mechanisms, causation and the russo- williamson thesis mechanism and causality 2009 9 th september...
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![Page 1: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/1.jpg)
Mechanisms, Causation and the Russo-Williamson Thesis
Mechanism and Causality 2009
9th September 2009
University of Kent, Canterbury
Brendan Clarke
Department of Science and Technology Studies
UCL
![Page 2: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/2.jpg)
The Russo-Williamson Thesis[Russo and Williamson, 2007]
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The Russo-Williamson Thesis[Russo and Williamson, 2007]
• Causation is monistic and epistemic
![Page 4: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/4.jpg)
The Russo-Williamson Thesis[Russo and Williamson, 2007]
• Causation is monistic and epistemic• But the evidence for this causation is pluralistic
![Page 5: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/5.jpg)
The Russo-Williamson Thesis[Russo and Williamson, 2007]
• Causation is monistic and epistemic• But the evidence for this causation is pluralistic
– Mechanistic (dependency)
![Page 6: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/6.jpg)
The Russo-Williamson Thesis[Russo and Williamson, 2007]
• Causation is monistic and epistemic• But the evidence for this causation is pluralistic
– Mechanistic (dependency)– Statistical (difference-making)
![Page 7: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/7.jpg)
The Russo-Williamson Thesis[Russo and Williamson, 2007]
• Causation is monistic and epistemic• But the evidence for this causation is pluralistic
– Mechanistic (dependency)– Statistical (difference-making)
• Theoretical, rather than historical, thesis
![Page 8: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/8.jpg)
The RWT as an empirical proposition
![Page 9: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/9.jpg)
The RWT as an empirical proposition
• How well does the RWT conform to medical practice as seen in the recent history of medicine?
![Page 10: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/10.jpg)
Why change the RWT?
• Causation without statistics– McArdle’s syndrome
• Causation without mechanism– Hepatitis B infection and liver cancer
• Statistics and mechanism without causation– Non-causation of cervical cancer by herpes simplex
virus
![Page 11: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/11.jpg)
The RWT as an empirical proposition
• How well does the RWT conform to medical practice as seen in the recent history of medicine?
• I suggest that it needs two specific amendments:
![Page 12: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/12.jpg)
The RWT as an empirical proposition
• How well does the RWT conform to medical practice as seen in the recent history of medicine?
• I suggest that it needs two specific amendments:
1. That the requirement for statistical evidence needs weakening (to accommodate difference-making evidence)
![Page 13: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/13.jpg)
The RWT as an empirical proposition
• How well does the RWT conform to medical practice as seen in the recent history of medicine?
• I suggest that it needs two specific amendments:
1. That the requirement for statistical evidence needs weakening (to accommodate difference-making evidence)
2. That some account of the integration of mechanistic and statistical evidence might be given in terms of research methodology
![Page 14: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/14.jpg)
Example 1: Causation without statisticsMcArdle’s syndrome
• Rare genetic disorder• Tiredness and muscle pain on exertion• Many (20+) mutations; one disease• Caused by a functional absence of
myophosphorylase
![Page 15: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/15.jpg)
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![Page 17: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/17.jpg)
Example 1: Causation without statisticsMcArdle’s syndrome
• Rare genetic disorder• Tiredness and muscle pain on exertion• Many (20+) mutations; one disease• Caused by a functional absence of
myophosphorylase
![Page 18: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/18.jpg)
Causation without Statistics?
• Discovered in three patients 1947—1961
![Page 19: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/19.jpg)
Causation without Statistics?
• Discovered in three patients 1947—1961• We have excellent mechanistic evidence...
