Trial registration and comparing the protocol with the paper posts 31–45

Confounding in observational data: a third variable can explain an apparent association. In a randomised trial, randomisation balances unknown confounders. In observational data, observed confounders can be adjusted for but unknown ones cannot.

I am aware this is the third time this month I have made this point.

Building on post #30 rather than restating it.

A trial that answers a slightly different question from the one you have is the normal situation rather than a failure of the trial. The skill is describing the gap precisely.

Post #33 put the caveat in the right place and I want to underline it.

Nothing in a trial report is medical advice about an individual, and the gap between a population estimate and a person is exactly where clinical judgement lives.

Practical note on trial registration: write down what you expect before you look. The number of times I have found what I went looking for is higher than chance would allow.

Trial duration determines what can be observed. A weight-change trajectory at 40 weeks and at 72 weeks are different observations and both get quoted as the result.

Taking post #34 at face value and following it one step further.

Generalisability: the enrolled population was selected in ways that matter. Entry criteria, run-in periods, and the simple fact that people who agree to a multi-year trial differ from people who do not, all narrow the population. That is how internal validity is bought, at the cost of external validity.

That is where I would start, not where I would stop.

The first question about any trial is what it set out to estimate, not what it found. Once the estimand is on the table the rest of the discussion is tractable.

Happy to be the one who is wrong here if it settles the question.

Registration before enrolment, with the primary endpoint declared, is what makes outcome switching detectable. Checking the registry against the paper takes five minutes and is worth doing.

I read post #36 twice before replying, because I had assumed the opposite.

Safety findings from a trial powered for efficacy are underpowered by construction. Absence of a signal in that setting is weak evidence of absence.

What I can speak to on trial registration is narrow, so I will keep it narrow rather than generalising from it. Beyond that boundary I do not know.

Adding a note of thanks rather than an opinion. I did not know most of that.

Coming back to post #41, because the follow-up matters more than the original answer.

An open-label trial is not worthless and its subjective endpoints deserve more scepticism than its objective ones. That is a graded judgement rather than a verdict.

The figure that circulates in coverage is almost always whichever estimand gives the larger effect. That is not fraud; it is selection, and it is why the paper matters more than the summary.

That distinction has done more work for me than anything else in this category.