1. CASE CONTROL STUDIES Dr. A. K. AVASARALA MBBS, M.D. PROFESSOR & HEAD DEPT OF COMMUNITY MEDICINE & EPIDEMIOLOGY PRATHIMA INSTITUTE OF MEDICAL SCIENCES, KARIMNAGAR, A.P. INDIA: +91505417 avasarala@yahoo.com

2. PROMPT TWO TEACHERS IN EPIDEMIOLOGY FROM CHINA AND ARGENTINA, REQUESTED FOR MY PERMISSION TO USE MY FIRST EPIDEMIOLOGY LECTURES FOR THEIR TEACHING. THIS PROMPTED ME TO DEVELOP AN EPIDEMIOLOGY COURSE WHICH HAS A CHANCE OF BEING USED ALL OVER THE WORLD. THIS LECTURE IS A PART OF THAT ENDEVOUR TO SPREAD EPIDEMIOLOGY.

3. LEARNING OBJECTIVES AT THE END OF THIS LECTURE LEARNER SHOULD BE 1.ABLE TO KNOW THE VARIOUS ANALYTICAL STUDIES, THEIR TYPES, AND THEIR INDICATIONS? 2.ABLE TO CHOOSE THE SUITABLE ANALYTICAL STUDY FOR TESTING THE HYPOTHESIS 3.ABLE TO ANALYZE AND TEST THE CAUSAL HYPOTHESIS 4.ABLE TO MEASURE THE VARIOUS RISKS IN POPULATION DUE TO THE SUSPECTED CAUSE?

4. PERFORMANCE OBJECTIVES 1.BY KNOWING THE POPULATION RISKS, HE MUST BE ABLE TO SAVE THAT POPULATION BY ELIMINATING THAT RISK.

5. DEFINITION CASE CONTROL STUDY IS AN ANALYTICAL AND COMPARATIVE METHOD OF OBSERVATIONAL NATURE TO TEST THE CAUSAL HYPOTHESIS.

6. CASE-CONTROL STUDIES TWO GROUPSOF PERSONS CASES AND CONTROLS (GROUP WITHOUT THE DISEASE IN QUESTION) FORM THE BASIS FOR THE STUDY, HENCE THE NAME.

7. PURPOSE THEY TRY TO 1.ESTABLISH THE CAUSE AND EFFECT RELATIONSHIP (CAUSAL ASSOCIATION) 2.THE STRENGTH OF THE CAUSAL ASSOCIATION

8. INDICATIONS TESTING CAUSAL HYPOTHESES FOR RARE DISEASES AND WHEN RESULTS ARE EXPECTED LESS EXPENSIVELY AND IN SHORT TIME

9. CASE CONTROL DESIGN

10. CASE CONTROL DESIGN IS AN ANALYTICAL AND COMPARATIVE DESIGN OF OBSERVATIONAL NATURE. PREVALENCE OR PROPORTION OF THE CAUSE IN CASES IS COMPARED TO THAT OF CONTROLS.

11. EXAMPLE SMOKING AND LUNG CANCER WE CHOOSE LUNG CANCER PATIENTS AS CASES AND COMPARE WITH NORMAL PEOPLE OR OTHER PATIENTS (OTHER THAN LUNG CANCER PATIENTS) AS CONTROL GROUP.

12. PROPORTION OF SMOKING IN CASES AND CONTROLS controls cases ARROWS SHOW THE EXTENT OF SMOKING AMONG CASES AND CONTROLS Smoking

13. 2/2 TABLE CASE CONTROL DESIGN Exposure to smoking Lung cancer present (cases) Lung cancer absent (controls) Total POSITIVEaba + b NEGATIVEcd c + d If a/a +c > b /b +d, the association may be causal. Odd’s ratio = ad/ bc Cases=a +c, controls = b +d

14. METHODOLOGY

15. STEPS OF CASE CONTROL STUDY 1.CASES SELECTED 2.CONTROLS SELECTED 3.MATCHED 4.ENQUIRY AND RECORDS’ VERIFICATION FOR THE AMOUNT OF EXPOSURE IN BOTH GROUPS 5.COMPARISON ANALYSIS AND RISK MEASUREMENT 6.IF EXPOSURE IS MORE IN CASES THAN IN CONTROLS CAUSAL ASSOCIATION SUSPECTED

16. .. GENERAL POPULATION HOSPITALSRELATIVESNEIGHBOURS AVOID SELECTION BIAS, INFORMATION BIAS & MEASURMENT BIASES CASESCONTROLS TO AVOID CONFOUNDING BIAS MATCHING OF CASES WITH CONTROLS FIND EXTENT OF CAUSE IN CASES FIND EXTENT OF CAUSE IN CONTROLS b / b+d IF a / a+c > b / b+d association may be causal.

17. CASES SELECTION STUDY BEGINS WITH CASES, i.e. THE PATIENTS IN WHOM THE DISEASE HAS ALREADY OCCURRED. PATIENTS WITH THE DISEASE IN QUESTION (CASES) WERE ENQUIRED FOR ALL THE DETAILS OF THEIR EXPOSURE TO THE SUSPECTED CAUSE.