![Page 20: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/20.jpg)
Mechanism and McArdle
![Page 21: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/21.jpg)
Mechanism and McArdle
• McArdle, 1951– Physical illness with characteristic symptoms– Apparently abnormal glucose metabolism
![Page 22: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/22.jpg)
Mechanism and McArdle
• McArdle, 1951– Physical illness with characteristic symptoms– Apparently abnormal glucose metabolism
• Mommaerts et al., 1959; Pearson et al., 1961– Identified myophosphorylase deficiency as causative entity– Refined clinical picture
![Page 23: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/23.jpg)
Mechanism and McArdle
• McArdle, 1951– Physical illness with characteristic symptoms– Apparently abnormal glucose metabolism
• Mommaerts et al., 1959; Pearson et al., 1961– Identified myophosphorylase deficiency as causative entity– Refined clinical picture
• Larner and Villar-Palasi, 1959; Schmid and Mahler, 1959; Schmid et al., 1959; Schmid and Hammaker, 1961– Clinical course– Second wind phenomena– Heritability
![Page 24: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/24.jpg)
Causation without Statistics?
• Discovered in three patients 1947—1961• We have excellent mechanistic evidence
![Page 25: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/25.jpg)
Causation without Statistics?
• Discovered in three patients 1947—1961• We have excellent mechanistic evidence• But, we have no statistical evidence apparent in
the formulation of this causal claim
![Page 26: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/26.jpg)
Causation without Statistics?
• Discovered in three patients 1947—1961• We have excellent mechanistic evidence• But, we have no statistical evidence apparent in
the formulation of this causal claim• Or do we...
![Page 27: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/27.jpg)
Where is the difference-making evidence?
![Page 28: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/28.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
![Page 29: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/29.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
• So instead of doing observational trials, researchers assumed that myophosphorylase deficiency was the salient difference-maker
![Page 30: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/30.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
• So instead of doing observational trials, researchers assumed that myophosphorylase deficiency was the salient difference-maker
• Is this a good assumption?
![Page 31: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/31.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
• So instead of doing observational trials, researchers assumed that myophosphorylase deficiency was the salient difference-maker
• Is this a good assumption?• Yes, the difference-making effect myophosphorylase deficiency exerts is
strong
![Page 32: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/32.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
• So instead of doing observational trials, researchers assumed that myophosphorylase deficiency was the salient difference-maker
• Is this a good assumption?• Yes, the difference-making effect myophosphorylase deficiency exerts is
strong– The behaviour that is required for the disease to become clinically apparent (exertion) is
common to the point of ubiquity
![Page 33: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/33.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
• So instead of doing observational trials, researchers assumed that myophosphorylase deficiency was the salient difference-maker
• Is this a good assumption?• Yes, the difference-making effect myophosphorylase deficiency exerts is
strong– The behaviour that is required for the disease to become clinically apparent (exertion) is
common to the point of ubiquity– McArdle’s syndrome is defined in terms of myophosphorylase deficiency
![Page 34: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/34.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
• So instead of doing observational trials, researchers assumed that myophosphorylase deficiency was the salient difference-maker
• Is this a good assumption?• Yes, the difference-making effect myophosphorylase deficiency exerts is
strong– The behaviour that is required for the disease to become clinically apparent (exertion) is
common to the point of ubiquity– McArdle’s syndrome is defined in terms of myophosphorylase deficiency– Even if we were to ‘accidentally’ find myophosphorylase deficiency in an asymptomatic person,
we would (probably) say they had asymptomatic McArdle’s disease
![Page 35: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/35.jpg)
Where is the difference-making evidence?
• We don’t find myophosphorylase deficiency in the normal population (hidden statistics?)
