causality assessment in poisoning essential for data quality
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Swiss Toxicological Information Centre 1
EAPCCT 2008: Causality Assessment in Poisoning
Causality Assessmentin Poisoning
Essential for Data Quality
Hugo Kupferschmidt, M.D.Director
Swiss Toxicological Information Centre
Zuerich
Seville, May 8, 2008XXVIII EAPCCT Congress, Melia Sevilla
Swiss Toxicological Information Centre 2
EAPCCT 2008: Causality Assessment in Poisoning
Overview
Definitions
History
Rationale
Causality assessment in adverse drug reactions
Limitations and weaknesses
Causality in poisoning
A proposal for standarized causality assessment in poisoning and drug overdose
Discussion
Swiss Toxicological Information Centre 3
EAPCCT 2008: Causality Assessment in Poisoning
Definitions
Causality assessment
is the evaluation of the likelyhood that a particular event (exposure) is the cause of an observed effect.
investigates the relationship between the exposure and the occurrence of an effect.
is an important component of pharmaco- and toxicovigilance
contributes to better evaluation of risk-benefit profiles
Auriche M et al. Drug Saf 1993; 9: 230-5Edwards IR et al. Drug Saf 1994; 10: 93-102
Meyboom RHB et al. Drug Saf 1997; 17: 374-89Agbabiaka TB et al. Drug Saf 2008; 31: 21-37
Swiss Toxicological Information Centre 4
EAPCCT 2008: Causality Assessment in Poisoning
Rationale
Source of data on human poisoning
Prospective cohort studies and RCTs are still lacking for most questions and aspects in clinical toxicology.
Poisons Centre data remain an important and sometimes unique source of information, particu-larly on rare kinds of poisoning.
Whereever prospective cohort studies and RCTs are not to be expected in the future, there is an obligation for Poisons Centres and clincal toxico-logists to collect data on such cases accurately, carefully, and as completely as possible.
Brent J. Clin Toxicol 2005; 43: 881-6
Swiss Toxicological Information Centre 5
EAPCCT 2008: Causality Assessment in Poisoning
Rationale
Quality of data on human poisoning
exposure uncertain no experimental setting
by history only (patient‘s, bystanders‘)
supported by the observed toxic effect
Having a measure on the likelyhood of expo-sure would be a substantial improvement of the data quality. information about the exposure itself
assessment of the toxic effect in the view of the exposure (causality)
Swiss Toxicological Information Centre 6
EAPCCT 2008: Causality Assessment in Poisoning
Rationale
Causality assessment is necessary
for statistical purposes
for epidemiological purposes
for toxicology databases
for publication (case reports and case series)
for the generation of data on prior probabilities for Bayesian statistics in the diagnostic process
Whyte IM. Clin Toxicol 2002; 40: 211-2Whyte IM et al. Clin Toxicol 2002; 40: 223-30
Swiss Toxicological Information Centre 7
EAPCCT 2008: Causality Assessment in Poisoning
Rationale
Link between severity grading and causality assess-ment The EAPCCT (together with the IPCS and the
European Commission) has developed a standard severity grading system, the PSS.
Severity grading implies that the symptoms described are related to the toxic exposure (i.e. there is a causal relationship between these symptoms and the exposure)
It is nothing than consequent now to continue in agreeing on a standard system of causality assessment.
Swiss Toxicological Information Centre 8
EAPCCT 2008: Causality Assessment in Poisoning
Standardisation
Standardized causality assessment
is aimed at decreasing ambiguity of the data
plays a key role in data exchange
limits the drawing of erroneous conclusions
... is therefore a major factor of data quality.
Meyboom RHB et al. Drug Saf 1997; 17: 374-89Agbabiaka TB et al. Drug Saf 2008; 31: 21-37
Swiss Toxicological Information Centre 9
EAPCCT 2008: Causality Assessment in Poisoning
History
Sir Austin Bradford Hill (1965): Strength of the association Consistency of the observed association Specificity Temporality (chronology) Biological gradient Plausibility Coherence Experiment Analogy
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
Causality in ADR
Assessment of causality is routine in pharmaco-vigilance (spontaneous reporting).