18. SELECTION OF CASES - (Contd) USUALLY NEW CASES (INCIDENT CASES) WILL BE CHOSEN EITHER FROM THE GENERAL POPULATION OR FROM HOSPITALS. THE NEW CASES, WHICH ARE SIMILAR CLINICALLY, HISTOLOGICALLY, PATHOLOGICALLY AND IN THEIR DURATION OF EXPOSURE (STAGE) WILL BE CHOSEN TO AVOID ANY ERROR AND FOR BETTER COMPARISON. THUS SPECIFICITY AND SENSITIVITY OF CASES ARE GIVEN IMPORTANCE WHILE CHOOSING THEM, AS THEIR LACK MAY LEAD TO ERRORS IN COMPARISON AND ANALYSIS.

19. SOURCES OF CASES CASES MAY BE CHOSEN EITHER FROM A SINGLE SOURCE (HOSPITAL) OR FROM MULTIPLE SOURCES.

20. SELECTION OF CONTROLS CONTROL GROUP OR COMPARISON GROUP MUST BE VERY CAREFULLY CHOSEN OTHERWISE VALIDITY OF THE STUDY WILL BE DEFECTIVE. THE USUAL PRINCIPLE THAT IS TO BE OBSERVED WHILE SELECTING CONTROLS SHOULD BE THAT “LIKE SHOULD BE COMPARED WITH THE LIKE” TO AVOID ERRORS AND FOR BETTER COMPARISON.

21. SOURCES FOR CONTROLS CONTROLS MAY BE OBTAINED EITHER FROM GENERAL POPULATION, HOSPITALS, RELATIVES (TWINS PREFERRED IF AVAILABLE) OR NEIGHBORS.

22. MATCHING MATCHING IS A COMPARATIVE TECHNIQUE OF NEUTRALIZING ALL OTHER VARIABLES PRESENT IN CASES AND CONTROLS, EXCEPT THE VARIABLE (DISEASE) UNDER STUDY, TO ELIMINATE THE SYSTEMATIC ERRORS (BIASES) WHILE CONDUCTING THE STUDY.

23. LIMITATION OF MATCHING BY MATCHING, WE CAN MATCH ONLY THE KNOWN CONFOUNDING VARIABLES LIKE AGE, SEX, OCCUPATION ETC, BUT NOT THE UNKNOWN CONFOUNDERS PLAYING A ROLE IN CAUSATION.

24. ENQUIRY ABOUT EXPOSURE AFTER THE CASES AND CONTROLS WERE MATCHED TO THE MAXIMUM REQUIRED EXTENT. INFORMATION WAS OBTAINED IN BOTH GROUPS IN A SIMILAR MANNER. SEARCHING THE AVAILABLE RECORDS WITH REGARD TO THE EXPOSURE TO THE SUSPECTED CAUSE AND ITS DURATION.

25. ANALYSIS FOR RISK MEASUREMENT THE PROPORTION OF THE CAUSE IN THE CASES (a/a+c) AND THAT IN CONTROLS ( b /b+d ) ARE MEASURED.

26. EXPOSURE RATES EXPOSURE RATES ONLY CAN BE DIRECTLY CALCULATED FROM THE CASE CONTROL DESIGN, BUT NOT THE INCIDENCE RATES OR RELATIVE RISK. FOR CASES, EXPOSURE RATE WILL BE a/ a+c AND FOR CONTROLS, IT IS b/ b+d.

27. ODD’S RATIO (OR) ODD’S RATIO (OR) OR CROSS- PRODUCT RATIO (ad/bc) WHICH ALSO ASSESSES THE RISK AND EQUALLY USEFUL AS RR CAN NOT BE DERIVED FROM THESE STUDIES.

28. WHY ODDS RATIO? WHEN THE DISEASE IS RARE WITH LOW INCIDENCE, OR REFLECTS RR AND IS EQUALLY USEFUL. OR WHICH CAN BE CALCULATED FROM THE CASE CONTROL DESIGN, HENCE SUGGESTS THE STRENGTH OF THE ASSOCIATION.

29. BIASES SYSTEMATIC ERRORS, OR DEVIATION OF RESULTS OR INFERENCES FROM THE TRUTH MAY ARISE AT ANY POINT IN THE COURSE OF STUDY OR THROUGHOUT DUE TO CHANCE.

30. SELECTION BIAS SELECTION BIAS IS THE COMMONEST ERROR USUALLY COMMITTED. EITHER MATCHING (TO SOME EXTENT) OR RANDOMIZATION OR BOTH CAN MINIMIZE IT.

31. CONFOUNDING BIAS CONFOUNDING VARIABLE OR FACTOR IS THE VARIABLE WHICH IS CAPABLE OF CAUSING THE EFFECT OR DISEASE DIRECTLY ON ITS OWN AND ALSO INDIRECTLY WITH THE ASSOCIATION OF ANOTHER FACTOR. ALLOWING THIS VARIABLE INTO THE STUDY IS CONFOUNDING BIAS.

