collective effect that case i has on predicting the survival times of m future observations with covariate

vectors ˜ x

1

, ˜ x

2

, . . . , ˜ x

m

is given by

ˆ

D

i

=

m

j =1

J(

ˆ

f

j

,

ˆ

f

j (i )

),

where

ˆ

f

j

and

ˆ

f

j (i )

are the estimated densities when x = ˜ x

j

. A possible choice for the ˜ x

j

is the covariate

values x

1

, x

2

, . . . , x

n

for the n cases in the sample. A large value of J(

ˆ

f

j

,

ˆ

f

j (i )

) or

ˆ

D

i

indicates that

deletion of case i results in different predicted survival probabilities than if it were retained, possibly

resulting in different inferences or decisions. Johnson (1985) proposed a similar diagnostic for logistic

regression.

To better understand the results, consider the log-normal model for which

J(

ˆ

f ,

ˆ

f

(i )

) = I (

ˆ

f ,

ˆ

f

(i )

) + I (

ˆ

f

(i )

,

ˆ

f )

= 0.5

_

ˆ σ

2

ˆ σ

2

(i )

+

ˆ σ

2

(i )

ˆ σ

2

− 2 + (

ˆ

β −

ˆ

β

(i )

)

xx

(

ˆ

β −

ˆ

β

(i )

)

_

1

ˆ σ

2

(i )

+

1

ˆ σ

2

__

.

A second-order Taylor series expansion of the ﬁrst part of J(

ˆ

f ,

ˆ

f

(i )

) gives

J(

ˆ

f ,

ˆ

f

(i )

)

.

=

2( ˆ σ − ˆ σ

(i )

)

2

ˆ σ

2

+ 0.5(

ˆ

β −

ˆ

β

(i )

)

xx

(

ˆ

β −

ˆ

β

(i )

)

_

1

ˆ σ

2

(i )

+

1

ˆ σ

2

_

.

If we aggregate the KL divergences over the n covariate values x

1

, x

2

, . . . , x

n

in the sample we get

ˆ

D

i

.

=

2n( ˆ σ − ˆ σ

(i )

)

2

ˆ σ

2

+ 0.5(

ˆ

β −

ˆ

β

(i )

)

X

X(

ˆ

β −

ˆ

β

(i )

)

_

1

ˆ σ

2

(i )

+

1

ˆ σ

2

_

, (2)

where X is the n × p design matrix with i th row x

i

. The diagnostic is the sum of two components

that separately measure the effect of the i th case on the estimated scale and regression coefﬁcients.

Alternatively, if we are interested in the prediction of the survival times for m future observations with

covariate values ˜ x

1

, ˜ x

2

, . . . , ˜ x

m

, then (2) holds with n = m and X = X

f

, where X

f

is the m × p matrix

with i th row ˜ x

i

.

2.2 Inﬂuence on estimated percentiles

The KL divergence

ˆ

D

i

measures the inﬂuence of individual cases on the survival distribution. The

inﬂuence on speciﬁc percentiles, say the median survival time, might also be of interest both in terms of

making summary prognoses for speciﬁc individuals or for estimating median survival for populations of

individuals with speciﬁc covariate combinations. To address this issue, note that the estimated α percentile

for the survival time T of a future observation with covariate vector ˜ x is

ˆ

T

α

= exp( ˜ x

ˆ

β + ˆ σu

α

) =

exp( ˜ x

α

ˆ

θ), where u

α

is the α percentile of the baseline distribution and ˜ x

α

= ( ˜ x

, u

α

). The estimated

variance of

ˆ

T

α

is

ˆ

T

2

α

˜ x

α

I(

ˆ

θ)

−1

˜ x

α

, where I(

ˆ

θ) = −

¨

l(

ˆ

θ) is the observed information matrix evaluated at

ˆ

θ.

An expression for −

¨

l(

ˆ

θ) is given in the Appendix.

The inﬂuence that the i th case has on the estimated percentile can be measured by

α,(i )

( ˜ x) =

(

ˆ

T

α

−

ˆ

T

α,(i )

)

2

ˆ

T

2

α

˜ x

α

I(

ˆ

θ)

−1

˜ x

α

,

Predictive inﬂuence in the accelerated failure time model 335

which is a scaled version of the relative change |

ˆ

T

α

−

ˆ

T

α,(i )

|/

ˆ

T

α

in the estimated percentile obtained

by holding out the i th case. Escobar & Meeker (1992) proposed an analogous measure based on local

inﬂuence.

The overall effect that individual observations have on the estimated percentiles for m future

observations with covariate values ˜ x

1

, ˜ x

2

, . . . , ˜ x

m

is given by

α,(i )

=

m

j =1

α,(i )

( ˜ x

j

).

As with

ˆ

D

i

, a possible choice for the ˜ x

j

is the covariate values for the n cases in the sample.

