1. The Bahrain Branch of the UK Cochrane Centre In Collaboration with Reyada Training & Management Consultancy, Dubai-UAE Cochrane Collaboration and Systematic Review Workshop, 20-21 February 2007, Dubai - UAE Dr. Zbys Fedorowicz, Dr. Dunia Al Hashimi, Dr. Ahmed Al Asfoor http://bahrain.cochrane.org http://www.rt.ae W03

2. Study Designs

3. Concepts to take home Recognize types of studies Recognize types of observational studies Strengths and weaknesses of case-control and cohort study designs. Recognize a controlled trial Understand randomization, blinding/masking, placebos Understand the ethics of clinical trials

4. Two Main Categories Observational –Identify subjects first, then –Observe and record characteristics Experimental –Identify subjects –Place in common context –Intervention, then –Observe effects of intervention

5. Types of studies Observational studies –Case report/Case series –Case control –Cohort Experimental studies

6. Basic Definitions Retrospective - Any design that looks at data that have already been gathered Prospective - Any design that collects data on groups of subjects over time, according to a carefully written protocol, beginning at time zero; this design yields data that enable comparisons of groups.

7. Basic Definitions Bias - A methodological problem resulting from a selection process that is not random Randomization - A process by which subjects are assigned to experimental or control groups so that the 2 groups are the same in all characteristics.

8. Basic Definitions Population/target population - The total group of people who are represented by the random selection of members, usually connoting the whole population but possibly connoting the population of any subset, eg, women Sample - A subset of subjects from the population of all who have a particular characteristic, such as a disease

9. Basic Definitions Blinding - The process by which the identity of a subject's group assignment (case or control) is kept hidden from the subject Double blinding - A process that ensures that both the subject and the caregiver or outcome assessor are unaware of whether the subject is assigned to the control or the experimental group.

10. Case control studies Attempt to make inference from existing observations (retrospective) Compares patients with outcome/disease with those without and attempts to identify factors that influenced that outcome (or caused that disease) Important concept: start with the result (disease) and work backwards for the cause

11. Controls A control is a standard of comparison for –Effects –Variability

12. Case-control studies Controlled studies Retrospective

13. Case-control study design ExposureDiseaseObserver ? Choose groups with and without disease, look back at what different exposures they may have had

14. The logic of Case-Control Studies Cases differ from controls only in having the disease. If exposure does not predispose to having the disease, then exposure should be equally distributed between the cases and controls. The extent of greater previous exposure among the cases reflects the increased risk that exposure confers

15. Strengths of case-control design Best study when have rare disease or outcome Relatively quick and inexpensive

16. Weaknesses (potential biases) Selection (confounding) bias: controls must be as similar to cases as possible Representativeness bias: cases should be “typical” Recall bias: cases may be able to remember events better because of its significance or may be prompted to remember by investigators Survival bias: dead people don’t make it into many case-cohort studies; and if they do, they don’t remember things very well

17. Cohort studies Studies whether exposure to a “risk factor” is associated with a subsequent “outcome” Select two populations who seem the same except for the hypothesized risk factor Follow them ahead in time and see how many have the outcome or disease Important concept: Start with the risk, then look for the outcome

18. Cohort studies Prospective Controlled Can determine causes and incidence of diseases as well as identify risk factors Generally expensive and difficult to carry out

19. Procedure for cohort study Identify groups of exposed subjects and control subjects Match for other risk factors Follow over time Record the fraction in each group who develop the condition of interest Compare these fractions using RR or OR

20. Logic of the cohort study Differences in the rate at which exposed and control subjects contract a disease is due to the differences in exposure, since other known risk factors are equally present in the two groups

21. Cohort study design (Prospective) ExposureObserver Disease ? Start with two groups of people who are exposed and unexposed, follow them to see who gets disease.

22. Strengths of cohort study Not only can you look at risk, you can calculate how many people actually get the disease (incidence rates) Since you enroll subjects before the outcome, you can measure multiple exposures without recall bias Best for rare exposures

23. Potential biases in cohort studies Selection (confounding) bias: have to match similar groups – “Healthy worker effect” Detection bias: measurement of outcomes needs to be objective and similar for both groups Length-time bias: study has to be long enough for outcome to happen Excursion bias: subjects may disappear or drop-out (lost to follow-up)

24. Some other problems Cohort studies may take a long time Cohort studies may require a large number of people especially if the outcome is uncommon Both of these make cohort studies expensive

25. Experimental design Investigator controls exposure to the risk or treatment by assigning subjects to one group (experimental group) or another (control group) Assignment to experimental or control attempts to make sure both group are similar in all ways except the experimental manipulation

26. Randomization of subjects To help assure that groups are similar, subjects are randomly assigned to experimental or control groups Randomization is performed to increase the likelihood that groups are matched in other, non-experimental ways Randomization does not assure that the groups are the same: still need to assess whether they are

27. Randomised controlled trial (RCT) Best form of healthcare evidence, or the “gold standard” for evidence about an intervention. lack of randomisation can give a 40 % over or underestimate of treatment effect synthesis of those trials statistical and clinical heterogeneity.

28. Randomised controlled trial population group 1 group 2 Outcome intervention control

29. RCT SYSTEMATIC REVIEW “STRONGER” EVIDENCE Meta-analysis

30. Randomization and Confounding Randomization is supposed to have the effect of distributing confounders both known and unknown between the intervention and control groups

31. Blinding Even after randomization, it is possible that experimental subjects may be treated differently than controls To combat this, “blinding” is often used (also called masking) Blinding means that the subject, investigator, or both (double-blind) do not know what group the subject is assigned to

32. Placebos Placebos are another way of trying to make both groups similar A placebo is a biologically inactive substance given to the control group so that they think they are being treated “Placebo effect” is important: many patients in the placebo group report getting better simply because they are taking the placebo!

33. Are placebos ethical? When there is no known successful therapy, a placebo is ethical (but withholding a treatment known to be effective is not!) Using a placebo instead of the experimental drug is ethical since the experimental drug is not known to be beneficial and could actually be harmful