Minimize bias: Minimize random noise: Randomize Conceal allocation Blind. Standardization of measurements

Transcription

1 Minimize bias: Randomize Conceal allocation lind Minimize random noise: Standardization of measurements

2 What are the problems with non random allocation of assignment? Systematic assignment date of birth date of presentation alternate assignment Judgment assignment (unacceptable)

3 Why randomize? Randomization removes the potential bias in the allocation of participants to the intervention or control group Randomization tends to produce comparable groups with respect to known and unknown risk factors Guarantees that statistical tests will have valid significance levels RCT are an essential tool for testing efficacy of a therapeutic intervention

4 Randomization should always be done after the subject is found to be eligible and has given his/her consent to participate no matter what is the intervention

5 Whom to randomize? Individuals Groups Communities Depends on the research question

6 Randomization schemes Simple/ unrestricted Restricted locking, random allocation rule iased coin or urn randomization Replacement randomization Stratified

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8 How to prepare simple randomization scheme using random number tables for two interventions (n=0, :) Decide allocation rule, e.g. for two groups Digits 0- to be assigned to intervention (group ) Digits 5-9 to be assigned to control (group ) Start at a random place on the table, go in a pre-decided direction and record one single digit number for each study participant.

9 Simple Randomization Worksheet Source of random numbers: first row, third column vertically down llocation rule: = 0-, = llocation Random Number Trial Number

10 How to prepare simple randomization scheme using random number tables for two interventions (n=0, :) Source of random numbers: bottom right corner llocation rule: =,,5,7,9, =0,,,6,8 Trial Number Random Number llocation

11 Example of allocation procedures for unrestricted randomization, for intervention groups C 6 9 C C 9 5 C 7 C 8 llocation Random Number Trial Number Source of random numbers : First column, first row llocation rule: = -, = - 6, C = 7-9, (0 ignored)

12 Example of allocation procedures for unrestricted randomization, for intervention groups C 6 8 C C D 7 D 8 llocation Random Number Trial Number Source of random numbers : first column, first row llocation rule: =-, = -, C= 5-6, D=7-8, (9, 0 ignored)

13 Exercises Generate simple randomization scheme using random number tables for two interventions for 0 participants (:)

14 SIMPLE RNDOMIZTION WORKSHEET Source of random numbers : llocation rule: Trial Number Random Number llocation

15 How to prepare a simple randomization scheme using computer programs Decide allocation rule, e.g. the number generated first would be allocated to intervention (group ) Decide computer program and set seed for generation of random numbers. If 0 participants are to be allocated to two groups, generate 5 random numbers between and 0, e.g. following numbers were generated: 6 9

16 Possible imbalance in simple randomization with two treatments. This table shows the difference in treatment number (or more extreme) liable to occur with probability at least 0.0 for various trial sizes. Total number Difference in numbers of patients Probability 0.05 Probability :8 :9 0 6: :6 50 8: 6: 00 0:60 7: : 8: :7 : :5 59:5

17 Restricted Randomization Ensures equal number in each group after fixed numbers of allocations lock size should be a multiple of the number of interventions lock size should not be known to the investigators lock size should not be very small

18 Example of allocation rule for a block size of, with two intervention groups, and llocation 5 6 Corresponding random number Ignore Codes 7, 8, 9,0

19 Source of random numbers : ppendix 7., column, block (going down the col) llocation rule: =, =, =, =, =5, =6, (Ignore Codes 7,8,9,0) Trial Number Random Number 7 llocation

20 Exercise: Generate block randomization scheme (block size ) using random number tables for two interventions for 6 participants llocation rule: Trial Number Random Number llocation

21 llocation using large block size Suppose block size is (to be allocated to group or ) Select random numbers (two digits) between 0 and ignoring numbers outsides 0- & those previously selected. llocation rule: = odd, = even (appendix 7., last column going down the column)

22 Trial Number Random Number llocation

23 llocation using large block size For treatments, blocks of 5 patients assign for -5 for 6-0 C for -5 Ignore 0 and 6-9 in random permutations of 0

24 Source of random numbers : ppendix 7., column, row (horizontally across) llocation rule: =-5, =6-0, C=-5 Trial Number Random Number llocation C C C C C

25 Exercise of generating block (block size ) random numbers using a random table

26 How to prepare a block randomization scheme using computer programs Small block size Large block size

27 Stratified randomization if :. if some strong risk factor is known/suspected to be present in the study population, or. intervention impact is expected to be substantially different in subgroups llocate in a way that equal numbers receive intervention of placebo within each subgroup. Example : Stratification by sex 000 subjects 00 males 700 females Intervention N=50 Control N=50 Intervention N=50 Control N=50 nalyze overall : intervention (n=500 ) vs. control (n=500)

28 How should we stratify? Identify major variable Categorize each variable into two or three levels : ge -6 mo, 7- mo. Wt for Ht 70 or > 70 NCHS S: -6 mo. & Wt for Ht < 70 NCHS S: -6 mo. & Wt for Ht > 70 NCHS S: 7- mo. & Wt for Ht < 70 NCHS S: 7- mo. & Wt for Ht >70 NCHS Separate randomization list for each strata using random permuted blocks Small block sizes used for several strata

29 Source of random numbers : Table 7., row, column across llocation rule: =even no. =odd no. S S Trial No. Random No. llocation Trial No. Random No. llocation

30 Source of random numbers : Table 7., row, column across llocation rule: =even no. =odd no. S S Trial No. Random No. llocation Trial No. Random No. llocation

31 Random permuted blocks of many strata may be self defeating mbulatory Non-ambulatory ge <50 >50 <50 >50 Disease-free interval (yrs) < > < > < > < > Dominant metastatic lesion: Visceral Osseous Soft tissue

32 llocation concealment : ias can always be introduced despite an adequate randomized sequence Protects an assignment sequence before & until allocation Prevents selection bias lways possible to have allocation concealment linding: Protects an assignment sequence after allocation Prevents ascertainment bias Not always possible to blind studies

33 Effective allocation concealment Sequentially numbered opaque sealed envelopes Pharmacy controlled Serially arranged numbered containers (not labeled as or when only two assignments) Central randomization

34 ssignments can be placed in advance in a set of sealed envelopes by someone not involved in opening the envelopes Envelop should be Numbered Opaque Tamperproof Only two types of containers ( & ) : easily un-blinded. Serially individually labeled containers

35 est to blind/mask everyone to the treatment as far as possible; removes the placebo effect Potential for bias if everyone knows what treatment each patient is receiving ssessment bias Differential monitoring by the treatment team Influence patients response

36 Sequence generation Random number tables or computer generated random number Unrestricted or restricted (blocked, stratified) llocation concealment Sealed envelopes, numbered container or central telephone Implementation Reporting of Randomization who generated allocation sequence, who enrolled patients, and who assigned participants to their groups

37 Reporting of Randomization Where is the list kept? When was the code broken?

38 Reporting of blinding Who was blinded and how? Information on mechanisms (capsules, tablets, bottles) Similarity of treatment characteristics