3. EXPLORING THE KULLBACK–LEIBLER DIVERGENCE

The KL divergence J(

ˆ

f ,

ˆ

f

(i )

) does not have an analytic form for certain AFT models, such as the log-

logistic. We consider two approximations to the KL divergence for such models, one based on numerical

integration, and the other based on a Taylor series expansion.

To develop the Taylor series approximation, consider I (

ˆ

f ,

ˆ

f

(i )

). Let u = {log(t ) −x

ˆ

β}/ ˆ σ, and deﬁne

a = ˆ σ/ ˆ σ

(i )

and b = x

(

ˆ

β −

ˆ

β

(i )

)/ ˆ σ

(i )

. Note that {log(t ) − x

ˆ

β

(i )

}/ ˆ σ

(i )

= au + b. Given this notation, a

change of variables gives

I (

ˆ

f ,

ˆ

f

(i )

) = −log(a) +

_

f

0

(u)log

_

f

0

(u)

f

0

(au + b)

_

du

= −log(a) + E{log f

0

(U) − log f

0

(aU + b)},

where U has density f

0

(u), and where a and b are constants with respect to the integration. Let H(u) ≡

∂log f

0

(u)/∂u and G(u) ≡ ∂

2

log f

0

(u)/∂u

2

. We show in the Appendix that a second-order Taylor series

expansion of I (

ˆ

f ,

ˆ

f

(i )

) about the point (a, b) = (1, 0) gives the following approximation:

I

A

(

ˆ

f ,

ˆ

f

(i )

) = −log(a) − E[{(a − 1)U + b}H(U)] − 0.5E[{(a − 1)U + b}

2

G(U)].

Table 2 gives expressions for I (

ˆ

f ,

ˆ

f

(i )

) and I

A

(

ˆ

f ,

ˆ

f

(i )

) for the three standard AFT models. Analogous

approximations apply to I (

ˆ

f

(i )

,

ˆ

f ), J(

ˆ

f ,

ˆ

f

(i )

), and

ˆ

D

i

. The approximation to

ˆ

D

i

will be denoted

ˆ

D

A,i

. It

is our experience that the approximations are accurate and that the approximation error has little impact on

identifying the inﬂuential cases. For example, the average relative error in the approximation to J(

ˆ

f ,

ˆ

f

(i )

)

is estimated to be 2% and 6% for the log-logistic and the Weibull models, respectively, when (a, b) is

uniformly distributed on the rectangle with log(2/3) log(a) log(3/2) and −1 b 1. The

approximations are exact for the log-normal model.

The KL divergence is a function of the MLEs, which must be computed iteratively. A one-step

approximation to the MLEs for the case-deleted samples

ˆ

θ

(i )

.

=

ˆ

θ + {

¨

l(

ˆ

θ) −

¨

l

i

(

ˆ

θ)}

−1

˙

l

i

(

ˆ

θ)

is recommended with the KL divergences (and other diagnostics) to simplify the calculations. We

explore the accuracy of the one-step approximation in Section 4. A general expression for the one-step

approximation is given in the Appendix.

3.1 A Comparison of the divergence and Cook’s distance

The effect that individual cases have on the parameter estimates can be measured by Cook’s distance

C

i

= (

ˆ

θ −

ˆ

θ

(i )

)

I(

ˆ

θ)(

ˆ

θ −

ˆ

θ

(i )

). Cook’s distances for subsets of θ, for example the individual regression

coefﬁcients β

j

, are deﬁned analogously.

336 E. J. BEDRICK ET AL.

Table 2. Exact and approximate KL divergences: I = I (

ˆ

f ,

ˆ

f

(i )

), I

A

= I

A

(

ˆ

f ,

ˆ

f

(i )

), where a =

ˆ σ/ ˆ σ

(i )

and b = x

(

ˆ

β −

ˆ

β

(i )

)/ ˆ σ

(i )

; γ = 0.577215 is Euler’s constant

Baseline Dist.

Normal I = 0.5(a

2

− 2log(a) − 1 + b

2

)

I

A

= 0.5(a

2

− 2log(a) − 1 + b

2

)

Logistic I = −log(a) − b − 2 + 2

_

+∞

0

log(1 + e

b

k

a

)/(1 + k)

2

dk.

I

A

= a − log(a) − 1 + 0.5(π

2

/9 − 2/3)(a − 1)

2

+ b

2

/6

Extreme value I = −log(a) + (a − 1)γ − b − 1 + e

b

(1 + a)

I

A

= a − log(a) − 1 + 0.5(a − 1)

2

(π

2

/6 + γ

2

− 2γ ) + 0.5b

2

+ (1 − γ )(a − 1)b

A primary difference between C

i

and

ˆ

D

i

is that C

i

gives different weights to censored and uncensored

cases. The KL divergence, which is used to assess the inﬂuence of the observed data on predictions of

future observations, does not distinguish between censored and uncensored values.