• So instead of doing observational trials, researchers assumed that myophosphorylase deficiency was the salient difference-maker
• Is this a good assumption?• Yes, the difference-making effect myophosphorylase deficiency exerts is
strong– The behaviour that is required for the disease to become clinically apparent (exertion) is
common to the point of ubiquity– McArdle’s syndrome is defined in terms of myophosphorylase deficiency– Even if we were to ‘accidentally’ find myophosphorylase deficiency in an asymptomatic person,
we would (probably) say they had asymptomatic McArdle’s disease
• As an aside, this is a very similar position to early germ-theory causation, before developments in the importance of host factors in disease
![Page 36: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/36.jpg)
Difference and statistics
• So we have non-statistical difference-making evidence in this case
![Page 37: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/37.jpg)
Difference and statistics
• So we have non-statistical difference-making evidence in this case
• I suggest we should modify the RWT to accept just such difference-making evidence
![Page 38: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/38.jpg)
Difference and statistics
• So we have non-statistical difference-making evidence in this case
• I suggest we should modify the RWT to accept just such difference-making evidence– Of which statistical evidence will be the most common
form
![Page 39: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/39.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
![Page 40: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/40.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
![Page 41: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/41.jpg)
![Page 42: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/42.jpg)
![Page 43: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/43.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
• What was the evidence in play that led to the causal claim?
![Page 44: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/44.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
• What was the evidence in play that led to the causal claim?– Statistical correlation between HBV and HCC in diverse
circumstances
![Page 45: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/45.jpg)
Summary of epidemiological evidence for HBV causing HCC
• 1956 – first anecdotal report of correlation between HBV and HCC
• 1970s – correlation between chronic HBV infection and HCC statistically investigated
• Mid-1970s – complications: aflatoxin, direction of causation• 1981 – RR of HCC given HBV vs no HBV 233:1
– 22707 male HBV +/- Taiwanese civil servants [Beasley et al, 1981]
![Page 46: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/46.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
• What was the evidence in play that led to the causal claim?– Statistical correlation between HBV and HCC in diverse
circumstances
![Page 47: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/47.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
• What was the evidence in play that led to the causal claim?– Statistical correlation between HBV and HCC in diverse
circumstances– Vaccination against hepatitis B prevented HCC
![Page 48: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/48.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
• What was the evidence in play that led to the causal claim?– Statistical correlation between HBV and HCC in diverse
circumstances– Vaccination against hepatitis B prevented HCC– Woodchuck hepatitis virus model
![Page 49: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/49.jpg)
http://en.wikipedia.org/wiki/File:Closeup_groundhog.jpg
![Page 50: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/50.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
• What was the evidence in play that led to the causal claim?– Statistical correlation between HBV and HCC in diverse
circumstances– Vaccination against hepatitis B prevented HCC– Woodchuck hepatitis virus model
![Page 51: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/51.jpg)
Example 2: Causation without mechanismHepatitis B Virus (HBV) and Hepatocellular Carcinoma (HCC)
• Chronic infection with hepatitis B virus (HBV) can cause primary liver cancer (hepatocellular carcinoma / HCC)
• What was the evidence in play that led to the causal claim?– Statistical correlation between HBV and HCC in diverse
circumstances– Vaccination against hepatitis B prevented HCC– Woodchuck hepatitis virus model– No specific oncogenic mechanism identified
![Page 52: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/52.jpg)
Why is this not evidence of mechanism?
![Page 53: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/53.jpg)
Why is this not evidence of mechanism?
• Question-begging
![Page 54: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/54.jpg)
Why is this not evidence of mechanism?
• Question-begging– Epidemiological correlation between HBV and HCC in
diverse circumstances
![Page 55: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/55.jpg)
Why is this not evidence of mechanism?
• Question-begging– Epidemiological correlation between HBV and HCC in
diverse circumstances– Vaccination against hepatitis B prevented HCC
![Page 56: Mechanisms, Causation and the Russo- Williamson Thesis Mechanism and Causality 2009 9 th September 2009 University of Kent, Canterbury Brendan Clarke Department](https://reader035.vdocuments.site/reader035/viewer/2022081602/551ae6685503466b6a8b5e70/html5/thumbnails/56.jpg)
Why is this not evidence of mechanism?
• Question-begging– Epidemiological correlation between HBV and HCC in
diverse circumstances– Vaccination against hepatitis B prevented HCC
• Analogy
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Why is this not evidence of mechanism?
