Prof E. P. van Puijenbroek, MD, PhD October 2018

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

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

Outline Counterfactual theory Hill criteria Examples exam-questions

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

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

Counterfactualtheory • 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.

Counterfactual theory Drug X Event B

Counterfactualtheory • 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

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

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.

Hill AB. The environment and disease: Association or causation? Proceedings of the Royal Society of Medicine 1965;58:295-300

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

Strength of evidence … focus of epidemiology …

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

Minutes… Days… Years…

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

Carbamaz/SJS NEJM 2011:364;12

Risk management plan

Chloroquine inducedmaculopathy

Nicolausyndrome

Amiodarone induced skin discoloration

Specificity of the association Aronson & Hauben. BMJ 2006;333:1267-69

Coherence

Picture: website LUMC

Intrinsic Intrinsic / Extrinsic experiment Intrinsic Biological gradient Intrinsic

“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 anddisease: Association or causation? Proceedings of the Royal Society of Medicine 1965;58:295-300.

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

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 occursafter X and B does notoccur without X, than X is consideredtobethecause of B” This statement is: • True • False

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

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

Literaturecausality assessment Hill, Austin Bradford (1965). "The Environment and Disease: Association or Causation?". Proceedings of the Royal Society of Medicine. 58 (5): 295–300.. PMID 14283879. Höfler M (2005). "The Bradford Hill considerations on causality: a counterfactual perspective?". Emerging themes in epidemiology. 2 (1): 11. doi:10.1186/1742-7622-2-11. PMID 16269083.

Thank you for your attention

Prof E. P. van Puijenbroek, MD, PhD October 2018

Prof E. P. van Puijenbroek, MD, PhD October 2018

Presentation Transcript

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