1. An Introduction to Clinical Epidemiology and Research Methodology
F. Farrokhyar, MPhil, PhD, PDoc
Department of Surgery
Department of Clinical Epidemiology and Biostatistics

2. Evidence-based Medicine
Explicit and judicious use of the best current evidence in making decisions about the care of the individual patient.
EBM and patient-derived outcomes assessment movements has led to an increased focus on the effectiveness of clinical care.
Clinical epidemiology provides the methodology with which we assess this effectiveness.

3. Pyramid of Evidence Clinical research Quantitative research
Qualitative research

4. Clinical Research Experimental RCTs Non-RCTs Observational Analytical
Cohort studies
Case-control studies
Descriptive studies – no control group
Case-series
Longitudinal studies

5. Clinical Research . . .
If treatment effect is very large, this is likely to be identified reliably in an observational study, if they are properly designed to control biases.
However, most interventions and procedures have moderate or small treatment effect and these biases would matter considerably.

6. What is a case series? Exposure Yes Patient Population Cases No
T I M E
Patient Population
Cases
Yes No
R E S E A R C H
A case-series is a common way of describing the clinical picture of a disease.
Case-series provide the least quality clinical evidence

7. Research question
How many patients with prostate cancer will have urinary tract infection after prostate resection surgery?

8. What is a case series?
Pre-op antibiotic
R E S E A R C H
Patient
population
Cases
yes No
T I M E 15 6
= 15/21 = 0.71 or 71% 21
140
Patients with prostate cancer underwent resection surgery
infection
= 21/140 = 0.15 = 15%
Major Limitations:
- no control group
- retrospective
- Cause - effect relationship - Hypothesis generating

9. Research question
Does the use of pre-op antibiotic decrease the urinary tract infection after prostate resection surgery?

10. Study of Cause-and-Effect Relationship

11. What is a case-control study?
Outcome/
disease
Intervention/
exposure?
Yes No
Cases
Controls
Pre-op antibiotic
Infection
Target population 15 85 40 60
100
800
OR = 15 x 60/40x85
= 0.26
Patients following prostate surgery
No infection
& 95% CI

12. Case-control studies Advantages: Feasible for rare conditions
Smaller sample size
Can assess outcome with many exposures
Overcome temporal delays
Cheap
Disadvantages:
Retrospective
Potential threats to internal validity
Selection bias
Measurement bias
Data extraction bias
Missing data
Recall bias

13. To control biases in case-control studies?
At the stage of study design – to control for selection bias
Restriction
Matching
At the stage of data analysis
Multivariable analysis
Stratified analysis

14. Study of Cause-and-Effect Relationship

15. What is a cohort?

16. What is a cohort study?
Intervention/ Exposure
Outcome?
Yes No
Target population
Sample
Does the use of pre-op antibiotic decrease the urinary tract infection after prostate resection surgery?

17. What is a cohort study? Pre-op antibiotic infection 85 130 115 70
Intervention/ Exposure
Outcome?
Yes No
infection
Target population
Sample 85
130
115 70
215
185
400
Patients before prostate surgery
No pre-op antibiotic
Odds ratios? (0.40)

18. Cohort studies Advantages: Prospective Estimate incidence
Feasible when randomization not possible
Can assess the relationship between exposure/ intervention and many outcomes
Disadvantages:
Not feasible for rare diseases
Expensive
Results not available for a long time.
Potential threats to internal validity
Selection bias
Performance bias
Detection/ascertainment bias
Measurement bias
Attrition bias

19. What are the potential threats to internal validity?
Selection bias – systematic differences in comparison groups.
Measurement bias – systematic differences in measuring variables
Performance bias – systematic differences in care provided apart form the intervention being evaluated.
Detection - systematic differences in outcome assessment
Attrition bias – systematic differences in withdrawals from the study.
provide as well as considers the - Participants have an equal chance to be assigned to one of two or more groups.
One gets the most widely accepted treatment (standard treatment)
The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than standard treatment

20. To control biases in cohort studies?
At the stage of study design
Restriction
Matching
At the stage of data analysis
Propensity score analysis
Multivariable analysis
Stratified analysis

22. Study of Cause-and-Effect Relationship

23. What is Randomization?

24. Why Randomization is Important?
The process of randomization provides comparable groups for most factors so that the differences in the outcome at the end of the trial can be attributed to the intervention alone.
Consequently, preventing biased assignment permits a more definitive interpretation of the trial’s results.

