Purpose

• Discuss the progression of evidence of smoking and disease

• Discuss, by examples, various forms of studies

• Examples of some forms of epidemiology - descriptive, geographic, genetic

• Introduce survival curves

Smoking

• Most epidemiologically studied condition

• Prior to 1890, lung cancer was virtually unheard of

• Became a epidemic particularly after WWI

Study Types

Case Reports•Generates best available evidence in areas without trial evidence•Sounds a warning - thalidomide•High sensitivity for detecting unexpected novelty - Viagra eg.•Stimulates clinical trials: Generates enough interest to gain financial support for trials:

•cure of duodenal ulcers by eradication Helicobacter pylori•bone marrow transplantation

Not sufficient evidence to establish efficacy of a therapeutic intervention + subject to bias

Journal of Clinical Epidemiology 58 (2005) 1227–1232; Case reports and case series from Lancet had significant impact on medical literature; Joerg Albrechta, Alexander Meves, Michael Bigby

Early Case Reports• Sommering, 1795 - found cancer lip

more common in smokers• Before 1890, lung cancer was

unheard of. Subsequently,it began making its presence in startlingly increasing numbers.

• 1939 - Surgeon Alton Ochsner published observations that almost all lung cancers patients were smokers

Case SeriesA description of cases – no control group

Can be misleading eg.- Homosexual immune deficiency erroneously attributed to use of amyl nitrate “poppers” before HIV virus discovered.

Smoking and Heart DiseaseObservational Case Studies

• Hardening arteries in legs (Intermittent Claudication) - 25 out of 45 patients were smokers (Erb, 1904)

• Howard, T., 1934 - 165 cases coronary occlusion (heart attack) - found smoking more common.

Vital Statistics - Descriptive

• Death rates from lung cancer skyrocketed after a 20 years delay from skyrocketing cigarette use.

Sudden Lung Cancer Rise

http://commons.wikimedia.org/wiki/Image:Cancer_smoking_lung_cancer_correlation_from_NIH.png

Germany1929-1939

• Recognized lung cancer epidemic

• 4-5 times more in men (who smoked much more than women at time)

Early Observational - Autopsy Studies

Case Control Study

Odds Ratio Used in Case Control

• Cancers Cases and Controls are not matched because they are looked at after the fact. The lung cancer cases could have occupational and other reasons besides smoking.

• Because the are could be different groups, all you can say is that the cancer group was exposed more to smoke and this might explain the differing stats - this exposure difference is called the ODDS RATIO.

Case Control Studies

• Diseased patients are identified. Their prior exposures and potential etiological factors compared with a control group

• Muller (German), 1939

• Schairer and Schoniger, 1943• Wassink (Dutch), 1948

Muller 1939

Case Control Studies

Uncovering the effects of smoking: historical perspective; Richard DollStatistical Methods in Medical Research 1998; 7: 87-117

Heart Disease - Case ControlWillius and Berkson

1940(Mayo)

Ecological studies

•Geographic and cultural Comparisons

•Varied disease rates that could be altered by differing cultural factors

•E.g. – differing lung cancer rates in Canada and Great Britain related to much higher smoking consumption in the latter.

Example

Difference in cancer rates explained by fact in Britain cigarette consumption per person was higher

Geographic - Mormon

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Epidemiology.html

Cross Sectional Studies• A snapshot of a population at one moment in

time - Quick and cheap

• See how many out of a certain number of people smoke, and how many people have lung cancer.

• Cancers take years to develop so would be overpopulated with normal cases

• Birth year group has considerable impact - differing smoking behaviours. Mixing birth year types dilutes this out and introduces a bias

Cross-Sectional Study

• Merely a survey at one point in time - a “snapshot” - like a census or election poll

• Used to determine prevalences and amount of symptoms

Cross-sectional Errors• Subject to bias - a university student could

do a “unbiased” survey but just manage to survey friends that are willing to fill out forms.

• Smoking companies, early on, did a couple of surveys which found smoking did not effect job performance or absences; - was questioned over whether they only surveyed the higher functioning workers.