• Question-begging– Epidemiological correlation between HBV and HCC in
diverse circumstances– Vaccination against hepatitis B prevented HCC
• Analogy– Woodchuck hepatitis virus model
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Example 3: Mechanism, statistics but no causationCervical cancer 1966—1983
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HPV and cervical cancer [Lowy and Howley, 2001: 2232]
• Caused by infection with the human papillomavirus (HPV)
• Complex biology:• More than 110 types
identified with varying propensity to cause cervical cancer
• High-risk types• 16, 18, 31, 45
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The history of cervical cancer causation: 3 phases
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The history of cervical cancer causation: 3 phases
• Phase 1 (up to 1966)– Largely epidemiological identification of risk factors
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The history of cervical cancer causation: 3 phases
• Phase 1 (up to 1966)– Largely epidemiological identification of risk factors
• Phase 2 (1966—83)– Causation by herpes simplex virus (HSV)
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The history of cervical cancer causation: 3 phases
• Phase 1 (up to 1966)– Largely epidemiological identification of risk factors
• Phase 2 (1966—83)– Causation by herpes simplex virus (HSV)
• Phase 3 (1987 onward)– Causation by HPV
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The history of cervical cancer causation: 3 phases
• Phase 1 (up to 1966)– Largely epidemiological identification of risk factors
• Phase 2 (1966—83)– Causation by herpes simplex virus (HSV)
• Phase 3 (1987 onward)– Causation by HPV
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Phase 2: Causation by HSV
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Phase 2: Causation by HSV
• Identification of a possibly viral aetiology of cervical cancer
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Phase 2: Causation by HSV
• Identification of a possibly viral aetiology of cervical cancer
• Suggestion that the causal virus is HSV
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Phase 2: Evidence for herpes simplex virus as cause of cervical cancer [Alexander, 1973: 1486]
1. HSV is a commensal organism
2. HSV is transmitted venerally
3. HSV is compatible with known risk factors, including:1. First coitus at early age
2. Multiple sexual partners or promiscuity
3. Low socioeconomic status
4. Herpes viruses are implicated in similar disease states
5. HSV is recoverable from some tumour cells
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Phase 2: Herpesviridae cause many tumours
Name Disease
Epstein-Barr virus (HHV-4) Burkitt’s lymphoma
Nasopharyngeal carcinoma
Various leukaemias and lymphomas
Kaposi’s sarcoma virus (HHV-8) Kaposi’s sarcoma
Abdominal cavity B-cell lymphoma / Primary effusion lymphoma
Multicentric Castleman’s disease
Gallid herpesvirus 2 (GaHV-2) Marek’s disease (chickens)
Saimiriine herpesvirus type 2 (HVS-2) Transmissible tumours in new world monkeys
Herpesvirus ateles type 1 (HVA-1) T-cell lymphomas in new world monkeys
Ranid herpesvirus 1 (RaHV-1) Lucké renal adenocarcinoma (Northern leopard frog)
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Phase 2: Causation by HSV
• Identification of a possibly viral aetiology of cervical cancer
• Suggestion that the causal virus is HSV
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Phase 2: Causation by HSV
• Identification of a possibly viral aetiology of cervical cancer
• Suggestion that the causal virus is HSV, partly by analogy with properties of other herpesviridae
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Phase 2: Causation by HSV
• Identification of a possibly viral aetiology of cervical cancer
• Suggestion that the causal virus is HSV, partly by analogy with properties of other herpesviridae
• Attempts to generate evidence linking HSV and cervical cancer
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Phase 2: So what’s the problem?
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Phase 2: So what’s the problem?
• Despite the apparently strong evidence, HSV does not cause cervical cancer
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Phase 2: So what’s the problem?
• Despite the apparently strong evidence, HSV does not cause cervical cancer
• Why was this research on HSV faulty, according to the RWT?
