1. Critique of Therapy
Article - Validity
Dr. Majdi N. Al-Jasim
SBFM, ABFM
Consultant Family Physician
PCFCM - AlAhsa
2. OBJECTIVES
•To explain how to choose article to read.
•To assess the quality of the therapy article to
determine if the conclusions are valid.
•To discuss the relevance of the read articles to
our practice and if we can apply their results.
Dr. Majdi Al-Jasim; SBFM, ABFM
3. Is it possible to be always updated?!
A lot of Articles
Dr. Majdi Al-Jasim; SBFM, ABFM
4. Before Reading
Before reading any article, try to answer these questions:
1. Is it relevant to my practice?
2. Is the sample similar to my patients?
3. Are the results DOE or POE?
4. Will it change my practice?
Dr. Majdi Al-Jasim; SBFM, ABFM
5. Will you read this article?
I doubt
that
Dr. Majdi Al-Jasim; SBFM, ABFM
7. Evidence Based Medicine
“Evidence-based medicine is the integration of best research evidence with
clinical expertise and patient values”
- Dave Sackett
Dr. Majdi Al-Jasim; SBFM, ABFM
8. Steps of EBM
1: ASK
Formulate clinical
question (PICO)
2: ACQUIRE
Searching the
evidence
3: APPRAISE
the evidence
4: APPLY
evidence into
decision-making
5: ASSESS
Evaluate the
process PATIENT-
CENTERED
Dr. Majdi Al-Jasim; SBFM, ABFM
9. What is Critical Appraisal?
It is a process of systematic examination of research
article to assess its validity, results and applicability.
The three key steps in critically appraising
an article are:
1. Was the study valid?
2. What are the results?
3. Are the results applicable to our patients?
Dr. Majdi Al-Jasim; SBFM, ABFM
10. How to evaluate an article
By using critical appraisal toolkit (CAT) for each
specific article type:
▪ Therapy (RCT)
▪ Systematic Review and Meta-analysis
▪ Prognosis (Cohort or case-control study)
▪ Diagnosis
Dr. Majdi Al-Jasim; SBFM, ABFM
12. Appropriate Study Designs
Diagnosis
Prospective cohort study with good quality
validation against “Gold Standard”
Therapy Randomized controlled clinical trial (RCT)
Etiology
Case-control study or retrospective cohort
study
Prognosis Prospective cohort study
Dr. Majdi Al-Jasim; SBFM, ABFM
14. Validity
Results
Apply it
Is the study done in a correct way?
(Methodology Section)
Are results significant?
(Results Section)
What are benefits and risks?
Is this study generalizable?
Critique of Therapy Article (RCT)
Dr. Majdi Al-Jasim; SBFM, ABFM
15. General Scheme of RCT
Eligible sample
Excluded
Dr. Majdi Al-Jasim; SBFM, ABFM
16. Types of Endpoint (Outcomes)
Primary Outcome:
Is the outcome of interest that has been set by the researcher at
the beginning of study.
Secondary Outcome:
Is the additional outcome that occurs during study.
Surrogate Outcome:
Is an indirect lab result or physical sign used as a substitute to
measure primary or secondary outcome. E.g. in some statin
trials, they measure LDL level to indicate the rate of IHD.
Dr. Majdi Al-Jasim; SBFM, ABFM
17. Types of Endpoint (Outcomes)
Composite Outcome:
Multiple outcomes combined together.
Example:
IHD deaths, arrhythmia deaths, valvular heart disease deaths
cardiac causes of death as composite.
Advantages:
▪ Easier.
▪ Increase number of events by magnifying the result.
Disadvantage:
When combined together, the event rate increases, so the
event of interest may reach significant or non-significant level
which may not reach if it was analyzed alone.
Dr. Majdi Al-Jasim; SBFM, ABFM
20. Closeness to the truthValidity
Internal
Look for the presence of Biases (the deviation of the
results of a study from the truth because of the way it
has been conducted, analyzed or reported).
Dr. Majdi Al-Jasim; SBFM, ABFM
21. Closeness to the truthValidity
External
Look for the presence of Random Error (when the study
sample is not representative to general population; i.e.
not similar to the community).
Applicability
Dr. Majdi Al-Jasim; SBFM, ABFM
26. Was the assignment of patient
“randomized”?
Dr. Majdi Al-Jasim; SBFM, ABFM
27. ▪ It is a process where each patient has
equal chance to be in control group or
experiment group.
