Bioequivalence and Bioavailability Forum 09:34 CEST

Main page Policy/Terms of Use Abbreviations Latest Posts

 Log in |  Register |  Search

jag009
Hero

NJ,
2016-12-20 04:48

Posting: # 16860
Views: 3,285
 

 Significant period effect [Design Issues]

Hi all,

Question. What can cause a period effect? Aside from carryover due to poor washout selection, and other unexplanable events (which I can't think of)?

If someone decides to analyze study samples by period instead of analyzing the samples after completion of all study periods, could that cause a significant period effect?

Is it possible to determine the interaction between period and sequence effect?

Thanks
John
ElMaestro
Hero

Denmark,
2016-12-20 12:17

@ jag009
Posting: # 16867
Views: 2,889
 

 Significant period effect

Hi jag009,

» Question. What can cause a period effect? Aside from carryover due to poor washout selection, and other unexplanable events (which I can't think of)?

Lots of speculation out there and regrettably very little actual substance.
Carry-over in terms of pharmacological effect (e.g. some effect on the liver or intestine starting after dosing in period 1, still present in period 2). Anxiety, "this drug made me sick in period 1, hell, I am going to get sick in period 2, too" and John Doe will have diarhoea way before he event reports to the clinic but won't say anything out of fear of reduced compensation. And so forth. Don't waste your time medlining it.

» If someone decides to analyze study samples by period instead of analyzing the samples after completion of all study periods, could that cause a significant period effect?

Well, in theory, yes? But then again. This is highly speculative and there would be a need to find the root cause (like stock instability of the IS or something like that).

» Is it possible to determine the interaction between period and sequence effect?

Yes. It is a treatment effect.
E.g. Period 1 in (or x) Sequence TR is effectively just treatment T (in that period). Note that some serious DF elimination may come into play depending on how you specify the model. For example, in the model matrix the columns for "period 1 in Seq TR" and "period 2 in Seq RT" will add up to exactly the column for the Treatment T effect. If you have the interaction before the treatment in your model spec, then the latter will get a type I SS and MS of zero.

if (3) 4

Best regards,
ElMaestro

"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
d_labes
Hero

Berlin, Germany,
2016-12-21 10:45

@ ElMaestro
Posting: # 16869
Views: 2,798
 

 period x sequence

Dear ElMaestro,

» » Is it possible to determine the interaction between period and sequence effect?
»
» Yes. It is a treatment effect.
» E.g. Period 1 in (or x) Sequence TR is effectively just treatment T (in that period). Note that some serious DF elimination may come into play depending on how you specify the model. For example, in the model matrix the columns for "period 1 in Seq TR" and "period 2 in Seq RT" will add up to exactly the column for the Treatment T effect. If you have the interaction before the treatment in your model spec, then the latter will get a type I SS and MS of zero.

IMHO your description is totally correct.

But my judgment to Johns question would be different:
No. Its not possible to to determine the interaction between period and sequence effect and the treatment effect in a classical 2x2 crossover. Both terms are confounded.
It's the same situation if you try to determine a carry-over effect and a direct sequence effect simultaneously.

Regards,

Detlew
jag009
Hero

NJ,
2016-12-21 22:21

@ d_labes
Posting: # 16872
Views: 2,685
 

 period x sequence

Thanks guys.

Yup d_labes, I tried to test for the interaction and it wasn't possible...

I was wondering if the lab did analyze samples by period but they didn't do that. So I guess it's a dead end...

John
libaiyi
Junior

China,
2018-06-29 12:02

@ ElMaestro
Posting: # 18996
Views: 859
 

 Significant period effect

Hi,ElMaestro

Sorry to reply in so many years. When I search for the reason of period effect, I found this post.

» » Question. What can cause a period effect? Aside from carryover due to poor washout selection, and other unexplanable events (which I can't think of)?
»
» Lots of speculation out there and regrettably very little actual substance.
» Carry-over in terms of pharmacological effect (e.g. some effect on the liver or intestine starting after dosing in period 1, still present in period 2). Anxiety, "this drug made me sick in period 1, hell, I am going to get sick in period 2, too" and John Doe will have diarhoea way before he event reports to the clinic but won't say anything out of fear of reduced compensation. And so forth. Don't waste your time medlining it.

I am a little confused that do you mean that carryover may cause carryover effect and period effect at the same time?

Thank you so much.
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2018-06-29 12:35

@ libaiyi
Posting: # 18998
Views: 854
 

 Confounded effects

Hi libaiyi,

» I am a little confused that do you mean that carryover may cause carryover effect and period effect at the same time?

See this post for examples: Two others here:
  • Period effect: 0%
    Sequence (carryover) effects: RT +20%, TR +20%
                           period     sequence
      sequence            1      2      means
         RT             100    114      107
         TR              95    120      107.5
    period means         97.5  117      107.25
    treatment means  R  110
                     T  104.5
                   T/R   95.00%

    Unbiased treatment effect in the presence of a period effect.
    Unbiased treatment effect in the presence of equal carryover effects.

  • Period effect: +10%
    Sequence (carryover) effects: RT +10%, TR +10%
                           period     sequence
      sequence            1      2      means
         RT             100    114      107
         TR              95    120      107.5
    period means         97.5  117      107.25
    treatment means  R  110
                     T  104.5
                   T/R   95.00%

    Unbiased treatment effect in the presence of a period effect.
    Unbiased treatment effect in the presence of equal carryover effects.
In a 2×2 design some effects are confounded (see what Detlew wrote above). Hence, if there are true and equal carryover effects, results are exactly the same as if there are none and only a true period effect (the second example in the other post).
I guess you could only sort it out with full replicate designs where you have sequences containing TT and RR (TRRT|RTTR, TTRR|RRTT, or TRR|RTT).

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
libaiyi
Junior

China,
2018-07-03 09:52

@ Helmut
Posting: # 19009
Views: 751
 

 Confounded effects

Hi, Helmut

Thank you so much! I understand now.
Back to the forum Activity
 Thread view
Bioequivalence and Bioavailability Forum |  Admin contact
18,761 posts in 3,996 threads, 1,264 registered users;
online 24 (0 registered, 24 guests [including 14 identified bots]).

The purpose of models is not to fit the data,
but to sharpen the questions.    Samuel Karlin

The BIOEQUIVALENCE / BIOAVAILABILITY FORUM is hosted by
BEBAC Ing. Helmut Schütz
HTML5 RSS Feed