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RANDOMIZATION METHODS

542-04-#1

RANDOMIZATION

Why randomize

How to randomize

542-04-#2

Randomization (1)

Rationale

Reduce risk of current and future patients of being

on harmful treatment

(Silverman: Scientific American 236:100-107, 1977)

542-04-#3

Randomization (2)

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

542-04-#4

Goal: Achieve Comparable Groups to Allow

Unbiased Estimate of Treatment

Baseline Comparisons

Propranolol Placebo

(N-1,916) (N-1,921)

Male (%) 83.8 85.2

White (%) 89.3 88.4

Systolic BP 112.3 111.7

Diastolic BP 72.6 72.3

Heart rate 76.2 75.7

Cholesterol 212.7 213.6

Current smoker (%) 57.3 56.8

542-04-#5

Randomization Basis for

Tests of Hypotheses

statistical test of the equality of treatments

randomization or permutation tests

consists of n choose na possible combinations of na patients on

treatment a out of n patients

542-04-#6

Statistical Properties of Randomization

A. Sampling-Based B. Randomization

Population Model Model

y~G(y|a) y~G(y|b)

Sample at Sample at

Random Random

yaj~G(y|a) ybj~G(y|b)

Randomization

na patients nb patients

542-04-#7

Randomization Model

Under H0, observed responses independent of treatment

Observed group differences depends ONLY on sequence

of n assignments (random).

Sc = nCna possible combinations, given na out of n

treatment group A?

set.

asymptotically equal to homogeneous population model test.

542-04-#8

Nature of Random Numbers

and Randomness

A completely random sequence of digits is a mathematical

idealization

Each digit occurs equally frequently in the whole sequence

Adjacent (set of) digits are completely independent of one another

Moderately long sections of the whole show substantial regularity

Produced by a process which will give results closely approximating

to the mathematical idealization

Tested to check that it behaves as a finite section from a

completely random series should

Randomness is a property of the table as a whole

Different numbers in the table are independent

542-04-#9

Table of Random Numbers

542-04-#10

Allocation Procedures

to Achieve Balance

Simple randomization

Stratified randomization

Minimization method

542-04-#11

Treatment Imbalance

Statistical Properties of Randomization

66-33 split reduces power 90% 87%

542-04-#12

Randomization & Balance (1)

n = 100

p=

s = #heads V(s) =

npq = 100 = 25

E(s) = n p = 50

PS 60 PS - np 60 - 50

S np 60 50

P

25 25

10

P

5

P 2 .025

542-04-#13

Randomization & Balance (2)

n = 20

p=

E(s) = 10

V(s) = np = 20/4 = 5

S np 12 10

PS 12 P

V(s) 5

2

P

5

542-04-#14

Simple Random Allocation

A specified probability, usually equal, of patients assigned

to each treatment arm, remains constant or may change

but not a function of covariates or response

n known in advance, exactly

n/2 selected at random & assigned to Trt A, rest to Trt B

n not exactly known

marginal and conditional probability of assignment = 1/2

analogous to a coin flip (random digits)

542-04-#15

Simple Randomization

Advantage: simple and easy to implement

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 0.5

With n = 100, the chance of a 60:40 split or worse is

approximately 0.025

Balance improves as the sample size n increases

ensure balance throughout the trial

542-04-#16

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)

542-04-#17

Permuted-Block Randomization (1)

Simple randomization does not guarantee balance in numbers

during trial

If patient characteristics change with time, early imbalances

can't be corrected

Need to avoid runs in Trt assignment

Basic Idea

Divide potential patients into B groups or blocks of size 2m

Randomize each block such that m patients are allocated to A and m to B

Total sample size of 2m B

For each block, there are 2mCm possible realizations

(assuming 2 treatments, A & B)

Maximum imbalance at any time = 2m/2 = m

542-04-#18

Permuted-Block Randomization (2)

Method 1: Example

Block size 2m = 4

2 Trts A,B } 4C2 = 6 possible

possible arrangements

542-04-#19

Permuted-Block Randomization (3)

random number for each treatment (Trt), then

rank the treatments in order

any order Number Rank rank order

A 0.07 1 A

A 0.73 3 B

B 0.87 4 A

B 0.31 2 B

542-04-#20

Permuted-Block Randomization (4)

Concerns

- If blocking is not masked, the sequence become

somewhat predictable (e.g. 2m = 4)

ABAB BAB? Must be A.

AA Must be B B.

- This could lead to selection bias

* Do not reveal blocking mechanism

* Use random block sizes

542-04-#21

Biased Coin Design (BCD)

Efron (1971) Biometrika

Allocation probability to Treatment A changes to keep

balance in each group nearly equal

BCD (p)

Assume two treatments A & B

D = nA -nB "running difference" n = nA + nB

Define p = prob of assigning Trt > 1/2

e.g. PA = prob of assigning Trt A

If D = 0, PA = 1/2

D > 0, PA = 1 - p Excess A's

D < 0, PA = p Excess B's

Efron suggests p=2/3

D > 0 PA = 1/3 D < 0 PA = 2/3

542-04-#22

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(, ) & two Trts (A,B)

0. Urn with white, red balls to start

1. Ball is drawn at random & replaced

2. If red, assign B

If white, assign A

3. Add balls of opposite color

(e.g. If red, add white)

4. Go to 1.

Permutational tests are available, but software not as easy.

