Field

The reference distribution the design supplies

Hold the outcomes fixed, re-run the rule that assigned them, and count. A p-value built that way needs no assumption about the outcomes, no large-sample argument and no nuisance parameter — it needs to be told the rule, which is the one thing the experimenter already knows. It repairs the adaptive design the previous field leaves broken, and it is not free.

The allocations the rule could have made, from these exact patients. One 200-patient trial allocated by response-adaptive randomisation, re-randomised 999 times. No outcome is redrawn anywhere in this figure: each re-randomisation runs the same rule over the same patients in the same order, so what is drawn is the set of experiments that could have happened rather than a sampling distribution. The observed |z| is 1.417, 258 of the 999 re-randomisations reach it, and the p-value is (1 + 258)/(1 + 999) = 0.2590. The curve is the half-normal the ordinary analysis reads the same statistic against; its 5% point is 1.96 and this distribution's is 2.101.

The experiments that could have happened

An adaptive trial's allocation is a function of the outcomes it will later be compared against, so the ordinary analysis rejects a true null 9.2% of the time. Hold the outcomes fixed, re-run the rule that assigned them, and count — the same statistic against a reference distribution the trial could actually have drawn from is back at 4.0%.

The test that needs the rule

A randomisation test assumes almost nothing about the data and one thing about the experiment. Tell it a fair coin produced an allocation that an adaptive rule produced — which is what every off-the-shelf permutation routine does — and it rejects 8.0% of true nulls where knowing the rule gives 4.0%.

Where the +1 matters, and why nobody has noticed that it does. The true size of the two rules at every B, computed rather than simulated: under the null the count of re-randomisations reaching the observed statistic is uniform over {0 … B}, so both sizes are integer arithmetic. With the +1 the size is (⌊α(B+1)⌋)/(B+1), which never exceeds 5%. Without it the size is (⌊αB⌋+1)/(B+1), which is larger except at B = 19, 39, 59 — the values with B + 1 a multiple of 1/α, and the values everybody uses. At B = 19 the two rules are the same rule; at B = 20 the uncorrected one is a 9.5% test. The marks are simulated on 500 trials of 120 patients, as the second route to the same numbers.

The plus one and the round number

A sampled randomisation test counts the observed allocation as one of its own reference draws, and the correction is invisible at B = 19, 39, 59 and 999 — every value anybody uses. At B = 20 the version without it is an 8.00% test where the corrected one is 3.80%, and the convention protecting everybody is a preference for round numbers minus one.

The cheap repair needs a number nobody has. The obvious alternative to re-randomising is to simulate the design under its null once and use the critical value that comes out — which is what the arm-dropping design does, where the critical value has to be solved for and is 2.313. It does not transfer here. The rule chases outcomes, so how imbalanced the allocation gets depends on how often anything succeeds, and the critical value moves from 1.668 at a success rate of 0.05 to 2.718 at 0.8. Calibrated at 0.3 and used at 0.8 the test's real size is 12.4%; used at 0.05 it is 0.12%. The randomisation test needs none of this, because it conditions on the outcomes that happened rather than on a rate they were supposed to come from.

What the exactness buys

Against a z test calibrated to reject exactly 5% of true nulls on this design, the randomisation test loses nineteen points of power. What it buys is that the calibration needs the success rate — which moves the critical value from 1.668 to 2.718 and is the quantity the trial was run to find out.

An exact test rejecting a true hypothesis a fifth of the time. How often each analysis reports an effect when the average treatment effect is exactly zero and the effect varies between units, at 150 units with 25% treated. The permutation test on the difference in means reads 4.20% where the effect is constant — where the two nulls coincide and its exactness applies — and 22.93% where the effect varies with a standard deviation of 3. The same test on the studentised difference reads 6.27% there, and the ordinary large-sample t, which makes no exactness claim at all, reads 6.60%.

The null the exactness is for

A permutation test is exact under the hypothesis that the treatment changed nothing for anybody. Under the hypothesis it changed nothing on average, with a quarter of the units treated and the effect varying between them, it rejects a true null 22.93% of the time.

One statistic that is right under both hypotheses. Rejection rates for both statistics under both nulls, at 25% of 150 units treated, with the weak-null readings taken at an effect spread of 3. The difference in means is exact under the sharp null and rejects 22.93% of true weak nulls. The studentised difference is exact under the sharp null — 4.07% — and reads 6.27% under the weak one. The repair is a change of statistic inside the same construction: the same re-randomisations, the same fixed outcomes, a different number compared across them.

A statistic that is exact twice

Dividing the difference in means by its own separate-variance standard error before permuting takes the rejection rate under a true weak null from 20.47% to 6.07%, keeps the exactness under the sharp null at 4.07%, and costs 0.8 points of power against a real effect. At an even split it changes nothing at all, in every draw.

How often four permutation tests of a covariate-adjusted effect reject a true weak null, effect varying with the outcome, 25% of 150 treated. At an effect spread of 0, 0.5, 1, 1.5, 2: the adjusted coefficient's permutation test rejects 5.9%, 10.8%, 13.2%, 16.6%, 14.8%; over its sandwich standard error, 5.7%, 5.0%, 3.4%, 3.4%, 3.0%; the coefficient with a treatment-by-covariate interaction, 5.1%, 10.2%, 12.8%, 14.7%, 14.0%; the same over its sandwich standard error, 5.7%, 5.2%, 5.2%, 5.1%, 3.9%.

The repair, with a covariate in it

Studentising a permutation test's statistic made the difference in means exact under the sharp null and nearly right under the weak one. Carried to the covariate-adjusted estimate a trial actually reports, the repair works only if the adjustment includes the treatment-by-covariate interaction. With a quarter of 150 units treated and effects that vary with the outcome, the adjusted estimate's permutation test rejects 14.8% of true weak nulls; over its sandwich standard error, 3.0%; the interacted estimate over its sandwich, 3.9%. When the effect varies with the covariate itself, even an even split does not protect: the adjusted test rejects none of a thousand true weak nulls, and at an average effect of 0.2 its power is 5.2% against the interacted, studentised test's 40.7%.

How often an adjusted permutation test rejects a true sharp null when the covariate is chosen after randomisation, held fixed or re-chosen inside every shuffle. 150 units, half treated, six baseline covariates of which three are prognostic; 2,000 experiments and 99 re-randomisations each, read on the adjusted coefficient over its sandwich standard error. Choosing the covariate most correlated with the outcome: 5.0% held fixed, 5.0% re-chosen. Choosing the covariate with the smallest residual variance: 5.5% held fixed, 5.3% re-chosen. Choosing the covariate most imbalanced between the arms: 3.0% held fixed, 4.8% re-chosen. Choosing the covariate with the smallest adjusted p-value: 10.4% held fixed, 5.1% re-chosen. Naming the most prognostic covariate in advance: 5.5%.

The covariate chosen afterwards

A trial that chooses which baseline covariate to adjust for after randomisation has two ways to run its permutation test: hold the chosen covariate fixed across the shuffles, which is what an analysis that reports adjusting for it actually does, or re-make the choice inside every shuffle, which is exact by construction. Holding it fixed, a choice made on significance rejects 10.4% of true sharp nulls, a choice made on imbalance only 3.0% — and pays seven and a half points of power for it — while a choice that never reads the arm labels is the same test either way. The interacted, studentised statistic keeps its weak-null behaviour only when the covariate chosen is the one the effect varies with.

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