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Phase 2: So what’s the problem?
• Despite the apparently strong evidence, HSV does not cause cervical cancer
• Why was this research on HSV faulty, according to the RWT?– Good statistical evidence
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Phase 2: So what’s the problem?
• Despite the apparently strong evidence, HSV does not cause cervical cancer
• Why was this research on HSV faulty, according to the RWT?– Good statistical evidence– Mechanism less so – over-reliance on plausibility, especially linking
HSV-oncogenesis with other herpesviridae
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Phase 2: So what’s the problem?
• Despite the apparently strong evidence, HSV does not cause cervical cancer
• Why was this research on HSV faulty, according to the RWT?– Good statistical evidence– Mechanism less so – over-reliance on plausibility, especially linking
HSV-oncogenesis with other herpesviridae– But not worse than many apparently correct causal claims (HBV-
HCC...
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How integrated is integrated enough?
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How integrated is integrated enough?
• I’d suggest that a study of methodology is the best way to solve the problem of integrated evidence
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How integrated is integrated enough?
• I’d suggest that a study of methodology is the best way to solve the problem of integrated evidence
• In this faulty case...
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How integrated is integrated enough?
• I’d suggest that a study of methodology is the best way to solve the problem of integrated evidence
• In this faulty case...– Problematic parts of mechanism remained
uninvestigated statistically, leading to unreliable mechanism of pathogenesis
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How integrated is integrated enough?
• I’d suggest that a study of methodology is the best way to solve the problem of integrated evidence
• In this faulty case...– Problematic parts of mechanism remained
uninvestigated statistically, leading to unreliable mechanism of pathogenesis
– Publication bias renders much of this confusion invisible
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How integrated is integrated enough?
• I’d suggest that a study of methodology is the best way to solve the problem of integrated evidence
• In this faulty case...– Problematic parts of mechanism remained
uninvestigated statistically, leading to unreliable mechanism of pathogenesis
– Publication bias renders much of this confusion invisible– Research programmes develop, but do not pose each
other answerable questions
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Ideally...
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Ideally...
• Integration of laboratory and epidemiological investigation in a recursive, interdependent process:
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Ideally...
• Integration of laboratory and epidemiological investigation in a recursive, interdependent process: – laboratory work guides epidemiology
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Ideally...
• Integration of laboratory and epidemiological investigation in a recursive, interdependent process: – laboratory work guides epidemiology– epidemiology guides laboratory work
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Ideally...
• Integration of laboratory and epidemiological investigation in a recursive, interdependent process: – laboratory work guides epidemiology– epidemiology guides laboratory work
• Production of interdependent mechanistic and statistical evidence is required
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So, to return to the cases...
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So, to return to the cases...
• So why was the CoC-HSV causal call incorrect, but the HCC-HBV one right?
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So, to return to the cases...
• So why was the CoC-HSV causal call incorrect, but the HCC-HBV one right?
• Blind luck?
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So, to return to the cases...
• So why was the CoC-HSV causal call incorrect, but the HCC-HBV one right?
• Blind luck?• Specific interventions versus general interventions
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The RWT as an empirical proposition
• How well does the RWT conform to medical practice as seen in the recent history of medicine?
• I suggest that it needs two specific amendments
1. That the requirement for statistical evidence needs weakening (to accommodate difference-making evidence)
2. That some account of the integration of mechanistic and statistical evidence might be given in terms of research methodology
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Philosophical bibliography
Bechtel, W. and Abrahamsen, A. 2005. “Explanation: A Mechanist Alternative,” Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences. 36(2): 421—41.
Glennan, S. 2002. “Rethinking Mechanistic Explanation,” Philosophy of Science. 69(S3): 342—53.
Machamer, P., Darden, L. and Craver, C.F. 2000. “Thinking about Mechanisms,” Philosophy of Science. 67(1): 1—25.
