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

Stopping — the series

20 essays on one idea, from the one that introduces it to the one that assumes the rest.
  1. 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.

    part 1 · sequential
  2. Four boundaries for 5 looks, all spending 5% in total. test at 0.05 every look: 1.96, 1.96, 1.96, 1.96, 1.96. Pocock — a constant, higher boundary: 2.41, 2.41, 2.41, 2.41, 2.41. O'Brien–Fleming — strict early, nearly nominal at the end: 4.55, 3.22, 2.63, 2.27, 2.03. Bonferroni across looks: 2.58, 2.58, 2.58, 2.58, 2.58. Every one except the first spends the same total error rate; they differ in when they spend it.

    Spending the error rate

    The repair for interim testing is to spend 5% across the looks rather than at each one. The boundaries are solvable rather than quotable, and a trial that can stop early uses 298 observations where a fixed design uses 400 — at a cost of half a point of power.

    part 2 · sequential
  3. What the interim sees, at an effect of 1. The same 60 observations, estimated two ways. Keeping the arms separate gives 0.995, which is σ. Pooling them without separating the arms — the price of staying blind to the comparison — gives 1.114, against the identity √(1 + Δ²/4σ²) = 1.118. The sample size is proportional to the variance, so a blinded design at this effect asks for 25% more units than it needs, and it does so systematically rather than by chance.

    Choosing n after looking

    Re-estimating the sample size from an interim is the one adaptation with a defence, and the defence is exactly what it costs: an analyst kept blind to the arms measures a spread that contains the effect, so the design overshoots by 1 + Δ²/4σ². Re-estimating the effect instead breaks the error rate.

    part 3 · adaptive
  4. 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.

    part 4 · adaptive
  5. One rule keeps its promise and the other keeps its budget. Both stopping rules at five requirements, 1,500 experiments each, with a first stage of 5. The upper curve is the two-stage rule: 97.1%, 96.2%, 95.9%, 96.1%, 96.0% — at or above 95% at every point, which is a theorem rather than a tendency, because its interval is built from a spread estimated before the stopping point was chosen. It pays 2.06×, 2.01×, 2.00×, 1.99×, 1.99× the observations that knowing σ would need. The lower curve is the rule that re-estimates after every observation: 94.5%, 89.3%, 91.0%, 91.5%, 94.3%, on 0.98×, 0.87×, 0.88×, 0.93×, 0.96×. The second rule is the one anybody would run and the first is the one whose claim is true.

    Stopping when it is precise enough

    An experiment that runs until its estimate is precise enough is the natural design and the one with a theorem against it. Its two-stage cousin keeps its promise exactly, for every unknown spread, and pays twice the observations for it.

    part 5 · guarantee
  6. Four intervals at one stopping time. 3,500 experiments under the sequential rule with a first stage of 5 and a required half-width of 0.4, which is a demand that knowing σ would meet with 24.0 observations and which the rule meets with 20.8. The rule's own interval covers 90.3%. Replacing the fixed width by a t interval on the same data gives 92.0%. Keeping the rule's own random sample size and drawing a fresh sample of that size gives 89.8% at the fixed width and 95.5% for a t interval — so the sample size being random costs nothing, and the sample size being chosen by the data the interval is built from costs the rest. The spread estimated at the stopping moment is 17.1% below the truth, which is the same fact one level down.

    The interval after a stop it chose

    A rule that stops when the estimated precision is good enough stops on the samples whose estimate was small. Its interval covers 90% and claims 95%, and a fresh sample of the same random size covers 95.4%.

    part 6 · guarantee
  7. Exact coverage, at every block size. Coverage of the interval each rule reports, at a nominal 95%, over 2,500 runs each with a standard error of 0.44 points. The blinded rule stops on the within-block contrasts and reports an interval built from the block means, and those two are independent whatever the rule does — so the interval is an ordinary t interval on b − 1 degrees of freedom and its coverage is exact. It is exact at every block size drawn. The interval a practitioner writes at the purely sequential rule's stopping time covers 91.72%, and Stein's two-stage rule is exact for the same reason as the blinded rule and spends 2.10 times the observations to be so. The bars are truncated at 86% so the differences can be seen.

    The rule that cannot see the mean

    A sequential rule stops when its own estimate of the spread is small, which is more often on the samples whose spread came out low — so the interval afterwards is short. There is a way to keep updating the estimate and stop being able to see the mean at all.

    part 7 · blind
  8. A third stage, between the two rules. Four rules for one requirement: a half-width of 0.4 at 95%, which knowing σ would meet with 24.0 observations, after a first stage of 5. Each bar is the mean number of observations as a multiple of that, and the note beside it is the coverage. The two-stage rule spends 2.03× and covers 95.42%, computed exactly. The three-stage rule — a second stage to half of what the first spread asks for, the spread re-read on everything, a third stage to the rest — spends 0.86× and covers 88.42%; given 8.50 more observations in every experiment's last stage it covers 95.00% on 1.20×. The rule that re-estimates after every observation spends 0.88× and covers 90.5% over 4,000 drawn experiments; it is the only row that has to be drawn, because it is the only one whose stopping point shares observations with the mean.

