7/26/2011 Levels of evidence 2 and 3 Epidemiology/Etiology · Epidemiology/Etiology Public Health...
Transcript of 7/26/2011 Levels of evidence 2 and 3 Epidemiology/Etiology · Epidemiology/Etiology Public Health...
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Levels of evidence 2 and 3Epidemiology/Etiology
Public Health Reports, 1994, 195
To date, there is no unambiguous evidence that any class of human cancers is regularly caused by a virus. Some cancers have been shown to be associated with elevated levels of antibody to certain viruses or viral components….However, no direct evidence exists that the viruses and the cancers are causally linked
Cecil textbook of Medicine 15th Editition 1979, p. 1910
Cancer Pathogen Year accepted
Burkitt’s lymphoma Epstein Barr virus ~1980
Adult t-cell leukemia Human T Lymphotropic virus I ~1980
Cervical cancer Human papilloma virus 1985
Nasopharyngeal cancer Epstein Barr virus 1990
Liver cancer Hepatitis B&C viruses 1995
Kaposi’s sarcoma Human herpesvirus 8 2000
Oropharyngeal cancer HPV 2005
Merkel cell cancer Merkel cell polyomavirus 2010
The future?
Washington Insured Population1993 to 1999
Periodontal procedures
Dentists Periodontal Specialists
Re-evaluation -46% -19%
Periodontal Surgery
-31% -39%
Robertson et al, 2001
US Population1990 to 1999
Periodontal procedures
Dentists Periodontal Specialists
Osseous surgery
-56% -23%
Scaling & Root planing
-21% -56%
Brown et al, 2002
Adults (20-64 years) 1988-1994 1999-2004Number of teeth present 24 25Edentulism 6.1% 3.8%*Periodontal disease ( one site with ≥ 3 mm attachment loss and ≥ 4 mm pocket depth
14.8% 8.5%
CDC-AAP definition of moderate-severe periodontitis
9.6% 5.1%
Periodontal disease among poor 28% 14%Dental visits 65.8% 59.9%
NHANES Forever
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Etiology
“Years ago periodontists were divided into two camps: the localists and the generalists.
The localists claimed that periodontal diseases were a result of local irritational and occlusal circumstances. The generalists said that systemic conditions were the immediate cause of periodontal disturbances. There is a
tendency today to consider systemic (intrinsic) influences of minor importance because of
our inability to pinpoint them”
Cyril O. Enwonwu
Courtesy Dr. Paul Robertson
Flossing
• Jews are twice as likely to floss daily as Italians?
• Women are almost twice as likely to floss than males?
• Individuals with a high school education are twice as likely to floss as individuals with no high school education?
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Flossing and Obesity
OR (95% confidence interval
OR (95% confidence interval
Underweight 0.82 (0.27-2.49) 1.31 (0.23-7.64)
Overweight 1.62 (1.23-2.13) 2.30 (1.45-3.63)
Obese 2.21 (1.58-3.11) 2.69 (1.53-4.72)
Morbidly Obese 21.56 (2.81-164.86) -
Weight and lack of daily flossingGeneralist
BAD GUMS BAD GUMS
BAD GUMS
BAD GUMSBAD GUMS
BAD GUMS
Localists
2006101 pts 15-25 yrsTea plantation workersØ 60% dropoutØ Age and calculusØ OR =4.3 (p=0.03)
2008428 pts 12-13 yearsPublic SchoolsØ 37% dropoutØ 0% smoking/diabetesØ RR =12.4 (p < 0.01)
200796 pts 11-17 yearsPublic SchoolsØ NR DropoutØ OR =15 (p < 0.01)
General remarks
• Young African or Asian adults• Aggregatibacter actinomycetemcomitans (AA) is
the only microbial marker that has been identified with disease initiation– AA ”is unique in that it possesses carbohydrate
utilization pathways”– Rarely a factor in disease progression in other
populations• AA may be a cause or a marker for nutrition,
CHO metabolism, smoking, or developmental anomalies
(J Bacteriol. 2007 September; 189(17): 6407–6414.)