To contrast the two diagnostics, we ﬁrst consider the log-normal model with known variance, for

which C

i

= (

ˆ

β −

ˆ

β

(i )

)

X

ˆ

W X(

ˆ

β −

ˆ

β

(i )

), where

ˆ

W is a diagonal matrix with j th diagonal element

ˆ w

j

= {δ

j

+ (1 − δ

j

)

˙

λ

0

(ˆ z

j

)}/σ

2

. Here ˆ z

j

= {log(t

j

) − x

j

ˆ

β}/σ is the j th standardized residual and

˙

λ

0

(·)

is the derivative of the baseline hazard λ

0

(·) = f

0

(·)/S

0

(·).

Using the one-step approximation yields a simple and easily interpretable expression for C

i

that

illustrates the distinction between deleting censored and uncensored cases. Let

ˆ

h

j

= ˆ w

j

x

j

(X

ˆ

W X)

−1

x

j

and deﬁne

R

2

i

=

_

_

ˆ z

i

_

1 −

ˆ

h

i

_

_

2

ˆ

h

i

1 −

ˆ

h

i

and S

2

i

=

_

_

λ

0

(ˆ z

i

)

_

˙

λ

0

(ˆ z

i

)(1 −

ˆ

h

i

)

_

_

2

ˆ

h

i

1 −

ˆ

h

i

.

Then C

i

.

= δ

i

R

2

i

+ (1 − δ

i

)S

2

i

, which reduces to the standard Cook (1977) statistic when there is no

censoring. An uncensored case with ˆ z

i

= 0 is not inﬂuential for β whereas a censored case can be.

Censored cases with large negative residuals ˆ z

i

have little inﬂuence because S

2

i

≈ 0, but censored cases

with large positive residuals have the same effect as an uncensored case because {λ

2

0

(ˆ z

i

)/

˙

λ

0

(ˆ z

i

)}/ˆ z

2

i

→ 1

as ˆ z

i

→ ∞.

In comparison, the KL divergence (aggregated over the observed covariate values) is

ˆ

D

i

=

1

σ

2

(

ˆ

β −

ˆ

β

(i )

)

X

X(

ˆ

β −

ˆ

β

(i )

) = C

i

+

j

_

1

σ

2

− ˆ w

j

_

(

ˆ

Y

j

−

ˆ

Y

j (i )

)

2

,

where

ˆ

Y

j

= x

j

ˆ

β and

ˆ

Y

j (i )

= x

j

ˆ

β

(i )

are the predicted values (on a log scale). An uncensored case has

ˆ w

j

= 1/σ

2

so only censored cases contribute to the second term in

ˆ

D

i

, which simpliﬁes to give

ˆ

D

i

= C

i

+

1

σ

2

δ

j

=0

{1 −

˙

λ

0

(ˆ z

j

)}(

ˆ

Y

j

−

ˆ

Y

j (i )

)

2

C

i

.

The inequality follows because

˙

λ

0

(·) is increasing and bounded between 0 and 1. If there is no censoring

then

ˆ

D

i

= C

i

. However, the second term in

ˆ

D

i

could be large if a substantial percentage of cases are

censored, and if holding out the i th case has a noticeable effect on the predicted values for the censored

Predictive inﬂuence in the accelerated failure time model 337

cases, especially if the censored cases have large negative residuals. Under these conditions,

ˆ

D

i

and C

i

may highlight different cases as inﬂuential.

If σ is unknown and there is no censoring then the information matrix is block diagonal under the

log-normal model (i.e.

ˆ

β and ˆ σ are independent) and

C

i

=

1

ˆ σ

2

{2n( ˆ σ − ˆ σ

(i )

)

2

+ (

ˆ

β −

ˆ

β

(i )

)

X

X(

ˆ

β −

ˆ

β

(i )

)}

.

=

ˆ

D

i

.

In this situation C

i

and

ˆ

D

i

should identify the same cases as potentially inﬂuential. If there is censoring,

C

i

includes a cross-product term in ( ˆ σ − ˆ σ

(i )

)(

ˆ

β −

ˆ

β

(i )

), which makes a comparison with

ˆ

D

i

difﬁcult,

regardless of the error distribution.

3.2 Two illustrations of differences between the diagnostics

It is difﬁcult to characterize when C

i

and

ˆ

D

i

will disagree. We speculate that the potential for differences

is tied to the degree of censoring. We present two brief analyses which show clear differences between

ˆ

D

i

(aggregated over the observed covariate values) and C

i

in data sets with heavy censoring. In Section 4,

ˆ

D

i

is tailored to examine the inﬂuence on predictions within a subset of the design space, and in such

settings, discrepancies with C

i

should not be surprising, regardless of the degree of censoring.

