Bioequivalence and Bioavailability Forum • Significant period effect

jag009
★★★

NJ,
2016-12-20 05:48
(3017 d 11:06 ago)

Posting: # 16860
Views: 10,845

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
★★★

Denmark,
2016-12-20 13:17
(3017 d 03:37 ago)

@ jag009
Posting: # 16867
Views: 9,690

Significant period effect

Post reply

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.

—
Pass or fail!
ElMaestro

d_labes
★★★

Berlin, Germany,
2016-12-21 11:45
(3016 d 05:09 ago)

@ ElMaestro
Posting: # 16869
Views: 9,740

period x sequence

Post reply

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 ★★★ NJ, 2016-12-21 23:21 (3015 d 17:33 ago) @ d_labes Posting: # 16872 Views: 9,444	period x sequence Post reply
	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
★

China,
2018-06-29 14:02
(2461 d 03:52 ago)

@ ElMaestro
Posting: # 18996
Views: 7,630

Significant period effect

Post reply

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
★★★

Vienna, Austria,
2018-06-29 14:35
(2461 d 03:19 ago)

@ libaiyi
Posting: # 18998
Views: 7,815

Confounded effects

Post reply

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).

—
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Helmut Schütz

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Science Quotes

libaiyi ★ China, 2018-07-03 11:52 (2457 d 06:02 ago) @ Helmut Posting: # 19009 Views: 7,599	Confounded effects Post reply
	Hi, Helmut Thank you so much! I understand now.