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cokinetic properties. Further evaluation of compound
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Supplementary data
Supplementary data associated with this article can be
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24. For the ZDF rat in vivo dose–response curves, the
minimal effective dose (MED) and ED50 were computed
using a four-parameter logistic model. The MED is
defined as the lowest dose at which the response is
statistically significantly better than the response at zero-
dose (vehicle). This is interpolated from the dose–response
curve using 95% confidence intervals. ED50 is defined as
the dose at which the response is 50% of the maximal
efficacy. Since the variability of the response is not equal
across dose levels for these data, the four-parameter
logistic model was fit using appropriate weights for the
response. The weights were estimated by the ‘power-of-
the-mean’ function using the pseudo-likelihood method.
For more details on the four-parameter logistic model and
weighting, see (Chapter 2 of Carroll and Ruppert, 1988,
Transformation and Weighting in Regression, Chapman
and Hall, New York). These analyses were performed
using S-PLUSÓ software/language, version 2000 (Insight-
ful Corp.), using a Windows-2000 workstation.