Meyboom RHB et al. Drug Saf 1997; 17: 374-89Agbabiaka TB et al. Drug Saf 2008; 31: 21-37
Arimone Y et al. Eur J Clin Pharmacol 2005; 61: 169-73
Categories of methods
Opinion of experts, clinical judgement or global introspection
(n=4; 12%)
algorithms or standardized assessment methods
(n=26; 76%)
Probabilistic or Bayesian approaches
(12%)
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EAPCCT 2008: Causality Assessment in Poisoning
Causality in ADR
Determining factors in causality assessment temporal sequence (chronology, temporality) time to onset previous information on the drug background epidemiological and clinical information dose relationship (e.g. overdoses) response pattern characteristics and mechanisms of the ADR rechallenge - dechallenge alternative aetiologies (differential diagnoses) concomitant drugs analytical confirmation
Wiholm BE. Drug Inf J 1984; 18: 267-9.Agbabiaka TB et al. Drug Saf 2008; 31: 21-37
Swiss Toxicological Information Centre 12
EAPCCT 2008: Causality Assessment in Poisoning
Causality in ADR
Classification of events, degrees of causality
definite / confirmed / certain
causative
probable / likely
possible
non-assessable / unclassifiable
unclassified / conditional
unlikely / coincidental / doubtful / remote / unlikely
exclude / negative / unrelatedWiholm BE. Drug Inf J 1984; 18: 267-9.
Agbabiaka TB et al. Drug Saf 2008; 31: 21-37
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EAPCCT 2008: Causality Assessment in Poisoning
Causality in ADR
Limitations and weaknesses High inter-rater variability:
Miremont (1994): Physicians tend to assign very high scores to suspected ADRs. Agreement of methods: 6%
Blanc (1979): Overall inter-rater agreement on a VAS was low (κ=0.20).
Some depend grossly on raters‘ knowledge Some are organ-specific No „gold standard“ algorithm Not all suitable to assess drug-drug interactions Either superficial or very time-consuming Data to compute prior odds often unavailable
Miremont G et al. Eur J clin Pharmacol 1994; 46: 285-9Blanc S et al. Clin Pharmacol Ther 1979; 25: 493-8
Arimone Y et al. Eur J Clin Pharmacol 2005; 61: 169-73Benahmed S et al. Eur J Clin Pharmacol 2005; 61: 537-41
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EAPCCT 2008: Causality Assessment in Poisoning
Causality in ADR
Consequences of limitations and weaknesses None of the assessment systems has ever been validated
(i.e. shown to consistently and reproducibly produce a fair approximation of the truth).
Causality assessment has therefore limited scientific value. It neither eliminates nor quantifies uncertainty but, at best, categorises it in a semiquantitative way.
Standardized causality assessment has not been able to neutralize the inherent limitations of spontaneous repor-ting systems (i.e. uncertainty regarding the causal involve-ment of the drug, and underreporting).
Meyboom RHB et al. Drug Saf 1997; 17: 374-89
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EAPCCT 2008: Causality Assessment in Poisoning
Causality in ADR
Perspecvtives (2008) The idea of creating standardized causality assessment
systems to provide reliable and reproducible measures of the relationship-likelihood in suspected cases of ADR seems unfeasible, since no single method has achived this to date.
The differences in ADR causality criteria and the unavoi-dable subjectivity of judgements may be responsible for the lack or reproducibility of most methods.
So far, no ADR causality assessment method has shown consistent and reproducible measurement of causality.
Therefore, no single method is universally accepted.
Agbabiaka TB et al. Drug Saf 2008; 31: 21-37
Swiss Toxicological Information Centre 16
EAPCCT 2008: Causality Assessment in Poisoning
Causality in Poisoning
Differences and similarities to adverse drug reactions
Spontaneous reporting similar in pharmacovigilance and Poisons Centres
Incomplete data frequent
Uncertainty of exposure more important in poisoning
Uncertainty of dose and differential diagnoses moreimportant in poisoning
Concept of dechallenge and rechallenge not feasible in toxicology
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EAPCCT 2008: Causality Assessment in Poisoning
Causality in Poisoning
Confirmation system by von Clarmann (1982)
von Clarmann M. Rote Liste 1982, p. 95-6
Toxin1
Exposure1
Effect1
Toxin1
Exposure1
Effect1
Toxin1
Exposure1
Effect1
Exclusion ofother causes: 1 → Score: 1-10
Level of presumptiveevidence
Level of confirmation
Level of independentconfirmation
Additional evidence
Swiss Toxicological Information Centre 18
EAPCCT 2008: Causality Assessment in Poisoning
Exposure-Effect Relationship
1. Exposure assessment confirmed
likely
unlikely
2. Causality assessment likely
unlikely
conditional
none
not assessable
particularly importantin asymptomatic cases
feasible onlyin symptomatic cases
Swiss Toxicological Information Centre 19
EAPCCT 2008: Causality Assessment in Poisoning
Likelihood of exposure
Exposure is... if... confirmed analytical detection of substance
(= objective measure)
likely observed exposure by others
realiable reliable history from patient
possible indirect evidence of exposure
unlikely no evidence of exposure
no exposure excluded by negative analytics
Swiss Toxicological Information Centre 20
EAPCCT 2008: Causality Assessment in Poisoning
Degrees of Causality
A causal relationship between exposure and effect is... likely adequate chronology
typical or expected symptomsno other causes
possible adequate chronologytypical symptoms but possible othercauses
conditional adequate chronologyatypical symptoms andno other cause
unlikely no adequate chronology and/oratypical symptomsother causes present
not assessable no symptoms, insufficient information
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EAPCCT 2008: Causality Assessment in Poisoning
Proposed Algorithm
temporal sequenceadequate?
