GM
★

India,
2019-07-20 07:36
(389 d 21:18 ago)

Posting: # 20410
Views: 2,279

## Possible reasons for group effect [Design Issues]

Hello Bebac Friends,

Hope all are doing well...!!!

When I am reading about fixed effects used in general crossover studies and possible reasons for significant results of these fixed effects, I didn't found any relevant reasons for the significant group effect.

Anybody know about the possible reasons for significant group effect...?

Best Regards,
GM
Helmut
★★★

Vienna, Austria,
2019-07-20 14:02
(389 d 14:52 ago)

@ GM
Posting: # 20413
Views: 2,041

## Group “effect”

Hi GM,

» […] fixed effects used in general crossover studies and possible reasons for significant results of these fixed effects, I didn't found any relevant reasons for the significant group effect.

The p-value tells you only how likely something occurs. If you set your limit to 0.05 that means that you consider a p-value <0.05 denoting an effect which occurred not by pure chance. The reason for an effect is beyond the reach of statistics.
Think about the subject-term. It is always highly significant.* Recode the common effects to something neutral (say, response → Y, sequence → a, subject → b, period → c, treatment → d ) and provide the data to a statistician without telling the background to evaluate the linear model $$\ln(Y) \sim a+b+c+d$$ or – if you insist on the stupid over-specified one given in the guidelines – $$\ln(Y) \sim a+b(a)+c+d$$ Hey, $$p(b)$$ or $$p(b(a)) = 0.00000314$$. Now ask for a “reason”.

Science is wonderfully equipped to answer the question “How?”
but it gets terribly confused when you ask the question “Why?”
Erwin Chargaff

Ask a physicist what gravity is. No, not how it is described in physics. You will be surprised.

» Anybody know about the possible reasons for significant group effect...?

Chance? IMHO, testing for it is futile (see there).

• Unless you perform the study in cloned subjects, which would violate an assumption of the model, namely independence. If I would ever see a study with a p-value >0.05 for the subject effect it would ring my alarm bells.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ElMaestro
★★★

Belgium?,
2019-07-20 19:20
(389 d 09:34 ago)

@ GM
Posting: # 20414
Views: 1,992

## Possible reasons for group effect

Hello GM,

there are always potential jokers in play:

1. Check if the volunteers within groups have something in common.
Were they recruited in a different manner, in spite of all subjects fulfilling the enrollment criteria? I have seen cases of that recently.
Eyeball if body weight, gender mix, age, or some other factor may differ a bit between groups. If it does then there is a likely -and I am not saying definite- reason, but it is not one associated with a ton of literature.

2. The use of groups is often a capacity issue, relating to the number of beds at the CRO.
Groups are then separated in time, for example by days or weeks, sometimes even months. And time has funky effects, not only on individuals but also on groups of individuals.
Heat wave in Mumbai? Some subjects will be borderline dehydrated when showing up, and they will not feel much like walking around.
Pollen season just set in in Winchester VA? Some subjects will be coughing and wheezing when showing up, even if they don't have a medical history of allergies.
I saw a TV add about vegan diets yesterday. Therefore, brainwashed as I am, the next two weeks I will be buying all the bran and celery soup available in the supermarket and I will be going full tilt into that thing until I realise it is just killing my quality of life, and all the while I will have a changing phenotype of sorts. Until I start living normally again. I find some comfort in knowing that there are others who saw the same TV add and who are suffering the same phenomenon (and the owner of the company selling celery is likely going on monthly vacations to Tonga or some such remote and exotic place, due to victims of his affairs like me, but this is another story).

And so forth.

Finally, bear in mind that phase III studies across centers often have significant center effects. I think this phenomenon is much comparable to the group effect, honestly. Such phase III trials get approved.

The group effect questions from regulators are often not too difficult to handle. They do not become a cause for rejection in my experience.

I could be wrong, but...

Best regards,
ElMaestro

"Pass or fail" (D. Potvin et al., 2008)
GM
★

India,
2019-07-23 06:23
(386 d 22:32 ago)

@ ElMaestro
Posting: # 20433
Views: 1,894

## Possible reasons for group effect

Hi Helmut and ElMaestro,

Thanks for reply. It helps me a lot.

I have seen one FDA BE review (see link) regarding group effect. Please see page 6 (Reviewer’s Comments) and page 52 (control document).

Here agency is asking for the BE of any one of the group, if group-by-treatment interaction is significant (p<0.05). Is it possible in studies conducted on HVD?

Best Regards,
GM
Helmut
★★★

Vienna, Austria,
2019-07-23 10:32
(386 d 18:22 ago)

@ GM
Posting: # 20435
Views: 1,872

## “Group-by-Treatment Interaction”

Hi GM,

» I have seen one FDA BE review […].

Yep, the 1999 (!) infamous one. Groups separated by two weeks. See the FDA’ applicable guidance (2001), Section VII.A.

» Here agency is asking for the BE of any one of the group, if group-by-treatment interaction is significant (p<0.05).

0.1 not 0.05. BTW, did you bother reading the presentation I linked in my OP?

» Is it possible in studies conducted on HVD?

Do you have a replicate design in mind? For ABE, no problem. For the EMA’s ABEL, doable. For the FDA’s RSABE, difficult. Ask three statisticians only to get get four options. Possible that the FDA insists on the fifth nobody has thought about. Difficult terrain.

Let’s assume that you plan the study in such a way that groups are not expected to differ (see ElMaestro’s post).
• FDA, Gulf Cooperation Council, Russian Federation, Eurasian Economic Union
Give a justification (in the protocol!) that all criteria will be met and go full throttle with the pooled analysis.
FDA: If in doubt, start a controlled correspondence.
The others: There are no scientific advices, only private dinners. Consider ‘Model II’.
• EMA
Thousand of studies accepted in multiple groups without problems (two exceptions in my presentation). If you prefer braces with suspenders, state ‘Model II’ in the protocol. Loss in power compared to the pooled analysis is negligible.
Do not (!) apply the framework suggested by the FDA in the dark ages!
• If there is no true group-by-treatment interaction, in 10% of cases you will detect one by pure chance (false positive). No pooling, analysis of separate groups, power to show BE – even in the largest one – low.
• Any pre-test can inflate the Type I Error.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes