1. Causal and non-causal associations Biases, confounding, confusion How to decide if a finding is real Ora Paltiel October 26, 2014

2. Causation Importance of studying causation 1. Clinical medicine Advice to patients Prevention 2. Social/environmental Compensation 3. Population Screeningprevention

3. “Cause” A factor which, if altered is followed by a change in the frequency or character of a disease. Probabilistic approach: X is a cause of Y if the probability that Y occurs is increased as a consequence of X. Problems: risk factor vs cause risk marker vs risk factor

4. Models Triangle המשולש האפידמיולוגי Host המאכסן Agent מחולל המחלה Environment הסביבה

5. Web of causation

6. Association and cause ExplanationFinding Association Bias in selectionYesNo or measurement ChanceLikelyUnlikely Confounding Yes No Cause

7. Types of association Positive vs inverse Linear, exponential, quadratic (U or J shaped) Two factors: additive multiplicative Effect modification

8. Relationship between asbestos exposure (particle-years) and relative risk of lung cancer

9. Wisconsin Card Sorting Test number of categories in early-onset, late-onset and control groups use of marijuana. Fontes M A et al. BJP 2011;198:442-447

10. Annual mortality (per 1000 men) from all causes related to alcohol consumption

11. Ischaemic heart disease

12. Age-standardized lung cancer death rates (per 100000 population) in relation to cigarette smoking and occupational exposure to asbestos dust

13. Prevalence of Actinic Keratoses in Psoriatics and Controls by Hair Colour Effect modification Odds ratio

14. Prevalence of Actinic Keratoses in Psoriatics and Controls by propensity to sunburn Effect modification Odds ratio

15. Association and cause ExplanationFinding Association Bias in selectionYesNo or measurement ChanceLikelyUnlikely Confounding Yes No Cause

16. Definition of bias “Any process at any stage of inference which tends to produce results or conclusions that differ systematically from the truth”

17. Stages of research in which bias can occur: 1. In reading-up on the field 2. In specifying and selecting the study sample 3. In executing the experimental maneuvre (or exposure) 4. In measuring exposures and outcomes 5. In analyzing the data 6. In publishing the results

18. Membership bias Membership in a group (the employed, joggers, etc…) may imply a degree of health which differs systematically from that of the general population.

19. Selection bias

20. Confirmation by randomized trial of observed effect in non-randomized trial: Salk vaccine for poliomyelitis Odds ratio (95% CI) Poliomyelitis cases/total (rate per 100,000) Type of study ControlVaccine 0.55 (0.44-0.68) 0.43 (0.32-0.56) 391/725173 (54) 142/201229 (71) 60/231902 (26) 57/200745 (28) Non- randomized Randomized External Validity

21. Confirmation by randomized trial of observed effect in non-randomized trial: Salk vaccine for poliomyelitis Odds ratio (95% CI) Poliomyelitis cases/total (rate per 100,000) Type of study ControlVaccine 0.55 (0.44-0.68) 0.43 (0.32-0.56) 391/725173 (54) 142/201229 (71) 60/231902 (26) 57/200745 (28) Non- randomized Randomized

22. Cumulative mortality from verified colorectal cancer in the control and screened groups

23. Cause specific mortality rates (per 1000 person years) in the intervention and control groups by faecal occult blood testing

24. Social approval bias

25. Intervention- letter, nutrition survey, benefits of fruits and veggies. 5-a day sticker Control- letter, nutrition survey,

26. Referral bias

27. Admission rate (Berkson) bias When combination of exposure and disease leads to higher rate of hospitalization, the relation between exposure and disease will become distorted in hospital based studies.

28. Measurement bias/ information bias esp.in case-control studies a) presence of the outcome directly affects the exposure. E.g. endometrial cancer and estrogen b) presence of the outcome affects the recollection of the exposure “recall bias”. E.g. birth defects and drug exposure c) presence of the outcome affects the measurement or recording of the exposure. Eg DVT and oral contraceptives

29. Association and cause ExplanationFinding Association Bias in selectionYesNo or measurement ChanceLikelyUnlikely Confounding Yes No Cause P value

30. Association and cause ExplanationFinding Association Bias in selectionYesNo or measurement ChanceLikelyUnlikely Confounding Yes No Cause

31. Confounding

32. Confounding: coffee drinking, cigarette smoking, and coronary heart disease EXPOSUREDISEASE (coffee drinking) (heart disease) CONFOUNDING VARIABLE (cigarette smoking)

33. Locations of potential bias in cohort studies 02 16 57 40 80 21 65 74 08

34. Association and cause ExplanationFinding Association Bias in selectionYesNo or measurement ChanceLikelyUnlikely Confounding Yes No Cause? Cause

35. Criteria for causation 1. Is there evidence from true experimentation in humans? 2. Is the association strong? 3. Is the association consistent from study to study? 4. Is the temporal association correct? 5. Is there a dose-response gradient? 6. Does the association make biological sense? 7. Is the association specific? (Adapted from Bradford Hill)

36. The isotretinoin dysmorphic syndrome Lancet, March 3 1984 Sir, - we describe here a case of human teratogenicity that confirms the need for the drug isotretinoin to be avoided in pregnancy. Post-mortem examination revealed a dysmorphic syndrome, with malformations of the ears, heart, and brain….This is the 1st case of human isotretinoin teratogenicity to be described in detail.

37. The isotretinoin teratogen syndrome Two infants with prominent frontal bossing, hydrocephalus, microphthalmia, and small malformed, low-set, undifferentiated ears were born to mothers, who had taken isotretinoin in the first trimester of pregnancy. A Dandy-Walker malformation, microcephaly, hypertelorism, small ear canals, cleft palate, small mouth, and congenital heart disease were also observed. Isotretinoin is a potent teratogen in many. Maternal ingestion early in pregnancy, leads to a distinct clinical pattern of anomalies. JAMA 1984; 251:3267-69.

38. Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. Coherence

39. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 6 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformation (relative risk = 25.6; 95% CI 11.4-57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structure. Specificity

40. Further criterion: Reversibility -rarely applicable

41. Relative risk for developing lung cancer by time since stopping smoking and total duration of smoking habit

42. LevelSource of Evidence IEvidence obtained from at least one properly designed randomized controlled trial II-1Evidence obtained from well-designed controlled trials without randomization II-2Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group II-3Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence IIIOpinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

43. Hierarchy of study methods to assess causation

44. Remember: Evidence based medicine means making decisions on BEST EVIDENCE, not IDEAL or PERFECT evidence