(toxicokinetics!)
effect typical/expected?described in literature or
pharmacology (mechanism)
other causesabsent or unlikely?
likely
other causesabsent / unlikely
possible
NO
NO
NO
YES
YES
YES
unlikely
conditional„new effect“
NO
YES
none
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EAPCCT 2008: Causality Assessment in Poisoning
10 Year Experience
Swiss Toxicol. Information Centre (1997-2006)
Degree of causality No. Percent S.D.confirmed 4875 10.1% 0.8%likely 27680 57.5% 0.5%possible 2095 4.3% 2.1%conditional 435 0.9% 3.2%unlikely 970 2.0% 1.8%not assessable 1844 3.8% 3.2%none 941 2.0% 1.7%
asymptomat 9247 19.2% 0.8%TOTAL 48162
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EAPCCT 2008: Causality Assessment in Poisoning
Discussion
Consequent causality assessment in Poisons Centres to their cases should be added to stan-dard features of data handling.
One important requirement would be routine collection of follow-up data.
A Bayesian approach would be preferable, but is unrealistic as the effort to obtain and calculate the prior odds would be immense. Furthermore these prior odds would not necessarily be appli-cable to different geographical places. Therefore an algorithm-based approach may be more fea-sible.
Buckley NA et al. Clin Toxicol 2002; 40: 213-22
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EAPCCT 2008: Causality Assessment in Poisoning
Discussion (2)
A long as prospective studies and RCTs are not available in certain fields of clinical toxicology, Poisons Centre data remain important sources of information.
This does not mean that not every effort should be taken to perform such trials.
Collecting data in Poisons Centres must not be a reason to prevent or impede efforts to perform high quality research.
Greller HA. Clin Toxicol 2004; 42: 129-30Buckley NA et al. Lancet 1996; 347: 1167-9
Whyte IM. Clin Toxicol 2002; 40: 211-2
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EAPCCT 2008: Causality Assessment in Poisoning
Discussion (3)
Causality assessment in Poisons Centres has its place mainly for the generation of „epidemio-logical“ data, and for hypothesis generation, rather than data on treatment effects.
Causality assessment will be a necessity for common data collection.
Only cases with sufficient causality (i.e. a likely relationship between exposure and effect) should be reported or published.
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EAPCCT 2008: Causality Assessment in Poisoning
Finis
hkupferschmidt@toxi.ch
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EAPCCT 2008: Causality Assessment in Poisoning
References
1. Agbabiaka TB, Savovic J, Ernst E. Methods for causality assessment of adverse drug reactions. A systematic review. Drug Saf 2008; 31: 21-37.
2. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 85: 295-300.
3. Wiholm BE. the Swedish drug-event assessment methods. Special workshop – regula-tory. Drug Inf J 1984; 18: 267-9.
4. Miremont G, Haramburu F, Bégaud B, Péré JC, Dangoumau J. Adverse drug reaction: Physician‘s opinions versus a causality assessment method. Eur J Clin Pharmacol 1994; 46: 285-9.
5. Blanc S, Leuenberger P, Berger JP, Brooke EM, Schelling JL. Judgements of trained observers on adverse drug reactions. Clin Pharmacol Ther 1979; 25: 493-8.
6. Karch FE, Lasagna L. Towards the operational identification of adeverse drug reactions. Clin Pharmacol Ther 1977; 21: 247-54.
7. Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm for the operational assessment of adverse drug reactions: I. Background, description, and instructions for use. JAMA 1979; 242: 623-32.
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EAPCCT 2008: Causality Assessment in Poisoning
References
8. Benahmed S, Picot MC, Hillaire-Buys D, Blayac JP, Dujols P, Demoly P. Comparison of pharmacovigilance algorithms in drug hypersensitivity reactions. Eur J Clin Pharmacol 2005; 61: 537-41.
