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Charting a middle road between the EBM movement, and Russo-Williamson

Charting a middle road between the EBM movement, and Russo-Williamson. Jeremy Howick Centre for Evidence-Based Medicine University of Oxford. Take home message.

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Charting a middle road between the EBM movement, and Russo-Williamson

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  1. Charting a middle road between the EBM movement, and Russo-Williamson Jeremy Howick Centre for Evidence-Based Medicine University of Oxford

  2. Take home message • The EBM movement are wrong to deny mechanistic reasoning any role in supporting efficacy (they have always recognized a role for mechanisms in generalizing). • Russo and Williamson are incorrect that mechanistic reasoning is required to support the hypotheses about efficacy. • The middle road: high-quality mechanistic reasoning can add evidential weight.

  3. Comparative clinical studies versus mechanistic reasoning Comparative clinical research Black Box I O Mechanistic reasoning Sudden Death Reduce risk Reduce risk Anti-arrhythmic drugs Serious arrhythmia Sudden Death Reduce risk Anti-arrhythmic drugs Therefore

  4. The EBM movement on mechanisms “[EBM] de-emphasizes clinical expertise and pathophysiologic rationale as sufficient grounds for clinical decision making and stresses the examination of evidence from clinical research”

  5. Russo and Williamson argue that mechanisms are necessary “To establish causal claims, scientists need the mutual support of mechanisms and dependencies”

  6. Misplaced rationale for the Russo Williamson claim:The Semmelweis case

  7. Mechanism for anti-arrhythmic drugs reduce the risk of sudden death More fine-grained mechanism for anti-arrhythmic drugs reduce the risk of sudden death Anti-arrhythmic drugs Anti-arrhythmic drugs Block Risk Sodium channels in the heart Ventricular extra beats (VEBs) Block Heart’s action potential Risk Slows Ventricular fibrillation Electric impulse Risk Risk Sudden death Ventricular extra beats (VEBs)

  8. Other examples where mechanistic reasoning led us astray • Anti-arrhythmic drugs to prevent sudden cardiac death. • Babies to sleep on their front to reduce risk of SIDS • HGH for hypercatabolism • Oxygen for organ failure • ERT for menopausal symptoms • Radical mastectomy for breast cancer • Rest for recovery • Early screening for breast cancer • …

  9. Mechanistic reasoning linking radiotherapy with improved respiratory function Evidence (from separate studies) induces impairs Respiratory function Goiter Obstruction shrinks Goiter Radiotherapy Mechanistic reasoning impairs induces shrinks Respiratory function Goiter Radiotherapy Obstruction

  10. High-quality mechanistic reasoning 1. All the links in the mechanism’s chain must be established as causal.

  11. Stochastic nature of mechanisms Sudden Death Reduce risk of by 90% Reduce risk of by 25%-50% Anti-arrhythmic drugs Serious arrhythmia Sudden Death Anti-arrhythmic drugs Strength???

  12. Paradoxical effects I2 a2 b2 c2 z2 O I a b c z ¬O a3 b3 c3 z3

  13. Reduce risk of by 90% Anti-arrhythmic drugs Serious arrhythmia Increase risk of by 10% Serious arrhythmia

  14. High-quality mechanistic reasoning • All the links in the mechanism’s chain must be established as causal. • The complexity and stochastic nature of mechanisms must be considered before drawing conclusions of the overall effect of the intervention on the clinically relevant outcome.

  15. Why the 2nd criterion is difficult to meet: the unknowns in biochemical mechanisms Pathways shown in blue represent the potentially beneficial effects of CETP inhibition, those shown in green may remain relatively unaffected, and those shown with dashed lines have potentially reduced activity after CETP inhibition.

  16. Why the 2nd criterion is unlikely to be met, cont’d. • “It is still unknown, if methyl oxidation at ring B occurs before or after esterification with phytol” • “In some microorganisms, cystathionine synthesis takes place via O-acetyl-L-homoserine” • …

  17. Summary • Mechanisms are not always required, especially when the comparative clinical studies are well-conducted. • Mechanisms are not always bad. • High-quality mechanistic reasoning can, and should, be used as evidence.

  18. Other roles for mechanisms • Generalizability? • Hypothesis generation? • Explanation? • Convincing people? • The quality criteria apply here too!

  19. Other potential roles for mechanisms: Generalizing the results of studies • This is a different problem than the one I was talking about. • Generalizability is a real problem (selected population, rarified circumstances…) • The same applies to mechanisms (as we saw yesterday in Carl’s talk). • Waving a wand and saying ‘mechanism’ doesn’t solve the problem. • We need to trace a causal pathway in the individual, and engage in high-quality mechanistic reasoning. • Mechanisms are not the only way to generalize…

  20. Thank you Questions welcome now or email: jeremy.howick@dphpc.ox.ac.uk

  21. How to combine mechanistic evidence with comparative clinical studies (a sketch for Lindsay) • Just as comparative clinical studies must reach a certain threshold of quality in order to be useful, so must mechanistic reasoning. • All evidence that reaches its respective quality threshold is sufficient to add evidential weight. • There is no need to get more specific than that.

  22. How to generalize without mechanisms • We cannot sample from the target population. • But no need to exclude 60%-90% of potentially eligible participants from trials. • We can make our exclusion criteria inclusive. • This will increase the variability and hence the size and cost of the trial. • But this is a cost that is well worth paying.

  23. Role 2: Persuasion • “The history of medicine presents many cases in which causal claims made solely on the basis of statistics have been rejected until backed by mechanistic … knowledge” • This is true (Semmelweis, Warren and Marshall). • “It is true that Kuhn’s ideas give a rather convincing explanation of Semmelweis’s failure, but it is important to remember that such an explanation is not a justification.”

  24. Role 3: Mechanisms for hypothesis generation • It is true that many of our hypotheses are generated by the basic sciences. • But are these efficient ways of generating hypotheses?

  25. The exaggerated stability of mechanisms • “entities and activities organized such that they are productive of regular changes from start or set-up to finish or termination conditions” (MDC) • “invariant, change-relating generalizations” (Glennan). • “… the existence of a mechanism provides evidence of the stability of a causal relationship” (Russo and Williamson)

  26. Basic science is not necessarily an efficient way to generate hypotheses • A study examined 101 major ‘mechanistic’ findings in the top basic science journals • [INSERT THESE IN TALK] • Science, Nature, Cell, Journal of Experimental Medicine, Journal of Clinical Investigation, and the Journal of Biological Chemistry between 1979 and 1983. • By 2002, 27 (25%) of the allegedly promising technologies had been clinically • 19 (20%) indicated a ‘positive’ benefit • 5 (5%) have been approved for marketing • 1 (1%) has a clinically relevant outcome • There are other ways of generating hypotheses • Chicken soup for the common cold

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