Comparability
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1976Sporn et al.Chemoprevention
1981PetoCall for controlled trials
Beta-Carotene: Striking Evidence
• Epidemiology: “In a dozen case-control and cohort studies, high intake of fruits and vegetables containing carotenoids has been associated with a reduced risk of lung cancer”
• “Available data strongly support the hypothesis that dietary carotenoids reduce the risk of lung cancer”
Willet, W.C., 1990
Bias & EpidemiologyLevels of Evidence 2 and 3
Confounding, selection bias, misclassification bias.
The ATBC Study Group (n=29,133)The ATBC Study Group (n=29,133)
§§ Unexpectedly, we observed a 18 % (95% CI: Unexpectedly, we observed a 18 % (95% CI: 3%3%--36% ) higher lung cancer incidence 36% ) higher lung cancer incidence among the men who received beta carotene among the men who received beta carotene than among those who did not. than among those who did not. §§ Total mortality was 8% (95% CI: 1%Total mortality was 8% (95% CI: 1%--16% ) 16% )
higher among the participants who received higher among the participants who received beta carotene than among those who did beta carotene than among those who did not.not.
N Engl J Med, 1994: 330
The PHS (n=22,071)
• The risk for cancer was 2% (95% CI:-11% to 18%) higher among individuals using beta-carotene§§ Total mortality was 2% (95% C: Total mortality was 2% (95% C: --7% 7%
to 11%) higher among the to 11%) higher among the participants who received beta participants who received beta carotene than among those who carotene than among those who did not.did not.
Hennekens, NEJM 1996
The CARET Study (n=18,314)The CARET Study (n=18,314)
§§ The activeThe active--treatment group had a 28% treatment group had a 28% (95% CI:4%(95% CI:4%--57% ) increased risk of lung 57% ) increased risk of lung cancer as compared with the placebo cancer as compared with the placebo group. group. §§ In the activeIn the active--treatment group, the risk of treatment group, the risk of
death from any cause was increased by death from any cause was increased by 17% (95% CI:3% 17% (95% CI:3% --33%); of death from lung 33%); of death from lung cancer by 46% (95% CI: 7% to 100%) and cancer by 46% (95% CI: 7% to 100%) and of death from cardiovascular disease by of death from cardiovascular disease by 26% (95% CI: 26% (95% CI: --1% to 61%).1% to 61%).
OmennN Engl J Med, 1996: 334
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Post-trial ATBC
Study Period β carotene RR (95% CI)
1985-1993 1.08 (1.01-1.16)
1993-1996 1.11 (0.99-1.24)
1996-1999 1.12 (1.01-1.25)
1999-2001 1.06 (0.93-1.20)
JAMA, 2003; 290: 476-485
Post-Trial Caret Study
OmennNCI, 2004; 96: 1743-50
“In sum, beta-carotene should be regulated as a human carcinogen”CHEST: Gilbert Omenn, 2004: 125: 123S-127S
Prospective Study of Fruit and Vegetable Consumption and Risk of
Lung Cancer Among Men and Women
Diane Feskanich, Regina G. Ziegler, Dominique S. Michaud,
Edward L. Giovannucci, Frank E. Speizer, Walter C. Willett, Graham A. Colditz
Model Smoking covariates Risk change*1 None 44% decreased
2 Smoking Status 14% decreased
3 Time since quitting 5% decreased4 Current quantity 3% decreased
5 Time since quitting and current quantity
7% increased
6 Age at start of smoking 12% increased
* More than 7.2 serving of fruits and vegetables versus less than 3.2 servings. Journal of the National Cancer Institute, 2000, 92: 1812.
Adjustment for Smoking
Beta-carotene Lung cancer
Smoking
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BetaBeta--Carotene and SmokingCarotene and Smoking
§§ “Smoking is a strong confounder and must be “Smoking is a strong confounder and must be assessed rigorously …”assessed rigorously …”
§§ “Control for detailed smoking characteristics “Control for detailed smoking characteristics substantially attenuated the initially estimated substantially attenuated the initially estimated protective effectsprotective effects.”