Children SmokingCross-sectional

Symptom Never Smoked Smoker RR Morning Cough

Boys 8.3 16.3 3.9Girls 8.3 28.6 6.8

Cough 3 monthsBoys 7.2 13.4 2.4Girls 6.0 10.7 2.6

Morning coughBoys 3.1 19.2 5.9Girls 1.8 13.5 6.8

Cough day or nightBoys 20.4 46.5 2.4Girls 18.5 47.3 2.6

BreathlessnessBoys 11.8 34.9 2.9Girls 16.5 39.2 2.3

Oechslts & van der Berg 1987

Cross Sectional versus Longitudinal Study of Adolescent Smoking

•Cross-sectional – one time snapshot

•Longitudinal – over time

X-sectional missed:

•Parenteral effects being constant

•Factors leading up to start smoking

•Incidence(new cases per year)

•Recognition group not homogenous

Longitudinal suffered from drop out biases Chassin, L., Presson, C. C., Sherman, S. J., Montello, D., & McGrew, J. (1986). Changes in peer and parent influence during adolescence: Longitudinal versus cross-sectional perspectives on smoking initiation. Developmental Psychology, 22, 327-334.

Azheimer’s Dementia(AD) and Smoking

•Case studies suggested smoking had a protective effect against AD

•Prospective Cohort (matched followup) study found that smokers who developed AD, died quickly and would never make it into case studies (too sick).

•Cohort found no benefit from smoking

Cohort Studies•Life stories obtained over time

•Cases matched (smoker versus nonsmoker) ahead of time and analyzed over time

•Can be done retrospectively (after the fact) or prospectively (followed)

•Avoids considerable biases but drop-outs

•Over 29 retrospective and over 9 prospective studies have been done on smoking - all positive

Prospective Cohort

http://www.socialresearchmethods.net/tutorial/Cho2/cohort.html

Examples of Cohort Studies

• Cancer Prevention Study I (Hammond)– 68,116 volunteers recruited over 1 million

adults– completed form on health habits– followed every two years for 20 years– death certificates obtain for each death

Doll & Hill 1950

British Doctor Study 1954

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=437141&blobtype=pdf

Canadian War Vets 1961

• initiated in 1954 - followed 7 years

• 60% more deaths among cigarette smokers than non-smokers

• autopsy confirmed

Association between cigarette smoking and

• increase in lung cancer

• heart disease.

Survival Curves

• Done “longitudinally” i.e. over time

• Survival plotted over this period of time

• Can be done retrospectively (after the fact) or prospectively (followed over time)

• Plotted as

number surviving / number to start

over time

Kaplan and Meier 1958Survival Curving

• In real world, some subjects are lost (called “censored data”.

• Current Survival curves are mathematically fudged to take that into account using K-M techniques

Retrospective Survival CurvePearl, 1938

Survival curves for white males by tobacco use:nonusers (solid line), moderate smokers (dashed line), heavysmokers (dotted line)

Pearl R. Tobacco smoking and longevity.Science 1938; 87: 216-17.

Prospective Survival CurveDoll, 1994

Doll R, Peto R, Wheatley K, Gray R,Sutherland I. Mortality in relation to smoking: 40 years' observations on male British doctors. British Medical Journal 1994;309: 901-11.

British Doctors Study Followup 2004

Report Warnings

• 1963 - Canadian Health Minister issues warning

• 1967 - US Surgeon General Report

Associations Established

• Using Causal criteria causation established though tobacco companies still insist

• “no direct link has been proven”

Temporality

• Lung cancer rose from obscurity to prevalence after a 20 year delay of smoking rise

Smoke-Cancer 20 Year Delay

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Epidemiology.html

Strength Association

Smoking Risks (Surgeon General 2006)• “Men who smoke increase their risk of

death from lung cancer by more than 22 times and from bronchitis and emphysema by nearly 10 times.”

• “Women who smoke increase their risk of dying from lung cancer by nearly 12 times and the risk of dying from bronchitis and emphysema by more than 10 times.”

• “Smoking triples the risk of dying from heart disease among middle-aged men and women.1”

Dose Response

Earliest ExampleBritish Doctor Study 1954

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=437141&blobtype=pdf

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Epidemiology.html

Dose Response in Cohort Studies

Replicability/Consistency

• > 36 studies confirming associations

• 29+ retrospective

• 7+ prospective

Biological Plausibility

• Problem with early studies not demonstrating lung tumors per se in rodents

• Found later needed a recovery period before tumors would be seen.