25. What is an RCT? Clinical uncertainty? Clinical equipoise? Intervention
Outcome?
Yes No
A .
B .
Target population R 55
145
200
125 75
Clinical uncertainty?
Clinical equipoise?
Calculation: RR, RRR, OR, RD, NNT/ NNH

26. What are the potential sources of bias in RCTs?
Concealment
Blinding care providers
Blinding outcome assessors
Minimize loss to follow-ups
…. blind patients, investigators, data entry personnel, data analyst
Selection bias
Performance bias
Detection/ascertainment bias
Attrition bias
provide as well as considers the - Participants have an equal chance to be assigned to one of two or more groups.
One gets the most widely accepted treatment (standard treatment)
The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than standard treatment

27. In a well-designed RCT:
Inclusion and exclusion criteria are predescribed and identical between the treatment groups.
All patients have the equal chance of receiving either treatment.
Known and unknown confounders are similar between the treatment groups. Any differences would be by chance.
Treatments are concurrent, avoiding temporal trends.
Data collection is prospective, concurrent, high quality and eliminates the differences in definitions and types of variables.
Assumptions underlying the statistical comparison tests are met.

28. Types of RCT in Surgery?
Three types of RCTs are commonly described “surgical”
Type I –comparison of medical treatments in surgical patients – traditional clinical trials
Type II – comparison of a surgical technique with a medical treatment or no treatment
Type III – comparison of two surgical techniques

29. Surgical trials vs. clinical trials

30. What are the Challenges of Surgical Trials?
Clinical trials do not risk any differential skills in administering the intervention.
A major difference between clinical trials and surgical trials is that surgical trials require skills and training to administer the intervention.
Surgery is a skilled and multi-step process and this makes the design of surgical trials challenging for the following reasons.

31. Ethical issues
Helsinki Declaration – all study subjects have the right to withdraw from a study at any time, without prejudice.
This is hardly possible in a surgical trial.
Sham surgery? is it ethical?
In drug trials, most likely the drug company is responsible in case of an adverse event or a bad outcome.
In surgical trials, surgeons, personally and legally, are responsible for their patients.

32. Learning curve

33. Why learning curve? differential bias
It takes training and experience to develop expertise in a surgical technique.
Surgeons tend to predominantly use a single surgical approach to treat a specific problem.
Even for a fully trained surgeon, there is a learning process to become an expert with a new technique.
If the participating surgeon is performing both new and standard techniques and has limited experiences with the new one, the results will be biased towards the standard technique.
differential bias

34. Expertise-based RCTs
Patients are randomized to surgeon who is an expert in that intervention.
Advantages;
Surgeons will perform only the procedure in which they have expertise
Procedural crossovers are less likely to occur because surgeons are doing the procedure they are most comfortable with.
It makes it easier to obtain informed consent and recruit patients into the trial

35. Surgeons’ Skill Variation

36. Surgeons’ Skill Variation
There is an inherent variation in performing a specific procedure by different experts.
There is also the effects of trainees, fellows and others in the operating room
It requires more sophisticated statistical analysis to adjust for the effect of surgeons’ skill variation in multicenter surgical trials.

38. Blinding
Clinical trials are traditionally double blinded : patients and investigators are blinded to the type of treatment
In surgical trials –
Surgeons cannot be blinded.
It is hard and unethical not to tell patients.
– sham surgery has been used in the evaluation of fetal tissue transplants in Parkinson’s disease
Blinded trials are not possible when comparing surgical and non-surgical treatments.
Outcome assessors and data analyst could be blinded

39. Outcome assessment
Patient’s knowledge of the procedure often influences their behaviour – Hawthorne effect
Investigators knowledge of the procedure influences their assessment of the outcome.
Co-intervention – patients often require extra treatment such as physiotherapy or rehabilitation in orthopaedic surgery.

40. Follow up time
It is hard to determine the appropriate duration of follow up in surgical trials.
The loss to follow up is higher when the duration of follow up is very long.
The loss to follow up is higher when no treatment is required after surgery.

41. Different types of RCTs
Equality trials
Superiority trials
Non-Inferiority trials
Equivalence trials
Cluster randomized trials
Cross-over trials

42. Study of Cause-and-Effect Relationship

43. In summary, …
Randomized controlled trials should have a very important role in the evaluation of surgical interventions. If properly designed, conducted, and interpreted the results are likely to make a substantial impact on the health of patients.

44. However, …
In those situations when it is deemed infeasible to conduct a randomized controlled trial, we need to choose alternatives such as inception cohort or case-control studies that may be less rigorous than the randomized controlled trial but more rigorous than the uncontrolled case-series.

45. Message to take home… Pilot study
In designing a research project consider:
Frequency of the disease
Treatment effect
Follow-up time
and
Ethics
Pilot study

46. Did investigator assign exposure/intervention?
Yes No
Did investigator assign exposure/intervention?
Experimental study
Random allocation
Comparison group?
Descriptive study
Analytical study
Direction?
Randomized controlled trial
Non-randomized controlled trial
Cohort
study
Case-control study
Cross-sectional study
Exposure Outcome
Outcome Exposure
Exposure and outcome
at the same time