    The fifth a third stage never reaches

    A three-stage stopping rule keeps the two-stage rule's independence and the sequential rule's budget. With a first stage of five it covers 88.4% — worse than the rule it was meant to repair — because in a fifth of experiments the second stage buys nothing.

    part 7 · guarantee
  9. One experiment, with the blocks getting smaller as the target comes into range. A single run at a requirement of 0.25, with the block sizes 5, 5, 11, 25, 11, 8, 3, 2 and a total of 70 observations in 8 blocks. The rule stops when the observations in hand reach z²σ̂²/d², with σ̂² pooled from the within-block contrasts — an estimate that moves as the run goes on, so the target moves too. Early blocks are large because the target is far away and cannot be overshot; late ones are small because a block is the granularity of the answer. The interval afterwards is built from the 8 block means and from nothing the rule looked at, and it has 7 degrees of freedom against the rule's 62.

    A block size that changes

    The blinded rule's exactness never needed the blocks to be the same size. Letting the size be chosen from the contrasts as the run goes on leaves the coverage exactly where it was — and runs straight into an identity that says what a schedule can and cannot buy.

    part 8 · pace
  10. Three repairs at one requirement. Coverage against spend at a half-width of 0.4 and a first stage of 5, all exact. A floor on the second stage at 5, 8, 10, 12, 15, 18, 21, 24 observations covers 88.4%, 91.4%, 92.4%, 93.1%, 93.9%, 94.6%, 95.3%, 96.0% at 0.86, 0.94, 0.97, 1.00, 1.02, 1.05, 1.09, 1.14 times the oracle's spend. The second stage reading with t, with its fraction dialled from 0.2 to 1, covers 88.1%, 89.0%, 90.6%, 92.1%, 93.4%, 94.4%, 95.2%, 95.9%, 96.4% at 0.84, 0.91, 1.02, 1.17, 1.34, 1.52, 1.70, 1.89, 2.08 times. A constant at the end covers 88.4%, 89.4%, 90.4%, 91.3%, 92.1%, 92.9%, 93.6%, 94.2%, 95.0%, 95.7% at 0.86, 0.90, 0.94, 0.98, 1.02, 1.06, 1.10, 1.14, 1.20, 1.26 times.

    A floor that reads the first stage

    A three-stage stopping rule fails at a first stage of five because a low first reading asks for nothing more, and the only floors that repair it were set near the answer, by somebody who already knew roughly what the spread was. Inflating the first reading by Stein's own factor needs no such knowledge, and it does cut the experiments left stuck from a fifth to a fifteenth. But those still stuck cover less than before, the rule needs a different dial at every requirement, and a floor of 26 observations covers 96.5% at the spend where the rule covers 92.1%, even met by a spread it was not set for.

    part 8 · guarantee
  11. What a schedule is allowed to read, and what happens when it reads more. The construction allows the block sizes to be anything at all as long as they are functions of the within-block contrasts, which are independent of every block mean. A schedule that shrinks the block whenever the between-block spread is running above what the contrasts say is a direct attempt to hold down the quantity the interval will be built from, and it succeeds: the estimate lands at 0.8373σ² against the honest 0.9831, and the coverage goes with it. Growing the block on the same spread instead pushes the other way and over-covers — which is not a repair, it is the same violation with the sign reversed, and the level is no longer a property of the procedure at all.

    A schedule that reads the mean

    The block sizes may be anything at all provided they are functions of the contrasts. Two natural schedules break that, in opposite directions — and the most natural mistake of the three is not a schedule at all but a stopping rule, at 86.87% coverage and fewer observations.

    part 9 · pace
  12. The stopping rule costs more than the weighting does. Coverage over 2000 runs of a trial whose variance ratio drifts by a factor of twenty, at three ways of deciding when to stop. Twelve blocks fixed in advance is the top line and reproduces what a trial of fixed length delivers. Stopping when the reported interval is short enough is the bottom line, and it costs between 3.0% and 5.5% of coverage — including for the rule that is told every block's true ratio, which is what says the shortfall belongs to the stopping and not to the weights. Stopping on a width predicted from the within-arm sums of squares is the middle line, and it is back at the fixed-length values. The standard error on each point is 0.49%.

    A width the trial has to stop for

    The weighting that covers at 94.9% on twelve blocks covers at 91.5% when the trial stops as soon as its interval is short enough — and so does the rule that is told every block's true variance ratio. The shortfall is the stopping, not the weights.

    part 10 · stop
  13. How much of the forbidden spread a stopping rule may read. The rule stops when the observations in hand reach z²ŝ²/d², with ŝ² a blend: a share 1 − κ of the pooled within-block estimate it may read, and a share κ of the between-block estimate the interval is built from, which it may not. At κ = 0 it is the honest rule; at κ = 1 it stops on the reported spread. Each curve is the coverage lost against κ = 0 on the same 6,000 runs, with two paired standard errors, at three requirements. At a half-width of 0.35 the loss is 0.87% at κ = 0.2 and peaks at 3.97%. At 0.25 it is 0.20% at 0.2, 0.98% at 0.5 and 5.50% at 1. At 0.15 nothing measurable is lost until κ = 0.9, and 3.73% at 1. The cost of reading is not proportional to how much is read; it is concentrated where the rule leans on the forbidden spread, and a longer experiment can lean further before paying.