• Cigarette smoke contains over 69 carcinogenic substances.(11 definitely to humans, 7 probably, 49 seen in animals)

Benzopyrene Level and Tumorigenicity

Experimental Tobacco Carcinogenesis E. L. Wynder and D. HoffmannSCIENCE, Vol. 162, No. 3856 (Nov. 22, 1968), 862-871

Molecular Epi EvidenceCarcinogenesis, Vol. 20, No. 9, 1769-1775, September 1999

Cigarette smoke induces direct DNA damage in the human B-lymphoid cell line Raji

Q. Yang, M. Hergenhahn1, A. Weninger and H. Bartsch

•Tobacco smoke induces DNA damage in tissue cultures

•Human P53 cancer causing mutations are common in lung cancers but the version seen in smokers is often different from ones found in non-smokers, suggesting it is directly related to DNA damageOncogene. 2002 Oct 21;21(48):7435-51. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-

associated cancers.

DNA breaks per Smoke Dose

Nature 314, 462 - 464 (04 April 1985); doi:10.1038/314462a0 Cigarette smoke induces DNA single-strand breaks in human cellsTsutomu Nakayama, Motohisa Kaneko, Masahiko Kodama & Chikayoshi Nagata

Alernative Explanations

• Radon gas exposure, Asbestos exposure, and toxic chemical exposures do not have sufficient power to explain the epidemic started by the smoking revolution

Genetic Epidemiology

• 80% identical twins smoke versus only 41% of fraternal twins

• Extroversion seems a factor"The Great Debate? Smoking, Lung Cancer, and Cancer Epidemiology

GERRY HILL WAYNE MILLAR JAMES CONNELLY

CBMH/BCMH 20(2) 2003, 367-386

Cessation of ExposureExperimental Proof

• Smoking cessation results in lower lung cancer rates

Steven Woloshin, Lisa M. Schwartz, and H. Gilbert Welch The Risk of Death by Age, Sex, and Smoking Status in the United States: Putting Health Risks in Context Journal of the National Cancer Institute Advance Access published on June 10, 2008 J. Natl. Cancer Inst. 2008 100: 845-853

Former Smokers Less Lung Cancer Risk

Specificity

• Smoking associated with lung cancer as well as many other diseases. Further, lung cancer results from smoking as well as other exposures (radon, asbestos)

• Specificity helps but absence does not preclude causation

http://publichealth.jbpub.com/aschengrau/ppts/causation.ppt

Analogy

• Has a similar relationship been observed with another exposure?

• Pipe smokers more cancer of lip

• Chewing tobacco associated with cancer of gums

Consistency With Other Knowledge

• As early as 1961, 6,000 articles had been published on hazards of smoking.

• Multiple studies in multiple countries have been done with same findings.

Smoking Issue and Tobacco Companies

Only Statistical - not Experimental Argument

• Mice didn’t get it so its not the problem.

Of Mice and Men

• Early Experiments with mice exposed to smoke were unable to produce tumors

• Yet smoke constituents painted onto backs of mice caused cancers - demonstrating carcinogenic compounds like NNK and benzopyrene

• It was thought it was not reasonable to expect tumor lung cancers because mice never get that. However the search was on for a mouse strain that would and a strain called A/J was eventually found

• Meanwhile tobacco companies were using this as indicating “no direct link is evident”

Need Recovery Period

• What was eventually found was that not only was smoke carcinogenic, it was cytotoxic - ie it made cells to sick to divide.

• Under those circumstances, no cancers were evident until the mice were allowed to recover for 4 months in filtered air. - something not seen in earlier studies where mice were killed after 90 days of smoke.

Public Health and Stop Smoking• 1969 - CBC bans tobacco adds

• 1970 - tobacco companies develop “instant win” promotions

• 1971 - US bans TV advertising

• 1971 - Canadian government pressures smoking companies to voluntarily give up certain advertising. Doesn’t work.

• 1987-91 - Canadian bills against smoking countered by massive campaigns by smoking companies. A phony letter writing campaign exposed. Though passed, struck down by courts.

• 1989 - Canadian consensus that nicotine addiction exists established

• 1993 - Nicotine patch available

• 1994 - study links smoking to 40 health problems. Aircraft smoking bans start.

• 1998 - restrictions on sponsorship. Phony companies with similar names to cigarette companies set up to sponsor.

