1. Causality assessment Theoretical background
Prof E. P. van Puijenbroek, MD, PhD
October 2018

2. Learning Objectives Understand the concept of counterfactuals
Apply the role of the Bradford Hill criteria in causality assessment

3. Counterfactual theory Hill criteria Examples exam-questions
Outline
Counterfactual theory
Hill criteria
Examples exam-questions

4. Question 1
It is important to annotate the strength of the causal relationship between drug and adverse drug reaction
Agree
Do not agree

5. Question 2
Do you think it is possible to determine the strength of the causal relationship between drug and adverse drug reaction?
Agree
Do not agree

6. Counterfactual theory
When B occurs after X and B does not occur without X, than X is considered to be the cause of B Someone entered his house (B) because the door was open (X) - Because he uses this drug (X), he got an Adverse Drug Reaction (B)
X causes B because the counterfactual “when X is not used, that B does not occur” is true.

7. Counterfactual theory
Drug X Event B

8. Counterfactual theory
Drug X Event B

9. Counterfactual theory
Theory, that tries to answer the question “how do I know if something is a cause of a certain event”?
Is a theoretical approach but it does not provide a practical solution for the assessement of the causal relationship
How to solve this problem?
Study setting: use control groups
Assessement of individual cases: causality models

10. The epidemiological approach..
Exchangeability of groups - Patients (using X)  occurrence of B, given use of X - Patients (no X)  occurrence of B, given no use of X
When both groups are “exchangeable”, and B differs between both groups, we stat the B has a causal relationship with X
Size of both groups should be very large when a small actual relationship exists

11. Conclusive epidemiological evidence?
Information about “chances” for events to occur in groups of patients may be available.
In medical practice, methods to assess the strength of the causal relationship are also needed.

12. Counterfactual theory Hill criteria Examples exam-questions
Outline
Counterfactual theory
Hill criteria
Examples exam-questions

13. Hill AB. The environment and disease: Association or causation
Hill AB. The environment and disease: Association or causation? Proceedings of the Royal Society of Medicine 1965;58:

14. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

15. … focus of epidemiology …
Strength of evidence
… focus of epidemiology …

16. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

17. Time to onset analysis
Van Holle et al. PEDS 2012;21:603-10

19. Minutes…
Days…
Years…

20. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

21. W.G. McBride, The Lancet 1961 dec 16:1358

22. Carbamaz/SJS NEJM 2011:364;12

23. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

24. Risk management plan

25. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

26. Chloroquine induced maculopathy

27. Nicolau syndrome

28. Amiodarone induced skin discoloration

29. Specificity of the association
Aronson & Hauben. BMJ 2006;333:

30. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

33. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

34. Coherence

35. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

36. Picture: website LUMC

37. Bradford Hill Criteria
Strength of the evidence
Order in time
Consistency
Plausibility
Specificity
Biological gradient
Coherence
Experiment
Analogy

39. Intrinsic Intrinsic / Extrinsic Intrinsic Intrinsic experiment
Biological gradient
Intrinsic

40. “None of these nine viewpoints can bring indisputable evidence for or against a cause and effect hypothesis… What they can do, with greater or less strength, is to help answer the fundamental question – is there any other way of explaining the set of facts before us, is there any other way to answer equally, or more, likely than cause and effect?”
Hill AB. The environment and disease: Association or causation? Proceedings of the Royal Society of Medicine 1965;58:

41. Summary Causation may be difficult to prove in practice
The counterfactual theory helps to understand causality
Bradford Hill criteria play a role in the assessement of the causal relationship between drug and adverse event

42. Counterfactual theory Hill criteria Examples exam-questions
Outline
Counterfactual theory
Hill criteria
Examples exam-questions

43. Exam question –example 1
The idea of counterfactual theories of causation is that the causal relationship between these events can be expressed by so called “counterfactual conditionals”. An example is for instance: “When B occurs after X and B does not occur without X, than X is considered to be the cause of B”
This statement is:
True
False

44. Exam question –example 2
One of the criteria used in causality model, originally formulated by the epidemiologist Bradford Hill, is the strength of the association. Where would you look for his type of information in daily practice? 
In medical literature
In de medical history of the patient
In de medication history of the patient
None of the above

45. Learning Objectives Understand the concept of counterfactuals
Apply the role of the Bradford Hill criteria in causality assessment

46. Literature causality assessment
Hill, Austin Bradford (1965). "The Environment and Disease: Association or Causation?". Proceedings of the Royal Society of Medicine. 58 (5): 295–300.. PMID 
Höfler M (2005). "The Bradford Hill considerations on causality: a counterfactual perspective?". Emerging themes in epidemiology. 2 (1): 11. doi: / PMID 

47. Thank you for your attention