Journal of the National Cancer Institute, 2000, 92: 1812
Diabetes
CHD Stroke Blindness Renal FailureLimb Amputation
Adverse Pregnancy outcome
Generalists
Periodontitis
Periodontitis
CHD Stroke Blindness Renal Failure Limb Amputation
Adverse Pregnancy outcome
Localists
Refutation
Fisher and Popper
“The importance of breaking the habit of clinging to and endlessly buttressing a single hypothesis is richly illustrated by research on cigarette smoking. Here hypotheses are embraced with such fervour that the thought of refutability becomes heresy”
Carol Buck. Int. J. Epid. 1975 4:159-168
Refutation
• When you have eliminated the impossible, whatever remains, however improbable, must be the truth (Sir Arthur Conan Doyle)
• When you have eliminated the impossible, whatever remains, however improbable, MAY be the truth (Sir Arthur Conan Doyle)
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Refutation
• “The most cogent test of a hypothesis available to scientists is to attempt disproof” (Sir Francis Bacon, 1559)
• “That the strongest argument in favour of the truth of a statement is the absence or impossibility of a demonstration of falsehood” (Karl Pearson, 1911)
Refutation
• “…if you’re doing an experiment, you should report everything that you think might make it invalid — not only what you think is right about it: other causes that could possibly explain your results.”
Feynman, 1974 Cargo Cult Science
Scientific Consensus
“The sum total of scientific evidence establishes beyond reasonable doubt that cigarette smoking is a causative factor in the rapidly increasing evidence of human epidermoid carcinoma of the lung.”
– National Cancer Institute, The American Heart Association, and the National Heart Institute, 1957
“The theory that increasing smoking is ‘the cause’ of the change in apparent incidence of lung cancer is not even tenable– Fisher, 1957
www.economics.soton.ac.uk
“Before one interferes with the peace of mind and habits of others, it seems to me that the scientific evidence – the exact weight of the evidence free from emotion – should be rather carefully examined” RA Fisher 1958
• Is it possible that a precancerous condition which is known to exist for year is one of the causes of cigarette smoking?
• Why does inhaling reduce lung cancer risk by 10%?
• Genetics? Smoking Lung cancer
Genetic Determinants
monozygotic twins resembled each other more with respect to smoking than dizygotic twins
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Smoking and Lung Cancer
Self-selection
smoking: 860 deaths/100,000person-years
no smoking: 49 deaths/100,000person years
Relative Risk: 17.4Relative risk adjusted for genetic factors= ?
Smoking and Single Nucleotide polymorphism (SNPs)
Number ofcigarettes
GG GT TT
1 to 10 1743 (29%) 1558 (25%) 326 (19%)
11-20 2727 (46%) 2865 (46%) 810 (48%)
21-30 1145 (19%) 1416 (23%) 427(25%)
31+ 341 (6%) 448 (7%) 139(8%)
5956 6287 1702
SNPs and Lung cancers
Single nucleotide polymorphism
Allele T
Lung cancer + 265 (39.8%) 400 665
- 9833 (34.2%) 18919 28752
29417
Nature 452, 638-642 (3 April 2008) | doi:10.1038/nature06846; Received 17 December 2007; Accepted 25 February 2008
New York – TWA 800July 17, 1996 8:31:12 pm
Washington, DC - White House July 17, 1996 10:00 pm
Pentagon, CIA, FBI, State Department, Secret Service, Justice DepartmentJoint Chiefs of Staff, FAA–“I don’t want a lukewarm response” President William Jefferson Clinton
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Disproving an hypothesis is challenging
• Most expensive FBI investigation ever (up until 9/11?)
• 98% of the plane was salvaged from the ocean floor
• World-wide search for possible terrorist suspects
Proving an hypothesis is simple
• One example of ‘proof’:– Suspicious middle-eastern looking men in row 25-
26– PETX was found on carpet in row 25-26– Central fuel tank is below row 25-26
• Plenty of other examples of apparently ‘convincing truths’ were found.
Refutation
• Disproving is challenging– Suspicious middle-eastern looking men in row 25-
26– PETX was found on carpet in row 25-26– Central fuel tank is below row 25-26
• Numerous potential leads suggesting terrorist activity where one by one disproved, sometimes at tremendous cost and effort.
But for now, he concluded, the FBI investigation of TWA flight 800 was over without having determined why the plane had exploded, but having painstakingly proven a negative: that the case of the crash was not criminal.
p. 336, The FBI Investigation of TWA flight 800Pat Milton 1999