Normal Distribution
nothing is called 95% until it has been counted
Concept

Interim analysis — where it appears

Looking at the data before the experiment is finished, usually to decide whether to continue. Every look is a chance to reject, so a procedure that looks ten times at the nominal level rejects a true null far more often than the level says.

Named by 8 essays across 3 fields — each of them below, with the objects they name alongside it.

Testing at 0.05 every time the data is looked at. The null is true in every one of these trials and the test is correct every time it is run. Looking once rejects 4.9% of the time, as it should; looking ten times rejects 19.2% of the time. Nothing changed except permission to look.

When the looking happens

A p-value is defined relative to a sampling plan, so the same data means different things under different stopping rules. Testing five times at the nominal level rejects a true null 14% of the time, and no observation in the dataset changed.

sequential · Stopping The best of 8 arms, tested as though it were the only one. 8,000 trials with no effect in any arm. Stage one runs 8 arms at 60 each, the best is carried forward, and stage two adds 30 more to it and to the control. The histogram is where the final statistic lands and the curve is the standard normal it is being read against — shifted right, because the arm was chosen for being ahead. 10.5% of these trials clear 1.96 against a claimed 5%, and the value that actually holds the rate for this design is 2.313.

Dropping the losers

Carrying the best of eight arms forward and testing it at 1.96 rejects a true null 10.3% of the time — the hypothesis was chosen by looking at the data, so the statistic is a maximum wearing a single comparison's clothes. The value that holds the rate is 2.313, and it has to be solved for.

adaptive · Stopping Forty O'Brien–Fleming trials at a true effect of 0.16, with the boundary written as an effect. The dashed line is the smallest effect a trial can report and still stop at each look: 0.510 at 80 observations, 0.255 at 160 observations, 0.170 at 240 observations, 0.128 at 320 observations, 0.102 at 400 observations. The true effect is 0.16, so at 3 of the five looks a trial cannot stop without reporting more than it. 29 of these forty trials stop before the last look, each marked where it stopped.

The effect a stopped trial reports

An O'Brien–Fleming trial at 88.45% power holds its error rate exactly and reports an effect 9.6% too large on average. The 11.39% of trials that stop at the second look report 1.83 times the truth, the ones that cross at the last look report 0.80 times it, and pooling every trial by its size gives the truth back to the last digit.

sequential · Stopping Three estimates of the same effect, and the honest one is the worst. 8,000 trials in which every arm has an effect of exactly 0. The arm carried forward is reported by its first stage at +0.187 above the truth — it was chosen for being ahead — and by its second stage at -0.0032, which is unbiased by construction because the selection could not see it. The combination that gets published is at 0.123, exactly the share of the first stage's bias the first stage contributes. Root mean squared error: 0.240, 0.261, 0.182 — the unbiased estimate is the least accurate of the three.

The estimate after the choice

An arm chosen for being ahead is ahead by more than it should be, and the trial then publishes the average of the stage that chose it and the stage that did not. The unbiased estimate is the one built from a third of the data — and it is the least accurate of the three.

adaptive · Curse Ordered stagewise: the outcomes at least as extreme as stopping at 160 observations with z = 3.3. Each column is one look of an O'Brien–Fleming trial; above the boundary a trial stops there. Highlighted are the outcomes that count as at least as extreme as the observed one when outcomes are ordered stagewise: at 80, z ≥ 4.56 (probability 2.54 × 10⁻⁶ with no effect); at 160, z ≥ 3.30 (probability 4.82 × 10⁻⁴ with no effect); at 240, none; at 320, none; at 400, none. The two-sided p-value is 9.69 × 10⁻⁴.

The outcomes a trial could have stopped with

A trial that stops at its second look with z = 3.3 has a two-sided p-value of 0.000969, 0.000987, 0.00187 or 0.0421, depending on how the outcomes it could have stopped with are ordered. One of the four orderings does not change when the looks the trial never reached are replanned, and the same one gives a trial that ran to the end with z = 6 a p-value of 0.0256.

sequential · Stopping Twenty runs simulating an exactly 95% interval, checked every 250 replications. Each line is one run's running estimate; the dashed band is where the Wilson interval of the running estimate still contains 95%, and a run stops, marked, the first time it leaves the band. 8 of these twenty stop before 10,000 replications. The exact probability of stopping, from the recursion over the count, is 29.54%.

A simulation that stops when it looks settled

A simulation of an interval that covers exactly 95%, checked every 250 replications for a significant departure and stopped when it finds one, flags that correct interval on 29.54% of runs. Stopped instead as soon as its estimate reaches 95%, it reports an interval that covers 94% as meeting its level on 37.21% of runs. Stopped when the estimate stops moving, it reports the right number — and has quietly chosen to run about fifteen hundred replications.

method · Seeds Forty trials at a true effect of 0.16, under the rule "power at the trend < 10%". The upper line is the benefit boundary (4.56, 3.23, 2.63, 2.28, 2.04); the lower line is where the rule stops a trial for futility (0.40 at 80, 0.66 at 160, 0.95 at 240, 1.31 at 320). Of forty trials with a real effect, 29 cross for benefit and 11 are stopped for futility.

A boundary for giving up

Adding "stop if z is below zero" to an O'Brien–Fleming trial costs 5.20 points of power at the effect it was designed for and halves the observations a trial with no effect uses. Stopping when conditional power at the observed trend falls under 10% costs 13.23 points and stops 21.28% of trials with a real effect. Making that rule binding lowers the benefit boundary from 2.040 to 1.901, and a binding rule that is then ignored rejects a true null 3.523% of the time instead of 2.5%.

sequential · Stopping The chance of crossing later from each interim z, under six schedules with O'Brien–Fleming-type spending boundaries. Exact. At an interim |z| of 1.0: end only 3.64%, +0.6 3.41%, +0.75 3.20%, +0.9 3.41%, every 0.125 3.00%, every 0.05 2.88%. At 2.5: end only 38.30%, +0.6 45.80%, +0.75 45.36%, +0.9 41.70%, every 0.125 50.08%, every 0.05 53.24%. The heavy line is the largest of the six at each z.

A look the trend asked for

Under an O'Brien–Fleming-type spending function, every schedule of looks fixed in advance spends exactly 5.0000%. A committee that adds a look at three quarters of the trial whenever the interim z is 1.5 or more spends 5.2323% — 5.315% counted over a hundred thousand trials — and the most a committee choosing among six schedules could spend is 5.4390%.

sequential · Stopping

Named alongside it

The objects these essays reach for when they reach for this one.

Error rateClosed formStopping ruleGroup-sequential designMonte CarloO'Brien–FlemingSelection biasStatistical powerSample sizeStagewise orderingAdaptive designConditional distribution

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