Paper Summary

Monotone Smoothing with Application to

Dose-Response Curves and
the Assessment of Synergism

Colleen Kelly and John Rice, Biometrics,

Vol. 46, No. 4, (Dec., 1990), pp. 1071-1085
 Outline
Introduction
Monotone Smoothing
Assessing Synergism
Bootstrap Method
Procedure
Application
Result
 Monotone Smoothing
To monotone smoothing is based on spline
function. Given a partition
a   0   1  ...   p 1  b of an interval [a, b]
a spline function is a polynomial on each
interval [ j ,  j 1 ).
We shall refer to the  i as "knots".
 Monotone Smoothing
Given data points ( xi , yi ) (i  1,..., n), a smoothing
spline is the function that  minimizes
n
Q (  )   (Yi   ( xi ))    [  ( x)]2 dx
xn
2
x1
i 1

The minimizing  is a cubic spline with

a knot at every data point.
 Monotone Smoothing

as   0,  tends to an interpolant of the data.

as   ,  tends to the LS line fit to the data.

The smaller p is, the quicker the running time,
especially when   0.
 Monotone Smoothing
Knot placement should depend on the density
of data points or on local behavior of curve.
Thus we control smoothing only with  .
1. Chosen the amount of smoothing to apply .
2. Leave-one-out cross-validation.
3. Doing a preliminary QR decomposition.
 Assessing Synergism

Synergistic if its effect is more than

would be expected form what is known
about the effect of the individuak
constituent.
Antagonistic if the effect is less.
Asynergistic if effect is the same.
 Assessing Synergism
Definition of synergism:
Let the repsone to dosages x and y of two
drug be denote by f ( x, y ).
Assume x  0 y  0, and f ( x, 0) f (0, y ) are
monotone.
 Assessing Synergism
For given response value z let xz and y z be
those dosages such that f ( xz , 0)  f (0, y z )  z.
x y
if f ( x, y )  z ,   1.
xz y z
Synergistic if left side is less than 1.
Antagonistic if it is greater than 1.
 Bootstrap Method

Parametric bootstrap samples

Model could be binomial or poisson.
Y  X    ,  ~(0, ), independent.
2

bootstrap residuals
 ˆi : i  1...n    *(b ) : b  1...B
bootstrap sample for Y is Y *(b) ˆ
 X  .
*( b )
 Procedure

Monotone spline

Parametric bootstrap sample

Check synergism
 Application I

Data form Le Pelley and Sullivan

(1936).
Alcoholic solutions of rotenone,
pyrethrins, and a mixture of the two.
The mixture series was 1:5 ratio and
1:15 ratio.
 Application I
Calculations
for the 1:5 ratio,  2 (3)  81.19 was synergism.
for the 1:15 ratio,  (3)  11.72 which is
2

not significant at   0.05.

 Application I

Bliss (1939);
Finney, using probit analysis (1952);
Chou and Talalay with median effect
analysis (1983)
All investigators concluded there was
synergism in the 1:5 ratio and slight
synergism in the 1:15 ratio.
 Application II
Data form Dr Stephen Howell of the UCSD
Cancer Center.
Ovarian cancer may be treated by VP-16 and
DPM.
There are 6 concentration levels for each
individual dose-reponse curve, with 18
observations.
There are 4 combination doses ratio 1:150 of
VP-16/DPM.
 Application II

Parametric bootstrap based on Poisson

model for the random variability under
asynergy.
Responses are to increasing
concentrations of a conmbination of both
drugs in a 1:150 ratio.
 Reference
Howell, S. B., Sanga, R., Vick, J., and Abramson, I. (1989a).
Comparison of the Synergistic Potentiation of Etoposide,
Doxorubicin, and Vinblastine Cytotoxicity by Dipyridamole.
Cancer Research 49, 4147-4153.
徐南蓉 , 統計計算上課講義 , lecture5, lecture6, lecture7.
Thank you for your listening.