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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