As a ﬁrst example, consider the following hypothetical sample of 19 lifetimes: 1.5

0

, 24, 42,

43

0

, 77, 89

0

, 105, 194, 270, 290

0

, 309

0

, 325

0

, 446, 503

0

, 561

0

, 643

0

, 1457

0

, 2060

0

, 2879,

where censored lifetimes are superscripted. Figure 1 gives index plots of the exact

ˆ

D

i

and C

i

for a

regression model with an intercept and scale. Plots are given for the three standard models. The diagnostics

were normalized to have a maximum of one within each series. Observations 2 and 18 are highlighted in

the plots. Observation 18 has the second highest lifetime, and the highest lifetime among the censored

cases, whereas observation 2 has the minimum lifetime among the uncensored cases.

Focusing on the log-normal model, observation 18 has a much larger impact on

ˆ

D

i

than it has on

C

i

probably because of the extensive censoring and the marked decrease in the estimated mean (the

predicted value for each case) and scale that is obtained by holding this case out. Cook’s distance suggests

that observation 2 is much more inﬂuential. Similar results were found for the log-logistic model. For the

Weibull model, observation 18 has the largest

ˆ

D

i

and C

i

, but observation 2, which has nearly the same

Cook’s distance as observation 18, has little effect as measured by the KL divergence.

As a second example, we consider data from a study of risk factors associated with coronary heart

disease, see, Roseman et al. (1975) and Selvin (1995, p. 436). The study involves 35 adult white males

with high cholesterol levels (above 340 mg per 100 ml). The response is the time in days until a coronary

event. Only eight of the responses are not censored.

We ﬁtted a log-normal model to the data, using body weight, cholesterol level and cigarette consump-

tion (cigarettes per day) as predictors. Cook’s distance and the KL divergence identify observations 15,

19, and 35 as the three most inﬂuential cases, but order the observations differently; see Table 3. Each

of these cases is uncensored. Observation 35, which corresponds to an individual who had an extremely

short response time given his relatively low cholesterol level and cigarette consumption, has the greatest

impact on prediction. Observation 19, which corresponds to an individual with a cholesterol level of 645

(the second highest level is 400) has the greatest inﬂuence on the parameter estimates. Our analysis in

Section 3.1 suggests that this discrepancy between C

i

and

ˆ

D

i

might be tied to the differential effect that

observations 19 and 35 have on the predicted values for the censored cases. Indeed, these predicted values

change noticeably when case 35 (or case 15) is held out, but change little when case 19 is removed.

338 E. J. BEDRICK ET AL.

Case

C

5 10 15

0

.

0

0

.

4

0

.

8

•

•

•

•

•

•

• • •

• • •

•

•

•

•

•

•

•

(a)

Case

5 10 15

0

.

0

0

.

4

0

.

8

•

•

•

•

•

•

• • •

• • •

•

•

•

•

•

•

•

(b)

Case

5 10 15

0

.

0

0

.

4

0

.

8

•

•

•

•

•

•

•

•

•

• • •

•

•

•

•

•

•

•

(c)

i

C

i

C

i

Fig. 1. Index plots for test data. The solid line is the KL divergence. The dots are the Cook distances. (a) Log normal;

(b) Log logistic; (c) Weibull.

Table 3. Inﬂuential cases in the

coronary study

Observation C

i

ˆ

D

i

15 1.05 27.38

19 11.14 13.54

35 7.57 193.85

4. EXAMPLES

4.1 Time Until Abortion in Dairy Cattle

We consider data from a study designed by Dr Mark Thurmond and Dr Sharon Hietala of the University

of California, Davis to examine factors that might affect the time to natural abortion in dairy cattle. The

data set includes the time in days from conception to abortion for 45 aborted cows, and information on

two covariates: IS, an indicator of infection status, (IS = 1 corresponds to cows infected with Neospora

caninum whereas IS = 0 corresponds to non-infected cows) and days open (DO), that is the number of

days between the most recent previous birth and conception. There are no censored observations in the

data set.

The scientists believed that infection status would be the more important variable in terms of predicting

Predictive inﬂuence in the accelerated failure time model 339

time to abortion, with abortion occurring later in infected animals. They also expected that increasing DO

would slightly increase the time to abortion. The primary goal of this study is to characterize and quantify

the effect of N. caninum on the time to abortion. This is part of an ongoing investigation of N. caninum and

other infectious abortifacients with the ultimate goal of reducing fetal wastage, see Thurmond & Hietala

(1997).

Even though it is known that Neospora infection is a causal agent for abortion, it is of interest to

quantify the distribution of times to abortion among infected and non-infected animals. The ability to

predict the time of abortion for particular animals is of interest since management policy can then be

adapted to take advantage of this knowledge. In particular, knowing that an animal is or is not infected,

and having the corresponding estimated survival curve, the dairy farmer can take preventive measures at

appropriate times before the abortion is expected. Since infected animals are known to abort later than non-

infected animals, the timing of intervention strategies will differ based on knowledge of type of animal.