▪ Every one in the sample has 50% chance
to be in either group, experiment group
or control group.
Randomization RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
28. Why randomization?
1. To ensure equal base-line characteristics in both
groups.
2. Both groups are equal in known or unknown
prognostic factors and other confounders.
Randomization RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
29. Concealed Allocation
▪ Assigning of patient to control or experiment group before the
beginning of study in a concealed manner.
▪ Concealment is done by opaque envelope, computerized
protected folder, and remote central call system.
Hide the patient
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
30. Selection Bias
Selection bias:
When you select intentionally
more healthy subject to be in the
experiment group and more ill
subject to be in the control group
in order to have excellent results
in experiment group.
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
31. Practice
You have come across this article in New England
Journal of Medicine, and you want to check its validity.
Dr. Majdi Al-Jasim; SBFM, ABFM
32.
33. RCT CAT:
Was the assignment of
patients to treatment
groups randomized?
Dr. Majdi Al-Jasim; SBFM, ABFM
34. Types of RCT Randomization Design
The RCT randomization design is how the experimental and
controlled groups are distributed randomly after sampling
takes place.
The most commonly used randomization designs are:
1. Parallel
2. Cross-over
3. Stratified (clustered)
4. Factorial
Dr. Majdi Al-Jasim; SBFM, ABFM
35. Parallel:
Each participant is randomly assigned to a group, and all the
participants in the group receive (or do not receive) an
intervention.
Types of RCT Randomization Design
Dr. Majdi Al-Jasim; SBFM, ABFM
36. Cross-over:
Each participant receives first treatment and then after period
received the second one in a random sequence. Its advantage is
the elimination of variations between groups.
Types of RCT Randomization Design
Dr. Majdi Al-Jasim; SBFM, ABFM
37. Stratified (clustered):
First you divide the sample into different strata (clusters) and
then do randomization from each strata. Its advantage is the
elimination of variations between groups.
Experiment
Females
Control
Sample
Experiment
Control
Males
Types of RCT Randomization Design
Dr. Majdi Al-Jasim; SBFM, ABFM
38. Factorial:
Each participant is randomly assigned to a group that receives a
particular intervention (alone or combination or neither one).
Types of RCT Randomization Design
Dr. Majdi Al-Jasim; SBFM, ABFM
40. Were all patient who entered the trial
properly “attributed” at its
conclusion?
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
41. Attrition (loss of F/U)
▪ This includes dropouts, and withdrawals.
▪ Accepted when ≥ 80% of patients completed the study to
maintain power of the study.
▪ Duration of study should be sufficient for primary outcome to
occur.
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
42. How to deal with cases of attrition if >20%?
1. Follow the events in dropped out participants:
▪ Just look for the occurrence of events in lost participants and
add them to their corresponding group events. This can be
achieved by reviewing their files in the same or other
hospitals.
▪ If this is impossible, you either considered them to have the
same event rates of those who continued the study, or do
sensitivity analysis (mostly used).
Attrition (loss of F/U) RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
43. How to deal with cases of attrition if >20%?
2. Sensitivity analysis:
▪ Re-analyzed the results based on best and worst case
scenario.
▪ If there is significant difference (p < 0.05) between actual
results and sensitivity analysis, then the study is affected by
loss of follow up.
Attrition (loss of F/U) RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
44. Attrition Bias
Attrition bias:
When you loss the follow up of your
participants in the study. It is more
common in Cohort and Randomized
Clinical Trials.
The accepted rate of loss of follow up
must be ≤ 20%.
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
45. RCT CAT:
Were all patient who
entered the trial
properly “attributed”
at its conclusion?
Nothing mentioned
about dropped out.
Dr. Majdi Al-Jasim; SBFM, ABFM
47. Were patients, physicians and those
during assessment "blind" to
treatment?
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
48. Blindness
RABI
Blindness could be:
1. Single: either patient or assessor blinds to treatment; but
usually it is the patient.
2. Double: patient and assessor blind to treatment.
3. Triple: patient, assessor and data analyst blind to treatment.
How is it done?
1. Same shape, color, taste for both control and experiment
treatment.
2. Dummy tablets.
Hide the treatment
Dr. Majdi Al-Jasim; SBFM, ABFM
49. Detection Bias
Detection bias:
When the assessor or the patient able to
predict the treatment that is used during
RCT.
This bias can happened in single-blind
trial or in open-label trial.
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
50. RCT CAT:
Were patients and
physicians and those
during assessment
blind to treatment?
