L4 & 5 - Experimental Health Research (RCTs)

Question 1

What is maturation/spontaneous recovery?

Answer 1

People just improve over time with no direct intervention

Question 2

What is the practice effect? (AKA learning effect)

Answer 2

Improvement on an assessment following exposure to one previously (the same or similar test)

Question 3

What is the placebo effect?

Answer 3

The placebo effect is when a fake treatment is given, and a bigger improvement is seen in their condition/pain/QoL than no intervention/treatment

Question 4

What is the dose response effect?

Answer 4

Increased amount of placebo = increased impact

Question 5

What are key elements of placebo?

Answer 5

• Dose response effect
• Branding on the packaging
• Route of administration - e.g. IV over pill

Question 6

When is placebo ethical?

Answer 6

• Not if you are withholding effective treatment
• If there is no proven, effective treatment

Question 7

Why randomise participants to research groups?

Answer 7

• To avoid selection bias
• In large enough groups, randomisation is likely mean confounders are distributed evenly across both groups

Question 8

What is selection bias?

Answer 8

Bias due to the selection of participants - it is not properly randomised, meaning the sample achieved doesn’t truly represent the populalation it aims to analyse.

Question 9

How should the comparison variable be chosen?

Answer 9

• Use the proven effective treatment
• If one doesnt exist, use placebo

Question 10

Why does allocation/assessment need to be blind to participants and researchers?

Answer 10

It is well established within research that assessment is biased if not blinded.

Question 11

What is allocation concealment?

Answer 11

• Allocating participants to groups thorugh the use of a pre-generated random sequence
• Allocation concealment means researchers should not be able to predict which group a participant will be allocated to

Question 12

What is the basic principle of randomisation in a trial as carried out by a statistician/CTU?

Answer 12

• The CTU generates a group allocation sequence (A, B, B, B, A, A, B, A, B, A, A etc) in advance, and allocates each participant accordingly to group A or group B as they enter the study

Question 13

What is fixed randomisation?

Answer 13

Group allocation has a prespecified probability of going into which group (if its a 2 arm trial, probs 50/50)

Question 14

What are the three types of fixed randomisation?

Answer 14

• Simple randomisation
• (permuted) block randomisation
• Stratified randomisation

Question 15

What is simple randomisation?

Answer 15

• The computer generates a random sequence for all 30 participants

Question 16

What are the potential problems with simple randomisation?

Answer 16

• Failure to recruit enough participants may lead to unequal group sizes
• Trials can be stopped early by the data monitoring committee

Question 17

What is the problem with unequal group sizes?

Answer 17

• Reduces statistical power

Question 18

Why may trials be stopped early?

Answer 18

• Trial can be stopped early by the data monitoring committee who monitor data as trial is ongoing to look out for serious, unexpected events
• Pre-specified rules as to when trial would be stopped:
  
  • if treatment is so beneficial it’d be unethical to withold it from all patients
  • if there is a clear and serious adverse events
• Interim analysis is difficult if/when group sizes are unequal

Question 19

What is block randomisation?

Answer 19

• Randomises the participants into small blocks to prevent large differences in group sizes at any point
  
  • Blocks should have an even number of participants
  • The number of people allocated to each group within a block must be the same - e.g. all blocks have 4 people in them
    
    • in 4-block groups, there would be a max difference of 2 if there was a failure to recruit

Question 20

When is block randomisation useful?

Answer 20

• When the participants characteristics vary throughout recruitment
• Monitoring if the study needs to be terminated early
• Failing to recruit the target number of participants

Question 21

What are the problems with block randomisation?

Answer 21

• Sometimes researchers and participants can work out which group they have been allocated to (e.g. if there is an anticipated side effect)
• If the length of the block/previous allocations are known, it could be worked out the group of person 4 in the block. This could affect recruitment
• Power needs to be high - the ability to detect a difference between the groups if one really exists.

Question 22

What is permuted block randomisation?

Answer 22

• Block size is varied randomly to prevent predictability
  
  • e.g. mix between 4/6

Question 23

What is stratified randomisation?

Answer 23

• Obtain comparable groups
• larger N (sample size) means this is more likely, but can’t be guaranteed
• Randomly allocates people based on important risk/prognosis factors that may affect the outcome
  
  • e.g:
    
    • gender
    • age
    • severity of cmmn impairment
• Recruit equally to each sub group

Question 24

Stratified Randomisation - Worked Example:

Answer 24

Question 25

What is a clinical endpoint?

Answer 25

• A clinical endpoint is an event or outcome that can be measured objectively to determine if the results of the study are beneficial

Question 26

What is a surrogate outcome?

Answer 26

• In clinical trials, a surrogate endpoint is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship.

Question 27

How to manage adverse events?

Answer 27

• Predict potential adverse events
• Monitor participants for unexpected adverse events - ensure they have an opportunity to feed back about this

Question 28

Are adverse events possible in SLT RCTs?

Answer 28

• Adverse events are always a possibility
  
  • e.g. PD study - negative emotional impact of therapy was linked to their preconcieved expectations

Question 29

What is a primary outcome?

Answer 29

• The most important outcome of the study
• The outcome that the study is based around
• There should only be one
• Has a real world meaning to patients
• Should include measures of PRO/QOL (physical and/or social functioning) where possible

Question 30

How do you calculate the sample size needed?

Answer 30

• Test varies depending on the planned statistical test
  
  • need:
    
    • Alpha (p value) - the probibility the study will find a difference if it doesn’t exist
    • Power - the probability the study will find a difference if one exists
    • Effect Size -
    • Pooled standard deviation - measure of the spread of data

Question 31

What is the alpha/p value?

Answer 31

• typically 0.05
• the liklihood we will find a difference if one doesn’t really exist

Question 32

When do you do a chi-squared test?

Answer 32

• Categorical data
• Looking to prove a correlation

Question 33

When do you do a t-test?

Answer 33

When the data is continuous, and normally distributed

Question 34

When do you do a Mann-Whitney U-test?

Answer 34

Continuous data, not normally distributed.

Question 35

What statistical test do you do for:

Categorical data?

Answer 35

chi-squared test

Question 36

What statistical test do you do for:

Normally distributed, continuous data?

Answer 36

t-test

Question 37

What statistical test do you do for:

Not normally distributed, continuous data?

Answer 37

Mann-Whitney U-test

Question 38

What are quality criteria for reading papers?

Answer 38

• Was the allocation sequence randomly generated?
• Was the allocation sequence adequately concealed?
• Was there a blinding of participants where possible?
• Was there a blinding of outcome assessors?
• Was there a sample size calculation?