32. EXAMPLES FOR CONFOUNDING BIAS AGE IS A BEST-KNOWN CONFOUNDER, AS BY ITS OWN INCREASE, IT CAN DIRECTLY CAUSE THE DISEASE AND INDIRECTLY AND COMBINEDLY BY MINGLING WITH OTHER FACTORS RELATED TO AGE. USUALLY PRESENCE OF CONFOUNDERS LEADS TO INDIRECT CAUSAL ASSOCIATIONS e.g. GOITRE IS SEEN MOSTLY AT HIGH ALTITUDES, BUT ACTUALLY, THE IODINE DEFICIENCY AT HIGH ALTITUDES IS THE CAUSE OF GOITRE THERE. SIMILARLY, ALCOHOLISM IS SUSPECTED TO BE THE CAUSE OF LIVER CANCER BUT THE SMOKING, WHICH IS USUALLY ASSOCIATED WITH ALCOHOLISM MAY BE THE COMFOUNDING VARIABLE CAUSING THE DISEASE.

33. INFORMATION BIAS ANY ERROR IN COLLECTING INFORMATION i.e. DATA ABOUT CAUSE WILL LEAD TO THE FALSE INFERENCE OR RESULTS. THIS BIAS IS VERY FREQUENTLY SEEN IN CASE CONTROL STUDIES, AS THE ENTIRE PROCESS INVOLVED IS MOSTLY SUBJECTIVE VERIFICATION.

34. INFORMATION BIAS CASE CONTROL DESIGN IS PRINCIPALLY AN INFORMATIVE DESIGN, IN THE SENSE, INFORMATION REGARDING CAUSE IS OBTAINED AND COMPARED FROM BOTH THE CASES AND CONTROLS. ANY SUBJECTIVE INFORMATION OBTAINED FROM CASES OR CONTROLS IS VULNERABLE FOR BIAS AND ONE MUST BE VERY CAREFUL WHILE COLLECTING THE INFORMATION

35. MEMORY BIAS OR RECALL BIAS IS THE INABILITY ON THE PART OF AN INDIVIDUAL (CASE OR CONTROL) TO RECOLLECT THINGS HAPPENED IN THE PAST ACCURATELY. SIMILARLY, PATIENT MAY GIVE WRONG INFORMATION OR EXAGGERATE TO PLEASE THE INVESTIGATOR.

36. INTERVIEWING BIAS ERRORS CAN OCCUR WHILE COLLECTING DATA BY INTERVIEWING, IF THE INTERVIEWING TECHNIQUES ARE NOT STANDARDIZED AND APPLIED IN A SIMILAR FASHION AND FOR SIMILAR DURATION FOR ALL THE CASES AND CONTROLS.

37. INVESTIGATOR BIAS THIS IS OCCASIONALLY ENCOUNTERED, USUALLY AN UNINTENTIONAL ONE. THE INVESTIGATOR MAY CONDUCT INTERVIEW ONE CASE OR A CONTROL FOR A LONGER TIME AND ANOTHER FOR A SHORT TIME. HE CAN PUT HIS IDEAS AND FEELINGS UNINTENTIONALLY WHILE INTERVIEWING DUE TO OVER ENTHUSIASM.

38. MEASUREMENT BIAS ERRORS USUALLY OCCUR WHILE MEASURING THE EXPOSURE FACTOR OR THE SUSPECTED CAUSE. MEASUREMENT BIAS WILL CREEP INTO THE STUDY AND SPOILS IT, IF IT IS NOT MEASURED IN A SIMILAR MANNER USING SIMILAR TECHNIQUE OR METHOD BOTH IN CASES AND CONTROLS.

39. ADVANTAGES CASE CONTROL STUDIES ARE VERY USEFUL WHEN THE DISEASE IS RARE AND WITH LOW INCIDENCE. IT IS PREFERRED EVEN TO THE COHORT AND RANDOMIZED TRIALS IN SUCH A CIRCUMSTANCE. IT IS ALSO USED WHEN RESULTS ARE EXPECTED QUICKLY AND LESS EXPENSIVELY. THERE IS NO NEED FOR FOLLOW UP AND THERE ARE NO ETHICAL PROBLEMS. IT IS BETTER THAN OTHER STUDIES IN CERTAIN CIRCUMSTANCES (RARE DISEASES) TO STUDY THE CAUSALITY.

40. EXAMPLES DOLL’S STUDY ON SMOKING AND LUNG CANCER THALIDOMIDE USE BY PREGNANT WOMEN AND CONGENITAL DEFECTS IN THE OFFSPRING STUDY ORAL CONTRACEPTIVES AND THROMBOEMBOLISM

41. SUMMARY LESS EXPENSIVE AND QUICKER ANALYTICAL STUDY TO TEST HYPOTHESIS IMMEDIATELY IF DONE CAREFULLY AND WISELY BY ELIMINATING BIASES, IT IS REALLY A VALUABLE FOR INVESTIGATING RARE DISEASES.