Dr. Majdi Al-Jasim; SBFM, ABFM
52. Were all patient who entered the trial
properly “accounted for” at its
conclusion?
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
53. Intention To Treat (ITT) analysis
▪ It is analysis of the primary outcome according to each group
original primary allocation.
▪ Once patients are randomized, they should be analyzed in the
same group even if there was drop out and because of that
the number of analyzed patients in primary outcome is the
same number of patients the trial started with.
▪ It is different from “Per Protocol Analysis” in which only
analysis occurs to only those who completed the study.
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
54. Advantage of ITT analysis:
Maintains randomization.
Disadvantage of ITT analysis:
Gives false effect estimate of experiment or control treatment
because of:
1) Including dropped out patients.
2) Including non-compliant patients.
3) Including patients with contamination and or cointervention
RABI
Intention To Treat (ITT) analysis
Dr. Majdi Al-Jasim; SBFM, ABFM
55. RCT CAT:
Were all patients who
entered the trial
properly “accounted
for” at its conclusion?
Dr. Majdi Al-Jasim; SBFM, ABFM
56. RCT CAT:
Were all patients who
entered the trial
properly “accounted
for” at its conclusion?
ITT analysis
Dr. Majdi Al-Jasim; SBFM, ABFM
57. Post Hoc Analysis
▪ When the researcher re-analyze data again and again in
different ways in order to find something extra (fishing data).
▪ This analysis type usually occurs after having non-significant
primary or secondary outcome.
▪ Most of authors used sub-group analysis as post hoc analysis in
which the analysis occurs in fragmented groups of the sample.
RABI
Fishing the
significant data.!!
Dr. Majdi Al-Jasim; SBFM, ABFM
58. 1 1.5 20.50
Overall
Males
Females
95% CI (0.6 – 1.3); p= 0.12
95% CI (0.3 – 0.8); p= 0.03
95% CI (0.8 – 1.4); p= 0.20
Favor treatment Favor placebo
Sex
Age
< 65
≥ 65
95% CI (0.5 – 1.3); p= 0.35
95% CI (0.6 – 1.4); p= 0.51
The overall
outcome is not
significant but
sub-group
analysis showed
that males
actually might
benefit from
treatment.
Post Hoc Analysis
Dr. Majdi Al-Jasim; SBFM, ABFM
61. ▪ Similarity in baseline prognostic factors, demographics,
comorbidity, disease severity, other known confounders.
▪ It is achieved by proper randomization in which the
resulted difference between study groups should be not
significant (p ≥ 0.05) to ensure similarity.
▪ Usually this information is presented in table 1 in article.
Identical
RABI
Dr. Majdi Al-Jasim; SBFM, ABFM
64. Aside from the intervention,
were the groups TREATED IN
THE SAME WAY ?
Dr. Majdi Al-Jasim; SBFM, ABFM
65. • Co-intervention
Any extra intervention other than study treatments to either group;
like outside drug.
• Contamination
Any member from one group received treatment from other group that
is included in the study.
• Compliance
✓ Was it mentioned?
✓ How is it looked for?
EQUAL TREATEMENT
Dr. Majdi Al-Jasim; SBFM, ABFM
66. Performance Bias
Performance bias:
When there is:
▪ Contamination.
▪ Co-intervention.
▪ No blindness.
▪ Placebo effect*.
*Placebo effect means the patient has a belief in
placebo treatment that it can cure him/her.
If the whole control group has the same belief, it may
affect the study results.
Dr. Majdi Al-Jasim; SBFM, ABFM
67. RCT CAT:
Aside from intervention,
were groups treated in
the same way?
Nothing mentioned
about contamination
or co-intervention.
Compliance
Dr. Majdi Al-Jasim; SBFM, ABFM
69. Applicability
Can I apply the study results on my patients?
Check if the study population are similar to your patients.Similarity
Dr. Majdi Al-Jasim; SBFM, ABFM
70. Applicability
Do benefits overweight risks
in applying the results?
Check for the important side
effects of this new treatment.
You need to calculate NNT and
NNH to compare.
Benefits
Risks
Dr. Majdi Al-Jasim; SBFM, ABFM
71. Applicability
Is its cost feasible?
How much will it cost?
Is it affordable to my
patients?
Dr. Majdi Al-Jasim; SBFM, ABFM
72. Applicability
Are the results DOE or POE?
Were quality of life used?
Were most important outcomes
(bad or good) mentioned?
Dr. Majdi Al-Jasim; SBFM, ABFM