Thus, if removing a particular case has a large impact on the resulting estimated survival curve, the end

result is a potentially harmful effect on the dairy farmer’s prognostic ability, which ultimately effects the

efﬁcacy of his/her intervention strategy.

We considered a log-logistic model for the time to abortion. This model provided a much better ﬁt

(based on minus twice the log-likelihood) than the Weibull model, and a marginally better ﬁt than the

log-normal model. The MLEs for the intercept, scale, and the regression coefﬁcients for IS, and DO, are

3.971, 0.257, 0.371, and 0.0030, with standard errors of 0.150, 0.031, 0.131, and 0.0012, respectively.

At the 5% level, the regression coefﬁcients for the two predictors are signiﬁcantly different from zero,

with IS having the larger z-statistic (2.82 for IS versus 2.41 for DO). These results are consistent with our

expectations.

Figures 2(a)–(d) give index plots of C

i

,

ˆ

D

i

,

ˆ

D

A,i

, and

0.5,(i )

, respectively, for the 45 observations.

Each ﬁgure gives a plot based on the exact MLEs for

ˆ

θ

(i )

and a plot based on the one-step approximation

to

ˆ

θ

(i )

. The diagnostics

ˆ

D

i

,

ˆ

D

A,i

and

0.5,(i )

were aggregated over the observed covariate values.

ˆ

D

i

was evaluated using numerical integration. The diagnostics that use the one-step approximation to

ˆ

θ

(i )

are accurate, but tend to overstate the inﬂuence of the most extreme cases. Furthermore, the difference

between C

i

and

ˆ

D

i

is small across cases, and the second-order approximation to

ˆ

D

i

is extremely accurate,

regardless of which version of

ˆ

θ

(i )

is considered.

Each of these diagnostics identify observations 10, 26 and 43 as the most inﬂuential cases. These

three observations have the ﬁrst, second, and fourth longest times to abortion (259, 254, and 149 days),

respectively, but correspond to uninfected cows with low numbers of days open (46, 61, and 54 days).

Observation 10 has little inﬂuence on predictive ability. Consideration of Figure 3 shows that the estimated

survival curves for cows with DO = 220 and IS = 0 based on the full and case-10-deleted data are

virtually indistinguishable. The corresponding effect on the curve with IS = 1 is probably not of practical

importance in terms of dairy management strategy (the difference in estimated medians was six days).

The parameter estimates changed by less than one-half a standard error when this case was removed, and

the standard errors changed only slightly, so inferences about θ are also not sensitive to whether case 10

is included in the analysis. Similar conclusions were reached when observation 26 was held out.

Aparticular interest in the study is to characterize the effect that infection has upon the time to abortion

for cows that are initially unable to conceive for an extended period of time. Figure 3(a) is particularly

relevant to this purpose, and comparison with Figure 3(b) establishes that deleting case 10 is not a cause

for concern. Pursuing this particular interest further, Figures 2(e) and (f) give index plots of

ˆ

D

i

and

0.5,(i )

assuming that we are interested in predicting the survival time for two cows left open for 220 days, one

of which is infected, and the other of which is not. Observation 22 is the most inﬂuential case here,

followed by observation 21. Observation 22 is an uninfected cow with 219 days open that aborted after

70 days. Figure 3(c) gives the estimated survival curves after holding out observation 22. The change in

340 E. J. BEDRICK ET AL.

•

•

•

•

•

•

•

••

•

•••

•

••

•

•

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•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

••

•

•

•

•

•

•

•

•

•

Observation

0 10 20 30 40

0

.

0

0

.

2

0

.

4

0

.

6

0

.

8

(a)

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•

•

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•••

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••

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•

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•

••

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•

•

Observation

0 10 20 30 40

0

.

0

0

.

2

0

.

4

0

.

6

0

.

8

(b)

•

•

•

•

•

•

•

•

•

•

•••

•

••

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•••

•

•

•

•

•

•

•

•

Observation

0 10 20 30 40

0

.

0

0

.

2

0

.

4

0

.

6

0

.

8

(c)

•

•

•

•

•

•

•

•

•

•

•

••

•

••

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

Observation

0 10 20 30 40

0

1

2

3

4

5

(d)

D

i

D

i

C

i

•

•

•

••

•

•

••

•

•

•

•

••••

•

•

•

•

•

•••

•

•

•

••••

•

•

•

•

•

•

•

••

•

•

•

•

Observation

D

0 10 20 30 40

0

.

0

0

.

0

2

0

.

0

4

0

.

0

6

(e)

•

•

•

••

••••

•

•

•

•

••••

•

•

•

•

•

•

••

•

•

•

•

•••

•

•

•

•

•

•

•

••

•

•

•

•

Observation

0 10 20 30 40

0

.

