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  1. 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

  2. Smoking • Most epidemiologically studied condition • Prior to 1890, lung cancer was virtually unheard of • Became a epidemic particularly after WWI

  3. Study Types

  4. 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

  5. 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

  6. Case Series A 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.

  7. 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.

  8. Vital Statistics - Descriptive • Death rates from lung cancer skyrocketed after a 20 years delay from skyrocketing cigarette use.

  9. Sudden Lung Cancer Rise

  10. Germany1929-1939 • Recognized lung cancer epidemic • 4-5 times more in men (who smoked much more than women at time)

  11. Early Observational - Autopsy Studies

  12. Case Control Study

  13. 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.

  14. 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

  15. Muller 1939

  16. Case Control Studies Uncovering the effects of smoking: historical perspective; Richard Doll Statistical Methods in Medical Research 1998; 7: 87-117

  17. Heart Disease - Case ControlWillius and Berkson 1940(Mayo)

  18. 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.

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

  20. Geographic - Mormon

  21. 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

  22. 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

  23. 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.

  24. Children SmokingCross-sectional Oechslts & van der Berg 1987

  25. 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.

  26. 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

  27. 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

  28. Prospective Cohort

  29. 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

  30. Doll & Hill 1950

  31. British Doctor Study 1954

  32. 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.

  33. 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

  34. 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

  35. Retrospective Survival CurvePearl, 1938 Survival curves for white males by tobacco use: nonusers (solid line), moderate smokers (dashed line), heavy smokers (dotted line) Pearl R. Tobacco smoking and longevity. Science 1938; 87: 216-17.

  36. 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.

  37. British Doctors Study Followup 2004

  38. Report Warnings • 1963 - Canadian Health Minister issues warning • 1967 - US Surgeon General Report

  39. Associations Established • Using Causal criteria causation established though tobacco companies still insist • “no direct link has been proven”

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

  41. Smoke-Cancer 20 Year Delay

  42. Strength Association

  43. 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”

  44. Dose Response

  45. Earliest ExampleBritish Doctor Study 1954

  46. Dose Response in Cohort Studies

  47. Replicability/Consistency • > 36 studies confirming associations • 29+ retrospective • 7+ prospective

  48. 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)