Adapted from EIS Case studies

A causal relationship between cigarette smoking and lung cancer was first suspected in the 1920s on the basis of clinical observations. To test this apparent association, numerous epidemiologic studies were undertaken between 1930 and 1960. Two studies were conducted by Richard Doll and Austin Bradford Hill in Great Britain.

The first was a case-control study begun in 1947 comparing the smoking habits of lung cancer patients with the smoking habits of other patients. The second was a cohort study begun in 1951 recording causes of death among British physicians in relation to smoking habits.

Data for the case-control study were obtained from hospitalized patients in London and vicinity over a 4-year period (April 1948 - February 1952). Initially, 20 hospitals, and later more, were asked to notify the investigators of all patients admitted with a new diagnosis of lung cancer. These patients were then interviewed concerning smoking habits, as were controls selected from patients with other disorders (primarily non-malignant) who were hospitalized in the same hospitals at the same time.

Data for the cohort study were obtained from the population of all physicians listed in the British Medical Register who resided in England and Wales as of October 1951. Information about present and past smoking habits was obtained by questionnaire. Information about lung cancer came from death certificates and other mortality data recorded during following years.

1.What makes the first study a case-control study?

2.What makes the second study a cohort study?

Questionnaires were mailed in October 1951, to 59,600 physicians. The questionnaire asked the physicians to classify themselves into one of three categories: 1) current smoker, 2) ex-smoker, or 3) non-smoker. Smokers and ex-smokers were asked the amount they smoked, their method of smoking, the age they started to smoke, and, if they had stopped smoking, how long it had been since they last smoked. Non-smokers were defined as persons who had never consistently smoked as much as one cigarette a day for as long as one year. Usable responses to the questionnaire were received from 40,637 (68%) physicians, of whom 34,445 were males and 6,192 were females.

3.How might a response rate of 68% affect the results of the study? Is this an example of bias? If so, explain.

The occurrence of lung cancer in physicians responding to the questionnaire was documented over a 10-year period (November 1951 through October 1961) from death certificates filed with the Registrar General of the United Kingdom and from lists of physician deaths provided by the British Medical Association. All certificates indicating that the deceased was a physician were abstracted. For each death attributed to lung cancer, medical records were reviewed to confirm the diagnosis.

Diagnoses of lung cancer were based on the best evidence available; about 70% were from biopsy, autopsy, or sputum cytology (combined with bronchoscopy or X-ray evidence); 29% were from cytology, bronchoscopy, or X-ray alone; and only 1% were from just case history, physical examination, or death certificate. Of 4,597 deaths in the cohort over the 10-year period, 157 were reported to have been caused by lung cancer; in 4 of the 157 cases this diagnosis could not be documented, leaving 153 confirmed deaths from lung cancer.

The following table shows numbers of lung cancer deaths by daily number of cigarettes smoked at the time of the 1951 questionnaire (for male physicians who were nonsmokers and current smokers only). Person-years of observation ("person-years at risk") are given for each smoking category. The number of cigarettes smoked was available for 136 of the persons who died from lung cancer.

Table 1. Number and rate (per 1,000 person-years) of lung cancer deaths by number of cigarettes smoked per day, Doll and Hill physician cohort study, Great Britain, 1951-1961.

Daily # of cigarettes smoked

Deaths from lung cancer

Person-years at risk

Mortality rate per 1000 person-years

Rate ratio

Rate difference per 1000 person-years

0

3

42,800

0.07

Referent

Referent

1-14

22

38,600

15-24

54

38,900

25+

57

25,100

All smokers

133

102,600

Total

136

145,400

Rate ratio = mortality rate in the exposed group/mortality rate in the non-exposed group

Rate difference = mortality rate in the exposed group - mortality rate in the non-exposed group

4.Please fill in the rest of the table. Use the above formulas to calculate the rate ratios and rate differences.

5.Interpret these results.

The study also provided mortality rates for cardiovascular disease among smokers and non-smokers. The following table presents lung cancer mortality data and comparable cardiovascular disease mortality data. Attributable risk percent is the percent of the mortality that can be attributable to the exposure.

Table 2. Mortality rates (per 1,000 person-years), rate ratios, and excess deaths from lung cancer and cardiovascular disease by smoking status, Doll and Hill physician cohort study, Great Britain, 1951-1961.

Mortality rate per 1,000 person-years

Smokers

Non-smokers

All

Rate ratio

Excess deaths per 1,000 person-years

Attributable risk percent among smokers

Lung cancer

1.30

0.07

0.94

18.5

1.23

95%

Cardiovascular disease

9.51

7.32

8.87

1.3

2.19

23%

6.Which cause of death has the stronger association with smoking? Why?

The following table shows the relationship between smoking and lung cancer mortality in terms of the effects of stopping smoking.

Table 3. Number and rate (per 1,000 person-years) of lung cancer deaths for current smokers and ex-smokers by years since quitting, Doll and Hill physician cohort study, Great Britain, 1951-1961.

Cigarette smoking status

Lung cancer deaths

Rate per 1,000 person-years

Rate ratio

Current smokers

133

1.30

18.5

For ex-smokers, years since quitting

Less than 5 years

5

0.67

9.6

5-9 years

7

0,49

7.0

10-19 years

3

0.18

2.6

20 + years

2

0.19

2.7

Non-smokers

3

0.07

1.0 (referent)

7.Interpret these data. What do these data imply for the practice of public health and preventive medicine?

8.What are the advantages of case-control versus cohort studies?

9.Which type of study would you have done first? Why? Why do the other type of study?

10.Which of the following criteria for causality are met by the evidence presented by this study?

Yes No

Strong association

Consistency among studies

Exposure precedes disease

Dose-response effect

Biologic plausibility