0

0

.

1

0

.

2

0

.

3

0

.

4

(f)

i

Fig. 2. Index plots for the cow abortion data. The solid line is based on exact MLEs. The dots are based on one-step

MLEs. (a) Cook’s distance C

i

; (b) prediction diagnostic D

i

; (c) second-order approximation to D

i

; (d) diagnostic for

median survival; (e) D

i

for prediction at two locations; (f) diagnostic for median survival at two locations.

survival curves and medians is more noticeable than when observation 10 was omitted. Indeed, the index

plot for

0.5,(i )

suggests that observation 10 should have relatively little effect on the estimated median

survival times at these two locations. This analysis emphasizes the point that the most inﬂuential cases

for prediction potentially depend on the prediction region and are not necessarily the most inﬂuential for

estimation. The estimated survival probabilities are slightly higher after observation 22 is deleted, and the

increase in estimated median times to abortion are marginally large enough to be of practical importance.

Predictive inﬂuence in the accelerated failure time model 341

Fetal age in days

P

r

o

b

a

b

i

l

i

t

y

0 50 100 150 200 250

0

.

0

0

.

4

0

.

8

102 148

IS=0

IS=1

(a)

Fetal age in days

P

r

o

b

a

b

i

l

i

t

y

0 50 100 150 200 250

0

.

0

0

.

4

0

.

8

103 154

IS=0

IS=1

(b)

Fetal age in days

P

r

o

b

a

b

i

l

i

t

y

0 50 100 150 200 250

0

.

0

0

.

4

0

.

8

112 158

IS=0

IS=1

(c)

Fig. 3. Estimated fetal survival curves in cow abortion data with DO = 220. (a) Full data; (b) holding out observation

10; (c) holding out observation 22.

There are only three cows in the sample that had not conceived by 200 days. It is not too surprising then

that one or more of these observations might be inﬂuential for estimating the survival curves at 220 days

open. Because a goal of the study is to estimate the survival distributions at such extreme covariate values,

we should consider collecting more data on cows with extended open periods as a means of minimizing

the potential impact that any one observation might have on the predictions.

4.2 Ovarian cancer data

Edmunson et al. (1979) designed a study to assess the effectiveness of various chemotherapy treatments

for women with ovarian cancer. The trial involved 26 women who had minimal residual disease after

having undergone surgery to excise all tumors greater than 2 cm in diameter. The response variable was

the survival time in days following randomization to one of the two chemotherapy treatments that either

used cyclophosphamide alone (Treatment = 1) or use cyclophosphamide combined with adriamycin

(Treatment = 2). In addition to the treatment, possible prognostic factors associated with the survival

times are a patient’s age, whether the residual disease was completely or partially excised, and a patient’s

performance status at the start of the trial (good or poor). Clearly one of the important goals of such a

study ought to be to develop survival curve estimates that can be used as prognostic tools for guiding

342 E. J. BEDRICK ET AL.

•

• •

•

•

• •

• •

•

•

• •

•

•

•

•

•

•

• • •

•

•

•

•

Observation

C

i

0 5 10 15 20 25

0

.

0

1

.

0

2

.

0

3

.

0

(a)

•

•

•

•

•

• •

• •

•

•

• •

•

•

• •

•

•

• • •

•

•

•

•

Observation

C

i

0 5 10 15 20 25

0

.

0

0

.

4

0

.

8

1

.

2

(b)

•

•

•

•

•

• •

• •

•

• • •

• •

•

• • • •

• •

•

• •

•

Observation

C

i

0 5 10 15 20 25

0

.

0

0

.

4

0

.

8

(c)

•

• •

•

•

• •

• •

•

•

• •

•

•

•

•

•

• • • •

•

•

•

•

Observation

D

i

0 5 10 15 20 25

0

2

4

6

8

(d)

Fig. 4. Index plots for the ovarian cancer data. The solid line is based on exact MLEs. The dots are based on one-

step MLEs. (a) Cook’s distance C

i

; (b) Cook’s distance C

i

for treatment coefﬁcient; (c) Cook’s distance C

i

for age

coefﬁcient; (d) prediction diagnostic D

i

.

the treatment of individual patients, and furthermore, to help an individual patient to make life decisions

based on their knowledge of the estimated curve that corresponds to them. Thus, it should be of great

interest to know if removal of a case appreciably alters these estimated curves.

Collett (1994) ﬁtted a Weibull model to these data and concluded that a patient’s age and treatment

were the only signiﬁcant predictors of survival time. The MLEs for the intercept, scale, and the regression

coefﬁcients for treatment and age are 10.425, 0.549, 0.561, and −0.079, with standard errors of 1.434,

0.129, 0.340, and 0.020, respectively. Figures 4(a)–(d) give index plots of C

i

, C

i

(Trt), C

i

(Age) and

ˆ

D

i

for the 26 observations ordered by increasing survival time. C

i

(Trt) and C

i

(Age) are Cook’s distances for

the treatment and age regression coefﬁcients, respectively.

