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Re: st: pk analysis suite: elementary questions about -pkequiv-, -pkcross-, and -pkshape-


From   Michael McCulloch <mm@pinestreetfoundation.org>
To   statalist@hsphsun2.harvard.edu
Subject   Re: st: pk analysis suite: elementary questions about -pkequiv-, -pkcross-, and -pkshape-
Date   Fri, 19 Feb 2010 21:55:06 -0800

Dear Joseph,
Thank you kindly for the very helpful response and example.
You write "the potential for carryover effects (by whatever name) to confound crossover studies is often more serious with outcomes other than chemical concentrations." Might you be able to recommend some reading (either published or online tutorials) on this issue in crossover studies?
Best regards,
Michael McCulloch


On Feb 19, 2010, at 8:11 PM, Joseph Coveney wrote:

Michael McCulloch wrote:

I'm studying the manual (v11) for the pk suite, and have 3 questions:
1. Regarding the "carry" variable created by -pkshape-, in the manual
example (p. 1325), is "carry" simply an indicator that shows whether
or not a measurement was made in the same period/treatment
combination, so that if
	"carry"==0, then no carryover is possible, and if
	"carry"==A, then a carryover effect is possible, but no evidence yet?

2. Can -pkcross- be used in to compare treatment response (e.g. pain
score) in an AB-BA crossover study design, that was not a test of a
biopharmaceutical drug concentration?

3. -pkequiv- performs bioequivalence tests using serum levels of
biopharmaceutical drug concentration. Can the command also be used
instead to measure *any* continuous outcome, measured following some
other non-pharmaceutical intervention?

--------------------------------------------------------------------------------

1. Carryover is a term that indicates what the treatment (drug formulation) was in the immediately preceding period. Carryover is zero during the first period; afterward (where the potential for carryover effects is of concern) its pattern distinguishes between sequences of first-through-penultimate treatments. In the two-sequence, two-formulation, two-period crossover design (i.e., AB BA), during the second period it is 1 for one of the treatments and 2 for the other. You can get a handle on what it does by inspecting the variables -treat- and -carry-
after running the do-file below.

2. There's no reason why not. As far as I'm aware, -pkcross- is nothing but a convenience command that calls -anova- and displays the ANOVA table in a format more familiar to biopharmaceutics scientists. Crossover study designs are not unique to pharmaceutical equivalence evaluation. And although the phenomenon is called "carryover" in biopharmaceutics, you will have the same concern in other disciplines, namely, that the first exposure to a condition might change things
so that a second exposure will result in a different score ("learning
phenomenon", "sensitization", "desensitization", "stimulus fatigue", "acquired
tolerance").

3. Again, there is no reason not to: the term *equivalence* has more general usage than for drug concentrations in blood plasma. Keep in mind that the potential for carryover effects (by whatever name) to confound crossover studies is often more serious with outcomes other than chemical concentrations. And it
sometimes gets tricky even with the latter.

Joseph Coveney

clear *
set more off
set seed `=date("2010-02-20", "YMD")'
input str1 trt
"A"
"B"
"C"
end
tempfile tmpfil0
save `tmpfil0'
rename trt seq
forvalues replicate = 1/2 {
   cross using `tmpfil0'
   replace seq = seq + trt
   drop trt
}
erase `tmpfil0'
generate byte id = 3
expand id
sort seq
replace id = _n
forvalues per = 1/3 {
   generate byte period`per' = floor(runiform() * 100)
}
pkshape id seq period1 period2 period3
sort id period
order id sequence period treat carry outcome
list, noobs sepby(id)
exit



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Best wishes,

Michael McCulloch
Pine Street Foundation
124 Pine Street
San Anselmo, CA 94960-2674
tel:	415-407-1357
fax: 	206-338-2391

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