Smoking and Women

• 1993 -U of T study finds a pack a day X 40 year female smoker has a 27 times risk of lung cancer - three times more dangerous than for men.

• Older women on birth control have 8-39 times risk of heart attack

• 1989 - lung cancer exceeds breast cancer as #1 cancer killer

Tobacco Industry and Passive Smoke

•Suppressed research - cigarette companies forced to open up its research to public, 1998. Between 1983-1997, Phillip Morris scientists found significant levels of NNK, a carcinogen, in second hand smoke. Kept it secret.

•Cancer Epidemiol Biomarkers Prev. 2007 Aug;16(8):1547-53. Concentrations of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in sidestream cigarette smoke increase after release into indoor air: results from unpublished tobacco industry research. Schick SF, Glantz S

Scientific Credibility 1986•Aware of growing evidence of hazards of second hand smoke, a private tobacco company sponsored study wrote:

“An attack on the credibility of evidence may well provide the rational argument to soften their [smokers’ and non-smokers’] attitudes[. . .] The challenge will be to find a sympathetic doctor who can be demonstrated to take a largely independent stance.”

Phony Research

•1987 Phillip Morris sponsors “research” on international scale. There were concerns this could be too transparent:

“We really should not be seen falling over each other when contacting independentscientists.”•Formed Center for Indoor Air Research (CIAR)•Hoped to use these scientists for power, credibility and clout

Scientist’s Job

• They were to testify before Congress and

other important regulatory bodies • Publish articles in scientific literature • Submit letters to editors in response to

adverse articles in scientific technical and general audience publications

• conduct media “tours” each monthJ Epidemiol Community Health 2001;55:588–594Tobacco industry efforts at discrediting scientific knowledge of environmental tobacco smoke: areview of internal industry documents; J Drope, S Chapman

• “Tobacco industry, industry used scientists,

lawyers, independent organizations

and symposiums to discredit scientific

knowledge of environmental tobacco

smoke.”

• “Environmental tobacco smoke (ETS),

industry” built up networks of scientists

sympathetic to its position that ETS is

insignificant health risk.”J Epidemiol Community Health 2001;55:588–594Tobacco industry efforts at discrediting scientific knowledge of environmental tobacco smoke: areview of internal industry documents; J Drope, S Chapman

Biased Presentations

Got their scientists as keynote speakers in Environmental Tobacco smoke conferences but seeing as there were not enough conferences, organized over half themselves.

Presentations were on potential confounders:

• radon• diet or cooking fuel. • sick building syndrome• No mention of smoking

Example• 1993, Canadian John Luik wrote Pandora’sbox: the dangers of politically corrupted

science for democratic public policy • to attack the recently released EPA

report that had classified second hand smoke as a human carcinogen.

• Tobacco supported him - tried to get his presentation in a Japanese symposium

• His complaint that 90% confidence interval used in EPA report- caused rejection by one publisher

Suppressed Good Research

• 90 day mice exposure tests negative but lifelong testing was not.

• Prevented one of their researcher from doing latter study.

J Epidemiol Community Health 2001;55:588–594Tobacco industry efforts at discrediting scientific knowledge of environmental tobacco smoke: areview of internal industry documents; J Drope, S Chapman

Got Final Say in Published Work• Afraid of the emotional impact of the

association of sudden infant death syndrome and smoking, Tobacco companies sponsored Frank Sullivan to write articles about how confounders were more important

• When all tobacco records were released due to litigation, it was clear the tobacco company had altered the final drafts of these submissions.

Pediatrics 2005;115;e356-e366Elisa K. Tong, Lucinda England and Stanton A. GlantzChanging Conclusions on Secondhand Smoke in a Sudden Infant Death Syndrome Review Funded by the Tobacco Industry

Tobacco Industry and Cardiovascular Disease

• When their researchers started to find a connection, terminated research

• Ran “indirect platelet aggregation studies, exposure chamber experiments, and literature reviews.” - poor research

• when some of them ended up positive, attributed it to “unproven epinephrine-related stress response from odor or large smoke exposure”

Circulation. 2007 Oct 16;116(16):1845-54. Tobacco industry efforts undermining evidence linking secondhand smoke with cardiovascular disease. Tong EK, Glantz SA

Tobacco’s Flawed 16 Cities Study• Designed to show home a more serious

second hand exposure site than work.