ˆ

D

i

was aggregated over the observed covariate

values. As in the analysis of times to abortion, the diagnostics that use the one-step approximation identify

the most inﬂuential cases but tend to overstate their inﬂuence. In contrast to the previous analysis, C

i

and

ˆ

D

i

differ noticeably, which, to a certain degree, reﬂects the extensive censoring (46%) in the sample.

Although not given here, we note that second-order approximation to

ˆ

D

i

was accurate.

Figure 4(d) shows that observations 26, 5, and 4 are the most inﬂuential cases for prediction. The

same three cases are highlighted by

0.5,(i )

, except that observation 5 had a slightly greater inﬂuence on

the median survival times than the other two cases. Observation 26 corresponds to a 59 year old woman

given cyclophosphamide combined with adriamycin (Treatment = 2) who was censored at 1227 days.

Observation 4 corresponds to a 74 year old woman given cyclophosphamide alone (Treatment = 1) who

Predictive inﬂuence in the accelerated failure time model 343

Days

P

r

o

b

a

b

i

l

i

t

y

0 500 1000 1500

0

.

0

0

.

4

0

.

8

1015 579

TRT=1

TRT=2

(a)

Days

P

r

o

b

a

b

i

l

i

t

y

0 500 1000 1500

0

.

0

0

.

4

0

.

8

1060 551

TRT=1

TRT=2

(b)

Days

P

r

o

b

a

b

i

l

i

t

y

0 500 1000 1500

0

.

0

0

.

4

0

.

8

1035 716

TRT=1

TRT=2

(c)

Days

P

r

o

b

a

b

i

l

i

t

y

0 500 1000 1500

0

.

0

0

.

4

0

.

8

808 578

TRT=1

TRT=2

(d)

Fig. 5. Estimated survival curves in ovarian cancer data when age = 56. (a) Full data; (b) holding out observation 4;

(c) holding out observation 5; (d) holding out observation 26.

survived 268 days. These two cases have the longest survival time and highest age, respectively, in the

data set. Observation 5 corresponds to a 43 year old woman given Treatment 1 who survived 329 days.

Some interesting trends emerge from examining the divergences J(

ˆ

f ,

ˆ

f

(i )

) for predicting individual

survival times. We found that observation 26 is the most inﬂuential case for predicting the survival time

of future patients that are given the combined treatment, regardless of their age. Observations 5 and 4

are the most inﬂuential cases for predicting the survival time of patients treated with cyclophosphamide

for which Age 62 and Age > 62, respectively. Figure 5, which gives estimated survival curves for a

56 year old woman, illustrates most of these trends. In particular, holding out observation 26 shifts the

survival curve for Treatment 2 considerably to the left, reducing the estimated median survival time from

1015 to 808. Deleting observation 5 shifts the survival curve for Treatment 1 considerably to the right.

Holding out observation 4 has little effect on the survival curves for 56 year olds.

Observations 26 and 4 have the largest inﬂuence on

ˆ

θ. The relative impact of these cases on the

regression coefﬁcients is isolated to a single predictor, with observations 26 and 4 having a large potential

impact on the treatment effect and age effect, respectively. Using the full data estimates, the median

survival time for patients given the combined treatment is 75% higher (exp(0.561) = 1.75)) than the

median survival time for patients given cyclophosphamide alone, regardless of their age. If observation 26

is held out, the relative increase in median survival time is reduced to 40% (exp(0.336) = 1.40)). The age

coefﬁcient is −0.096 when observation 4 is held out, so this case has a smaller impact on the age effect

than observation 26 has on the treatment effect.

344 E. J. BEDRICK ET AL.

5. CONCLUDING REMARKS

We proposed the KL divergence as a case deletion diagnostic for prediction of future observations

in the accelerated failure time model. We developed simple approximations to the divergence, and

showed that the approximations were accurate in two examples. A concern with plug-in methods, such

as the prediction diagnostics considered here, is that they fail to account for uncertainty in the estimated

densities. A Bayesian analysis using predictive densities is a natural way to account for the uncertainty

in

ˆ

θ and

ˆ

f . However, given that the predictive density for the survival time of a future observation is

reasonably approximated by the estimative density

ˆ

f (t ), we expect that our diagnostic will identify the

same cases that would be identiﬁed as potentially inﬂuential were this uncertainty taken into account.

ACKNOWLEDGEMENTS

The work of Wes Johnson and Mark Thurmond was supported in part from USDA NRI grant no

98-2517.

APPENDIX

A1. Derivation of the approximation to the KL divergence

Write I (

ˆ

f ,

ˆ

f

(i )

) = −log(a) + g(a, b), where

g(a, b) ≡

_

+∞

−∞

f

0

(u){log f

0

(u) − log f

0

(au + b)} du.

