Section B

Assessing the Risk of Bias in Clinical Trials:

Selection Bias

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Sources of Bias in an RCT

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Random Sequence Generation

! Occurs at the start of a trial before allocation of participants

! Determines a random order of assigning people into intervention and control groups

! Accounts for known and unknown confounders

! Prevents systematic differences between groups

! " Prevents selection bias

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Studies of Coronary Artery Bypass Graft Surgery

Pooled differences in mortality between medically and surgically treated patient,

by study design
Mean
Mean % Mean %
Number of difference
Type of study mortality mortality S.D.
studies in %
(medical) (surgical)
mortality
Randomized
controlled 8 12.0% 7.6% 4.4% 5.5%
trials
Quasi- 13 28.5% 14.7% 13.8% 16.9%
experimental

Source: Wortman, P.M. & Yeaton, W.H. (1983). Eval Stud Review Ann. 4
Does Randomization Protect against Bias?

! In studies comparing randomized and non-randomized trials of the same intervention,

it was not possible to predict the magnitude or direction of findings based on study
design

Source: (2011). Odgaard-Jensen CDSR. 5

Random Sequence Generation

! Low risk of bias—unpredictable

! Random numbers table
! Computer random number generator
! Stratified or block randomization
! Coin toss, shuffling cards or envelopes, throwing dice

! High risk of bias—predictable

! Quasi-random—date of birth, day of visit, ID or record number, alternate allocation
! Non-random—choice of clinician or participant, test results, availability

See Section 8.9 of the Cochrane Handbook 6

Allocation Concealment

! Occurs at the start of the trial during allocation of

participants

! When a person is recruited to a study, no one is able to

predict which group the person will be allocated to

! Ensures strict implementation of the randomly generated

sequence
! Prevents changing the order
! Prevents selecting who to recruit

! " Prevents selection bias

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Trials Where Randomization Is Inadequately Concealed Are More Likely to
Show a Beneficial Effect

Source: Pildal, J. et al. (2008). Int. J. Epidemiol, 37:422; doi:10.1093/ije/dyn046 8

Comparison No. of Ratio of Ratio of odds P value of Variability in
(No of meta-analyses trials* odds ratios ratios (95% CI) test of bias¶ (P value)
interaction
Overall (76) 314 v 432
0.93 (0.83 to 1.04) -- 0.11 (<0.001)
All cause mortality (18) 79 v 121
Other outcomes (58) 235 v 311 1.04 (0.95 to 1.14) 0.011 0.01 (0.27)
0.83 (0.70 to 0.98) 0.18 (<0.001)
Objective outcomes (44) 210 v 227
Subjective outcomes (32) 104 v 205 1.01 (0.92 to 1.10) 0.01 0.08 (<0.001)
0.75 (0.61 to 0.82) 0.14 (0.001)
Drug intervention (57) 250 v 372
Other intervention (19) 64 v 60 0.92 (0.81 to 1.05) 0.66 0.10 (<0.001)
1.00 (0.71 to 1.39) 0.22 (0.003)
0.5 0.75 1 1.5 2
*Non-blinded v blinded Non-blinded Non-blinded
¶ Between-meta-analysis more less
heterogeneity variance beneficial beneficial

Ratios of odds ratios comparing intervention effect estimates in 314 non-blinded trials versus 432
blinded trials. Columns on the right show P values from tests of interaction, and estimates of the
variability between meta-analyses in the size of bias
Adapted from Wood, L. et al. (Mar 3 2008). BMJ. 9
Allocation Concealment

! Low risk of bias—unpredictable

! Central allocation (phone, web, pharmacy)
! Sequentially numbered, sealed, opaque envelopes
! Sequentially numbered, identical drug containers

! High risk of bias—predictable

! Random sequence known to staff in advance
! Envelopes or packaging without all safeguards
! Non-random, predictable sequence

See Section 8.10 of the Cochrane Handbook 10