9. Brent J. 2005 Louis Roche Lecture. Professional societies and evidence-based clinical toxicology. Delivered at the XXV International Congress of the EAPCCT, Berlin, Germany. Clin Toxicol 2005; 43: 881-6.
10. Greller HA. How to position our practice. Clin Toxicol 2004; 42: 129-30.
11. Isbister GK. Data collection in clinical toxinology: Debunking myths and developing diagnosic algorithms. Clin Toxicol 2002; 40: 231-7.
12. Buckley NA, Whyte IM, Dawson AH. Diagnostic data in clinical toxicology – Should we use a Bayesian approach? Clin Toxicol 2002; 40: 213-22.
13. Buckley NA, Karalliedde L, Dawson A, Senanayake N, Eddleston M. Where is the evidence for treatments used in pesticide poisoning? Is clinical toxicology fiddling while the developing world burns? J Toxicol Clin Toxicol 2004; 42: 113-6.
14. Whyte IM. Introduction: Research in clkinical toxicology – The value of high quality data. Clin Toxicol 2002; 40: 211-2.
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EAPCCT 2008: Causality Assessment in Poisoning
References
15. Whyte IM, Buckley NA, Dawson AH. Data collection in clinical toxicology: Are there too many variables? Clin Toxicol 2002; 40: 223-30.
16. Hoffman RS. Dies consensus euqal correctness? Clin Toxicol 2000; 38: 689-90.
17. Buckley NA, smith AJ. Evidence-based medicine in toxicology: Where is the evidence? Lancet 1996; 347: 1067-9.
18. Arimone Y, Bégaud B, Miremont-Salamé G, Fourrier-Réglat A, Moore N, Molimard M, Harambouru F. Agreement of expert judgement in causality assessment of adverse drug reactions. Eur J Clin Pharmacol 2005; 61: 169-73.
19. Meyboom RHB, Hekster YA, Egberts ACG, Gribnau FWJ, Edwards IR. Causal or casual? The role of causality assessment in pharmacovigilance. Drug Saf 1997; 17: 374-89.
20. Auriche M, Loupi E. Does proff of causality ever exist in pharmacovigilance? Drug Saf 1993; 9: 230-5.
21. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994; 10: 93-102.
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EAPCCT 2008: Causality Assessment in Poisoning
References
22. Meyboom RHB, Egberts ACG, Edwards IR, Hekster YA, de Koning FHP, Gribnau FWJ. Principles of signal detection in Pharmacovigilance. Drug Saf 1997; 16: 355-65.
23. Neubert A, Dormann H, Weiss J, Criegee-Rieck M, Ackermann A, Levy M, Brune K, Rascher W. Are computerized monitoring systems of value to improve pharmacovigilance in pediatric patients? Eur J Clin Pharmacol 2006; 62: 959-65.
24. Hauben M, Reich L, Gerrits CM, Younus M. Illusions of objectivity and a recommendation for reporting data mining results. Eur J Clin Pharmacol 2007; 63: 517-21.
25. von Clarmann M. Rote Liste 1982. p. 95-6.
* * *
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causality (1965)
1. Strength of the association:
Size of the effect
Examples: Scrotal cancer from soot exposure in chimney
sweepers (Pott P, 1775)
Mortality from lung cancer in smokers
Mortality from cholera (Snow J, London 1855)
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causality (1965)
2. Consistency:
Has the effect been observed repeatedly?By different persons, in different places, circumstances and times?
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causality (1965)
3. Specificity:
The association is limited to specific expo-sures and the disease shows specific features.
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causality (1965)
4. Temporality:
„Which is the cart and which is the horse?“
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causality (1965)
5. Biological gradient:
Dose-response effect
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causation (1965)
6. Plausibility:
Is the causation biologically plausibe?
Limitations „But this is a feature we cannot demand. What is
biologically plausible depends on the biological knowledge of the day.“
„When you have eliminated the impossible, whatever remains, however improbable, must be the truth“ (Sherlock Holmes to Dr. Watson)
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causation (1965)
7. Coherence:
„... the cause-and effect interpretation [...] should not seriously conflict with the generally known facts of the natural history and biology of the disease ...“
Hill AB. Proc R Soc Med 1965; 85: 295-300
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EAPCCT 2008: Causality Assessment in Poisoning
A.B. Hill on causation (1965)
8. Experiment:
Does experimental evidence support the cause-and-effect interpretation of our observation?
Example: Reduction of the effect after the introduction of
preventive measures
Hill AB. Proc R Soc Med 1965; 85: 295-300
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