    How much of the forbidden spread a rule may read

    A stopping rule that reads the spread its interval will report breaks the interval. Blend that spread into what the rule reads, a share at a time, and the cost is not proportional to the share — at a tight requirement a rule can read four fifths of it before anything is lost, and the last fifth costs nearly four points.

    part 10 · pace
  14. 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.

    part 11 · sequential
  15. Coverage lost against the honest rule. Coverage lost in points against the rule that reads only within-block spreads, on the same observations, blocks of 2, 6000 runs, at half-widths 0.5, 0.35, 0.25, 0.15. the reported spread in full: 0.32 ± 0.27, 2.53 ± 0.37, 5.33 ± 0.41, 3.75 ± 0.35. a fixed half: 0.72 ± 0.26, 2.43 ± 0.29, 0.98 ± 0.26, -0.25 ± 0.20. κ = (b − 1)/(N − 1): 0.37 ± 0.21, 1.18 ± 0.25, 0.58 ± 0.23, -0.18 ± 0.19. the same, phased in as b/(b + 20): 0.22 ± 0.10, 0.35 ± 0.16, 0.23 ± 0.18, -0.10 ± 0.19. the same, read in only after twenty blocks: 0.00 ± 0.00, -0.02 ± 0.04, 0.17 ± 0.19, -0.17 ± 0.19.

    A rule that sets its own κ

    A stopping rule may read the spread inside its blocks and may not read the spread between them, and the dial between the two costs nothing for a long stretch and then a lot. The share an efficiency argument recommends is each estimate's share of the degrees of freedom, and on blocks of two at a half-width of 0.15 that loses nothing and steadies the experiment by 30%. At 0.35 it loses 1.18 points. Deferring the forbidden reading until twenty blocks costs nothing measurable at any requirement, and it keeps most of the steadiness where steadiness can be had.

    part 11 · pace
  16. 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.

    part 12 · sequential
  17. 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%.

    part 13 · sequential
  18. 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%.

    part 14 · sequential
  19. Power against expected observations for two fixed schedules and a look added when the interim trend is close, O'Brien–Fleming-type spending. Straight to the end: power 89.01% at 338.9 expected observations. A look at three quarters always: 88.38% at 300.7. Adding the look when the interim |z| is at least 0.5, 1, 1.5, 2, 2.5, with boundaries corrected to spend exactly 5%: 88.41% at 302.0; 88.45% at 302.8; 88.56% at 306.3; 88.76% at 315.5; 88.95% at 330.1. With the spending boundaries alone the same rules spend 5.059%, 5.156%, 5.232%, 5.187%, 5.058%.

    A look added by a rule

    A monitoring committee's rule — add a look at three quarters of the trial when the interim |z| is at least 1.5 — spends 5.2323% under O'Brien–Fleming-type boundaries. Written into the protocol it can be given boundaries that spend exactly 5%, three ways: raise the added look's boundaries by 2.05%, raise every later boundary by 0.99%, or preserve at each interim value the chance of crossing the plan would have given. All three cost the same, 0.38 points of power, from 88.94% to 88.56%, because the power the uncorrected rule seemed to keep was the excess error. Made exact, the rule is a design between the two fixed schedules — and at every trigger slightly better than randomising between them.

    part 15 · sequential
  20. How much a look added at three quarters spends above 5%, by what the decision to add it reads. A two-look O'Brien–Fleming-type trial, interim at half the information, adds a look at three quarters with a stated chance under the null. Its error rate above 5%, in points, at chances of 0.1, 0.3, 0.5, 0.7, 0.9: triggered by a calendar or by the within-arm variance, 0.00000, 0.00000, 0.00000, 0.00000, 0.00000; by the blinded variance with 20 patients at the interim, 0.034, 0.064, 0.069, 0.054, 0.022; with 100, 0.014, 0.027, 0.030, 0.025, 0.012; with 1,000, 0.004, 0.008, 0.009, 0.008, 0.004; by the interim trend itself, 0.234, 0.163, 0.089, 0.042, 0.013. Exact integrals over the interim statistic.

    The variance that contains the effect

    A monitoring committee that adds an interim look because the variance came in higher than planned is reading a nuisance quantity, and a look added on a nuisance quantity should leave the spending function's 5% alone. It does, exactly, when the variance is the within-arm one, and when the trigger is the calendar. It does not when the variance is the one computed with the arm labels hidden: that variance is the within-arm sum of squares plus the interim statistic squared, so it is high more often when the trend is strong. The excess is 0.069 points at a twenty-patient interim and falls as one over the square root of the interim's size — a tenth of what a trigger on the trend itself spends, and never zero.

    part 16 · sequential

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