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RANDOMIZATION METHODS
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RANDOMIZATION
Why randomize What a random series is How to randomize
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Randomization (1)
Rationale Reference: Byar et al (1976) NEJM 274:74-80.
Best way to find out which therapy is best Reduce risk of current and future patients of being on harmful treatment
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Randomization (2)
Basic Benefits of Randomization
Eliminates assignment basis Tends to produce comparable groups Produces valid statistical tests
Basic Methods
Ref: Zelen JCD 27:365-375, 1974. Pocock Biometrics 35:183-197, 1979
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Population a y~G(y|Ua)
Population b y~G(y|Ub)
Study Sample
Sample at Random
Sample at Random
na patients yaj~G(y|Ua)
nb patients ybj~G(y|Ub)
n = nb + nb patients
Randomization
na patients
nb patients 542-04-#7
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Simple Randomization
Disadvantage: At any point in time, there may be an imbalance in the number of subjects on each treatment
With n = 20 on two treatments A and B, the chance of a 12:8 split or worse is approximately 0.19 With n = 100, the chance of a 60:40 split or worse is approximately 0.025 Balance improves as the sample size n increases
P_ u 60a ! PS - u 60 - 50
S S np 60 50 ! P u 25 25 10 ! P u 5 ! P u 2
! .025
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S np 12 10 PS u 12
! P u V(s) 5 2 ! P u 5 = 0.19
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Restricted Randomization
Simple randomization does not guarantee balance over time in each realization Patient characteristics can change during recruitment (e.g. early pts sicker than later) Restricted randomizations guarantee balance 1. Permuted-block 2. Biased coin (Efron) 3. Urn design (LJ Wei)
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Rank 1 3 4 2
Simple Solution to Selection Bias * Do not reveal blocking mechanism * Use random block sizes If treatment is double blind, no selection bias
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Urn Randomization
Wei & Lachin: Controlled Clinical Trials, 1988
A generalization of Biased Coin Designs BCD correction probability (e.g. 2/3) remains constant regardless of the degree of imbalance Urn design modifies p as a function of the degree of imbalance U(E, F) & two Trts (A,B)
0. Urn with E white, E red balls to start 1. Ball is drawn at random & replaced 2. If red, assign B If white, assign A 3. Add F balls of opposite color (e.g. If red, add F white) 4. Go to 1.
Model based inferences not affected by treatment allocation scheme. Ref: Begg & Kalish (Biometrics, 1984)
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Number of strata
TN
i i !1
f = # risk factors; li = number of categories in factor i Randomize within each stratum For stratified randomization, randomization must be restricted! Otherwise, (if CRD was used), no balance is guaranteed despite the effort.
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Example
H M L
1 2
H L
3 4
For stratified randomization, randomization must be restricted! Otherwise, (if CRD was used), no balance is guaranteed despite the effort!
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Comment
For multicenter trials, clinic should be a factor Gives replication of same experiment. Strictly speaking, analysis should take the particular randomization process into account; usually ignored (especially blocking) & thereby losing some sensitivity. Stratification can be used only to a limited extent, especially for small trials where it's the most useful; i.e. many empty or partly filled strata. If stratification is used, restricted randomization within strata must be used.
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Sex Age
Disease
Total
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( ( ) *
) (F)
( i ) ( ) ( ) ( ) *
tal
N w d t rmi
B( ) and B( ) f r ati nt # (t = )
If assigned reatment
t trt ) t =
Trt Group
N w r sed X K p X11K 16 17 14 14
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Range =|17-14| = 3
Total 26 24 50
(a) Calculate B(t) (Assign Pt #51 to trt 1) (2) Factor 2, Level 3 (Low Risk) K 1 2 X2K X12K 4 p 5 6 6
t=1
Trt Group
(c) Rank B(1) and B(2), measures of imbalance Assign t with probability 2/3 1/3
t 2 1
B(t) 9 11
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Play-thePlay-the-Winner Rule
Zelen (1969)
Treatment assignment depends on the outcome of previous patients Response adaptive assignment When response is determined quickly 1st subject: toss a coin, H = Trt A, T = Trt B On subsequent subjects, assign previous treatment if it was successful Otherwise, switch treatment assignment for next patient Advantage: Potentially more patients receive the better treatment Disadvantage: Investigator knows the next assignment
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Patient 1 2 3 4 5 6 7 8 9 ......
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TwoTwo-armed Bandit or Randomized Play-the-Winner Rule Play-the Treatment assignment probabilities depend on observed success probabilities at each time point Example: ECMO trial Advantage: Attempts to maximize the number of subjects on the superior treatment Disadvantage: When unequal treatment numbers result, there is loss of statistical power in the treatment comparison
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ECMO Example
References Michigan 1a. Bartlett R., Roloff D., et al.; Pediatrics (1985) 1b. Begg C.; Biometrika (1990) Harvard 2a. ORourke P., Crone R., et al.; Pediatrics (1989) 2b. Ware J.; Statistical Science (1989) 2c. Royall R.; Statistical Science (1991) Extracoporeal Membrane Oxygenator(ECMO)
treat newborn infants with respiratory failure or hypertension ECMO vs. conventional care
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5 S
6 S
7 S
8 S
9 S
10 S
*sickest patient
1st
Randomization (permuted block) switch to superior treatment after 4 deaths in worst arm Stay with best treatment
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2nd
P = .054 (Fisher)
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MultiMulti-institutional Trials
Often in multi-institutional trials, there is a marked institution effect on outcome measures Using permuted blocks within strata, adding institution as yet another stratification factor will probably lead to sparse cells (and potentially more cells than patients!) Use permuted block randomization balanced within institutions Or use the minimization method, using institution as a stratification factor
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4. 5.
2. Blocked (No stratification) (a) 10 A's & 10 B's (b) H: 4 A's & 6 B's L: 6 A's & 4 B's 3. Stratified with simple randomization (a) 5 A's & 15 B's (b) H: 1 A & 9 B's L: 4 A's & 6 B's 4. Stratified with blocking (a) 10 A's & 10 B's (b) H: 5 A's & 5 B's L: 5 A's & 5 B's MUST BLOCK TO MAKE STRATIFICATION PAY OFF
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