• Subjects wore filter pumps to detect levels of airborne material and had salivary nicotine levels done

• Found smoking home much more serious

• Neglected to mention that many of the office sites were non-smoking or smoking restricted

• Tobacco companies used study to counter restrictions on workplace smoking

Cigarette Filter Tips• Following Surgeon General report of lung

cancer potential, many cigarettes made with filters (90% now)

• Research, now public, has demonstrated these filters are defective and release cellulose acetate and carbon particles that end up in lungs.

Tobacco Control 2002;11:i51-i61

Cigarettes with defective filters marketed for 40 years: what Philip Morris never told smokers

J L Pauly, A B Mepani, J D Lesses, K M Cummings, R J Streck

Low Tar Cigarette•People just inhaled more often and deeper, [and use more cigarettes to] get same dose

•Addition of ventilation holes at base to dilute smoke intake is overcome by smokers by covering the holes with ones’ fingers.

•With more deep inhalation came more deeply situated tumors - more gland-like adenocarcinoma type situated peripherallyBMJ 2001;322:693 ( 24 March ) Low tar cigarettes linked to rise in adenocarcinomas Tony Sheldon, Utrecht

•RR are higher today despite 60% lower tarHistorical perspective: the low tar lie; DONALD R SHOPLAND, Tob Control 2001;10(Suppl 1):i1-i3 ( Winter)

Light Cigarette Gimmick

• Can J Public Health. 2005 May-Jun;96(3):167-72.

The unbearable lightness of "light" cigarettes: a comparison of smoke yields in six varieties of Canadian

“light" cigarettes. Gendreau PL, Vitaro F.

Canadian study, 2005

• “The six varieties of "light" cigarettes examined in this study do not differ substantially from "regular" cigarettes in terms of smoke yields.”

Deny, Deny, Deny

Selection bias - use of hospital patients no good because they often have more than one illness and the non-smoke related one could be the cause.

Information Bias - Pathologists are over-diagnosing lung cancers at autopsy. They might make mistakes on their smoking status too.

- People who say they are non-smokers could lie

• Mortality ratios are inaccurate because they ignore fact other factors were involved in death beyond the lung cancer

Confounding• Genotype

• Air quality (London fog for example)

• Radon

• Home cooking fuels

• Sick building syndrome (molds, formaldehyde)

• Asbestos

• Occupational exposures

Government Help Limited

• Government worried about reduced about reduced tax sales

• Hysteria over poor tobacco farmers who were making ten times the money per acre as other produce growers

• Lobbying (Prime minister Mulroney had close tobacco friend),

• Multi lawyer court cases stuck down some Canadian anti-smoking laws

Lack of Specificity

• Multiple tumor types (including bladder, cancer of cervix etc.) seen associated so connection must be spurious

Metanalysis Issue

• Process whereby data from many studies are combined to come up with enough subjects to get statistically significant results

• Used in Environmental protection agency (EPA) conclusion that second hand smoke was carcinogenic

General Problems with Metanalysis

• Some studies are bad - design flaws

• Studies where up to 40% of subjects that said they were non-smokers actually smoked

• Groups studied could be different

Metanalysis Selection Bias-Admission Criteria Setting

• “Arbitrary imposition of criteria for deciding which studies constituted valid evidence.” -

• which ones are accepted often depend on the “vested ideological interest”

• Example - for psychotherapy metanalysis - omitting results from “inexperienced” therapists

Second Hand smoke RR 1.25

• Control group used was general population which would have included smokers so probably underestimated

• Generally RR needed to be taken seriously needs to be 2-3 or more but in this case can be circumvented by sheer numbers as long as the confidence intervals are not to wide

• EPA second hand smoke report used a confidence interval of 90% for which cigarette companies cried “foul” and used it to discredit everything they said

Confidence Interval Used 90%

Adolescent Targets

• Smoking rate drop blunted by young people smoking. More movies than even are showing smoking and there is a link there with adolescent use.

• 2007 - Study demonstrates that adolescents can be addicted on first cigarette if they find it relaxing. Adolescent self quit rates low.

Third World Targets

• Smoking is going out of control in 3rd world countries as are smoke related diseases.

• Use rates in Northern Canada for women same as third world

Rise of Epidemiology

• In the aftermath of the smoking debate, Epidemiology became a force to be reckoned with. It rose to prominence in Universities and forged itself as a new discipline.