If k and l are either 0 or 1 with k +l = 1, then

∂

k+l

g(a, b)/∂a

k

∂b

l

= −

_

+∞

−∞

u

k

f

0

(u)H(au + b) du = −E{U

k

H(aU + b)},

whereas if k and l are either 0, 1, or 2 with k +l = 2, then

∂

k+l

g(a, b)/∂a

k

∂b

l

= −

_

+∞

−∞

u

k

f

0

(u)G(au + b) du = −E{U

k

G(aU + b)}.

A second-order Taylor series expansion of g(a, b) about the point (a, b) = (1, 0) gives

g(a, b)

.

= g(1, 0) − (a − 1) E{UH(U)} − b E{H(U)}

−0.5[(a − 1)

2

E{U

2

G(U)} + 2(a − 1)b E{UG(U)} + b

2

E{G(U)}].

Noting that g(1, 0) = 0 we get the approximation given in Section 3:

I (

ˆ

f ,

ˆ

f

(i )

)

.

= I

A

(

ˆ

f ,

ˆ

f

(i )

)

= −log(a) − E[{(a − 1)U + b}H(U)] − 0.5E[{(a − 1)U + b}

2

G(U)].

A2. Evaluation of the KL divergence for the Weibull model

We sketch the derivations of the exact and approximate KL divergences for the Weibull model. The results

given in Table 2 for the log-normal and log-logistic follow from similar calculations.

For the Weibull, log f

0

(u) = u − e

u

, so H(u) = 1 − e

u

and G(u) = −e

u

. Also, with γ identifying

Euler’s constant, E(U) = −γ

.

= −0.577215, E(e

U

) = 1, E(Ue

U

) = 1 − γ, and E(U

2

e

U

) = π

2

/6+

Predictive inﬂuence in the accelerated failure time model 345

γ

2

− 2γ , see Lawless (1982). A short calculation then gives

I

A

(

ˆ

f ,

ˆ

f

(i )

) = (a − log(a) − 1) + (π

2

/6 + γ

2

− 2γ )(a − 1)

2

/2 + 0.5b

2

+ (1 − γ )(a − 1)b.

To get the exact KL divergence, note that

log f

0

(u) − log f

0

(au + b) = −(a − 1)u − b − e

u

+ e

au+b

and E(e

aU

) = (1 + a), and thus

I (

ˆ

f ,

ˆ

f

(i )

) = −log(a) + (a − 1)γ − b − 1 + e

b

(1 + a).

A3. Observed information matrix and one-step approximations to MLEs

Let z

j

= {log(t

j

) − x

j

β}/σ, c

j

= (z

j

a

j

− δ

j

)/σ and v

j

= a

j

/σ, where

a

j

= −δ

j

H(z

j

) + (1 − δ

j

)λ

0

(z

j

),

and λ

0

(z

j

) = f

0

(z

j

)/S

0

(z

j

) is the baseline hazard function. Also, deﬁne w

j

= (∂a

j

/∂z

j

)/σ

2

, d

j

=

a

j

/σ

2

+ z

j

w

j

, and e

j

= (2z

j

a

j

− δ

j

)/σ

2

+ z

2

j

w

j

. Then the score function and observed information

matrix are given by

˙

l(θ) =

n

j =1

˙

l

j

(θ) =

_

∂l

∂β

∂l

∂σ

_

=

_

n

j =1

v

j

x

j

n

j =1

c

j

_

and −

¨

l(θ), respectively, where

¨

l(θ) =

n

j =1

¨

l

j

(θ) =

_

∂

2

l

∂β∂β

∂

2

l

∂β∂σ

∂

2

l

∂σ∂β

∂

2

l

∂σ∂σ

_

= −

_

n

j =1

w

j

x

j

x

j

n

j =1

d

j

x

j

n

j =1

d

j

x

j

n

j =1

e

j

_

,

see Kalbﬂeisch & Prentice (1980, page 55).

A one-step approximation to

ˆ

θ

(i )

is given by

ˆ

θ

(i )

.

=

ˆ

θ + {

¨

l(

ˆ

θ) −

¨

l

i

(

ˆ

θ)}

−1

˙

l

i

(

ˆ

θ) which reduces to

_

ˆ

β

(i )

ˆ σ

(i )

_

.

=

_

ˆ

β

ˆ σ

_

−

_

j =i

ˆ w

j

x

j

x

j

j =i

ˆ

d

j

x

j

j =i

ˆ

d

j

x

j

j =i

ˆ e

j

_

−1 _

ˆ v

i

x

i

ˆ c

i

_

,

where, for example, ˆ w

j

= w

j

(

ˆ

θ).

REFERENCES

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[Received July 28, 2000; revised August 9, 2001; accepted for publication November 14, 2001]

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