542-04-#23

Analysis & Inference

Most analyses do not incorporate blocking

Actually, most important question is whether we should use complete

randomization and take a chance of imbalance or use permuted-block

and ignore blocks

Homogeneous in Time

Blocking probably not needed, but if blocking ignored, no problem

Heterogeneoous in Time

Blocking useful, intrablock correlations induced

Ignoring blocking most likely conservative

scheme. Ref: Begg & Kalish (Biometrics, 1984)

542-04-#24

Kalish & Begg

Controlled Clinical Trials, 1985

Time Trend

Impact of typical time trends (based on ECOG pts)

on nominal p-values likely to be negligible

effect on p-value

rates, adjust for time strata as a co-variate. This

variation likely to be noticed during interim

analysis.

542-04-#25

Balancing on

Baseline Covariates

Stratified Randomization

Covariate Adaptive

Minimization

Pocock & Simon

542-04-#26

Stratified Randomization (1)

May desire to have treatment groups balanced with respect

to prognostic or risk factors (co-variates)

For large studies, randomization tends to give balance

For smaller studies a better guarantee may be needed

f

Number of strata

i 1

i

f = # risk factors;

li = number of categories in factor i

Randomize within each stratum

restricted! Otherwise, (if CRD was used), no balance is

guaranteed despite the effort.

542-04-#27

Example

H 1 2 Factors

Sex (M,F) X

M L

2 2 Levels in

and each

Risk (H,L)

F H 4 Strata

L 3

Otherwise, (if CRD was used), no balance is guaranteed despite

the effort!

542-04-#28

Stratified Randomization (2)

Define strata

and is usually blocked

Total number of strata = 3 x 2 = 6

41-60 BBAA, ABAB, ... ABAB, BBAA, ...

>60 AABB, ABBA, ... BAAB, ABAB, ..

542-04-#29

Stratified Randomization (3)

The block size should be relative small to maintain balance in

small strata, and to insure that the overall imbalance is not too

great

number of levels within strata lead to fewer patients per stratum

the purpose of stratification

542-04-#30

Comment

For multicenter trials, clinic should be a factor

Gives replication of same experiment.

randomization process into account; usually ignored

(especially blocking) & thereby losing some sensitivity.

especially for small trials where it's the most useful;

i.e. many empty or partly filled strata.

strata must be used.

542-04-#31

Minimization Method (1)

An attempt to resolve the problem of empty strata when trying

to balance on many factors with a small number of subjects

Balances Trt assignment simultaneously over many strata

Used when the number of strata is large relative to sample

size as stratified randomization would yield sparse strata

A multiple risk factors need to be incorporated into a score

for degree of imbalance

Need to keep a running total of allocation by strata

Also known as the dynamic allocation

Logistically more complicated

Does not balance within cross-classified stratum cells;

balances over the marginal totals of each stratum, separately

542-04-#32

Example: Minimization Method (a)

Three stratification factors: Sex (2 levels),

age (3 levels), and disease stage (3 levels)

Suppose there are 50 patients enrolled and the

51st patient is male, age 63, and stage III

Trt A Trt B

Sex Male 16 14

Female 10 10

Age < 40 13 12

41-60 9 6

> 60 4 6

Disease Stage I 6 4

Stage II 13 16

Stage III 7 4

Total 26 24 542-04-#33

Example: Minimization Method (b)

each treatment for each stratification factor level

patient's stratification levels only

Sign of

Trt A Trt B Difference

Male 16 14 +

Age > 60 4 6 -

Stage III 7 4 +

Total 27 24 2 +s and 1 -

542-04-#34

Example: Minimization Method (c)

each category. Trt A is ahead in two categories

out of three, so assign the patient to Trt B

Since Trt A is ahead, assign the patient to Trt B

542-04-#35

Minimization Method (2)

These two criteria will usually agree, but not always

entire study

Generalization is possible

treatment balance, or balance within stratum cells

542-04-#36

Covariate Adaptive Allocation

(Sequential Balanced Stratification)

Pocock & Simon, Biometrics, 1975;

Efron, Biometrika, 1971

numbers of subjects

In a simple case, if at some point Trt A has more older patients that

Trt B, next few older patients should more likely be given Trt B

until "balance" is achieved

imbalance B(t) for placing next patient on treatment t (A or B)

the smallest B(t), or the least imbalance

top" computer

542-04-#37

Example: Baseline Adaptive Randomization

Assume 2 treatments (1 & 2)

2 prognostic factors (1 & 2) (Gender & Risk Group)

Factor 1 - 2 levels (M & F)

2

Factor 2 - 3 levels (High, Medium & Low Risk)

Let B(t) = Wi Range (xit1, xit2) wi = weight for each factor

i 1

e.g. w1 = 3 w1/w2 = 1.5

w2 = 2

xij = number of patients in ith factor and jth treatment

xitj = change in xij if next patient assigned treatment t

Assume we have already randomized 50 patients

Now 51st pt.