Russo, F. and Williamson, J. 2007. “Interpreting Causality in the Health Sciences,” International Studies in the Philosophy of Science. 21(2): 157—70.
Woodward, J. 2002. "What is a Mechanism? A Counterfactual Account," Philosophy of Science. 69(S3): S366—77.
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McArdle’s syndrome bibliography
Hilton-Jones, D., 2001. “McArdle’s Disease”, Practical Neurology, 1: 122–125.Larner, J. and Villar-Palasi, C., 1959. “Enzymes in a Glycogen Storage Myopathy”, Proceedings of the National Academy of Sciences of the United States of America, 45: 1234–1235.McArdle, B., 1951. “Myopathy Due to a Defect in Muscle Glycogen Breakdown”, Clinical Science, 10: 13–33.Mommaerts, W.F., Illingworth, B., Pearson, C.M., Guillory, R.J. and Seraydarian, K., 1959. “A Functional Disorder of Muscle Associated with the Absence of Phosphorylase”, Proceedings of the National Academy of Sciences of the United States of America, 45: 791–797.Pearson, C., Rimer, D. and Mommaerts, W., 1961. “A Metabolic Myopathy Due to Absence of Muscle Phosphorylase”, The American Journal of Medicine, 30: 502–517.Schmid, R. and Hammaker, L., 1961. “Hereditary Absence of Muscle Phosphorylase (McArdle’s Syndrome)”, The New England Journal of Medicine, 264: 223–225.Schmid, R. and Mahler, R., 1959. “Chronic Progressive Myopathy with Myoglobinuria: Demonstration of a Glycogenolytic Defect in the Muscle”, The Journal of Clinical Investigation, 38: 2044–2058.Schmid, R., Robbins, P. and Traut, R., 1959. “Glycogen Synthesis in Muscle Lacking Phosphorylase”, Proceedings of the National Academy of Sciences of the United States of America, 45: 1236–1240.
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Hepatitis B and HCC bibliography
Beasley, R.P. et al., 1981. Hepatocellular Carcinoma and Hepatitis B Virus: A Prospective Study of 22 707 Men in Taiwan. The Lancet, 318(8256), 1129-1133. Payet, M., Camain, R. and Pene, P. 1956. [Primary cancer of the liver; critical study of 240 cases.]. Revue Internationale D‘Hépatologie. 6(1): 1—86.
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Cervical cancer bibliography
Alexander, E. 1973. “Possible Etiologies of Cancer of the Cervix Other Than Herpesvirus,” Cancer Research. 33(6): 1485—90.
Dürst, M. et al. 1983. “A Papillomavirus DNA from a Cervical Carcinoma and its Prevalence in Cancer Biopsy Samples from Different Geographic Regions,” Proceedings of the National Academy of Sciences of the United States of America. 80(12): 3812—5.
Lowy, D. and Howley, P. 2001. “Papillomaviruses,” in Field's Virology. Philadelphia: Lippincott Williams and Company. 2231—2264.
Vonka, V., Kanka, J. and Roth, Z. 1987. “Herpes Simplex Type 2 Virus and Cervical Neoplasia,” Advances in Cancer Research. 48: 149—191.
zur Hausen, H. 1989. “Papillomavirus in Anogenital Cancer: The Dilemma of Epidemiologic Approaches,” Journal of the National Cancer Institute. 81(22): 1680—2.
zur Hausen, H. 2006. Infections Causing Human Cancer. Weinheim: Wiley—VCH.
(useful review text on the biomedical issues in viral oncogenesis)
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Interaction: From mechanism to statistics
• Mechanisms give us grounds to epistemically partition our data
• Thus, features arising from mechanistic inquiry suggest the direction that statistical work should take
• Help with confounding
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Interaction: From statistics to mechanism
• In turn, statistical results inform us of the applicability of our mechanisms
• For instance, is a (mechanistically discovered) aetiological pathway clinically significant for disease causation?