Male (1st level, factor 1)

Low Risk (3rd level, factor 2)

542-04-#38

Factor 1(Sex) 2(Risk)

Level 1(M) 2(F) 1(H) 2(M) 3(L) Total

Patient 1 16* 10 13 9 4* 26

Group 2 14 10 12 6 6 24

Total 30 20 25 15 10 50

If assigned Treatment 1 (t = 1)

(1) Factor 1, Level 1

(Male)

Now Proposed

K X1K X11K

Trt Group 1 16 17

2 14 14

Range =|17-14| = 3 542-04-#39

Factor 1(Sex) 2(Risk)

Level 1(M) 2(F) 1(H) 2(M) 3(L) Total

Patient 1 16* 10 13 9 4* 26

Group 2 14 10 12 6 6 24

Total 30 20 25 15 10 50

(Low Risk)

K X2K X12K

Trt Group 1 4 5

2 6 6

Range = |5-6|, = 1

542-04-#40

(b) Calculate B(2) (Assign Pt #51 to trt 2) t=2

(Male)

K X1K X21K

Group 1 16 16

2 14 15

Range = |16-15| = 1

(Low Risk)

K X2k X22k

Group 1 4 4

2 6 7

Range = |4-7| = 3

542-04-#41

(c) Rank B(1) and B(2), measures of imbalance

Assign t

t B(t) with probability

2 9 2/3

1 11 1/3

2 for sure

542-04-#42

Response Adaptive

Allocation Procedures

Use outcome data obtained during trial to influence

allocation of patient to treatment

Data-driven

i.e. dependent on outcome of previous patients

Assumes patient response known before next patient

The goal is to allocate as few patients as possible to

a seemingly inferior treatment

Issues of proper analyses quite complicated

Not widely used though much written about

Very controversial

542-04-#43

Play-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

542-04-#44

Response Adaptive

Randomization

Example

"Play-the-winner Zelen (1969) JASA

TRT B SF

Patient 1 2 3 4 5 6 7 8 9 ......

542-04-#45

Two-armed Bandit or

Randomized Play-the-Winner Rule

Treatment assignment probabilities depend on observed

success probabilities at each time point

on the superior treatment

there is loss of statistical power in the treatment

comparison

542-04-#46

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)

treat newborn infants with respiratory failure or hypertension

ECMO vs. conventional care

542-04-#47

Michigan ECMO Trial

Bartlett Pediatrics (1985)

Modified play-the-winner

Urn model

A ball ECMO

B ball Standard control

If success on A, add another A ball .

Wei & Durham JASA (1978)

Randomized Consent Design

Results

1 2* 3 4 5 6 7 8 9 10

ECMO S S S S S S S S S

CONTROL F

*sickest patient

P-Values, depending on method, values ranged

.001 6 .05 6 .28

542-04-#48

Harvard ECMO Trial (1)

ORourke, et al.; Pediatrics (1989)

Background

Controversy of Michigan Trial

Harvard experience of standard

11/13 died

Two stage

1st Randomization (permuted block) switch to

superior treatment after 4 deaths in worst arm

542-04-#49

Harvard ECMO Trial (2)

Results

Survival

1st 2nd*

ECMO 9/9 19/20

CONTROL 6/10

* less severe patients

P = .054 (Fisher)

542-04-#50

Multi-institutional Trials

Often in multi-institutional trials, there is a marked

institution effect on outcome measures

as yet another stratification factor will probably lead to

sparse cells (and potentially more cells than patients!)

institutions

stratification factor

542-04-#51

Mechanics of Randomization (1)

* Timing

prior to initiation of therapy

Example

Alprenolol Trial, Ahlmark et al (1976)

393 patients randomized two weeks before therapy

Only 162 patients treated, 69 alprenolol & 93 placebo

542-04-#52

Mechanics of Randomization (2)

* Operational

1. Sequenced sealed envelopes (prone to tampering!)

2. Sequenced bottles/packets

- Live response

- Voice Response System

5. Web based

Example of Previous Methods (1)

20 subjects, treatment A or B, risk H or L

Subject Risk

1 H Randomize Using

2 L

3 L 1. Simple

4 H

5 L 2. Blocked (Size=4)

6 L

7 L 3. Stratify by risk + use simple

8 L

9 H 4. Stratify by risk + block

10 L

11 H

12 H For each compute

13 H

14 H 1. Percent pts on A

15 L

16 L 2. For each risk group, percent of pts on A

17 H

18 H

19 L 10 subjects with H

20 H 10 subjects with L

542-04-#54

Example of Previous Methods (2)

1. Simple 1st Try 2nd Try

(a) 9/20 A's 7/20 A's OVERALL BY

(b) H: 5/10 A's 3/10 A's SUBGROUP

L: 4/10 A's 4/10 A's

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 MUST BLOCK TO MAKE

STRATIFICATION PAY

(b) H: 5 A's & 5 B's OFF

L: 5 A's & 5 B's

542-04-#55

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