McCallum Lecture for FOM Annual Scientific Meeting

at Royal College of Physicians

28th May, 2014

"Observation and Experiment : an appreciation of Bradford Hill"

Professor Sir Anthony Newman Taylor CBE, FRCP, FFOM, FMedSci

Imperial College London

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1950

Bradford Hill

TB is curable

Lung cancer is preventable

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5

After being bedbound for nearly two years

and having an artificial pneumothorax, a lung

abscess and two years of convalescence, I

emerged to complete (at this time of writing)

nearly 66 years of (officially) 100% disability.

from A. Bradford Hill

in ‘A pilot in the First World War’

BMJ 1983;287:1947-1949

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7

Bradford Hill

Pre 1950

Increased death rates recorded in 1910-1943 from cancer

of lung (5x) and skin (25x) in chemical factory workers

exposed to inorganic As compounds.

Increased death rates from cancer of lung (5x) and nasal

sinuses (150x) in nickel refinery workers in S. Wales

employed before 1923.

1937 Principles of Medical Statistics. Initially series of

articles in Lancet. Subsequently published as book. 11th

edition in 1984

Fig 1 Hospital for Consumption and Diseases of the Chest, Brompton.

Green M BMJ 2011;343:bmj.d7505

©2011 by British Medical Journal Publishing Group

The role of the physician is to

amuse his patients, while nature

takes its course

Voltaire

Cod liver oil and tuberculosis

Standard treatment Standard treatment

plus cod liver oil

Number of patients 542 535

Improved 60.8% 63.1%

Arrested 5.6% 18.1%

Deteriorated or died 33.3% 18.8%

From First Medical Report of the Hospital for

Consumption and Diseases of the Chest, Brompton 1848

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0

1000

2000

3000

4000

5000

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Deaths from TB in England and Wales, 1930

Number

of deaths

Age (yrs)

Cause of largest number

of deaths ages 10 to 45yrs

MRC Streptomycin trial

Ethical considerations

Only small amounts of Streptomycin available at time

in UK (foreign exchange not available to buy more)

Ethical use of limited supplies

(1) Miliary and meningeal TB (otherwise invariably fatal)

(2) What remained sufficient for only small proportion of

cases of TB, “it would have been unethical not to have

seized the opportunity to design a strictly controlled

trial which could speedily and effectively reveal the

value of treatment”. Hill A. B.

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Clinical trial

“To one group is given that treatment

from one group it is witheld”

A. Bradford Hill

MRC Streptomycin in Pulm TB trial

Patients Patients with “acute progressive bilateral

pulmonary tuberculosis, of presumably

recent origin, bacteriologically proved,

unsuitable for collapse therapy, age group

15-25 (later extended to 30)

Intervention Streptomycin

Control Bed rest

Outcome Improvement on CXR

Reduction in mortality rate

Time 6 months

(later extended to 3 years)

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R.C.T. Streptomycin in pulmonary TB

6 months

n Considerable Death

improvement

Bed rest 52 4 14

Bed rest +

Sm 4 hrly 55 27 4

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MRC, 1948

MRC Streptomycin trial

Landmarks

1. Random (concealed) allocation

2. Strict criteria for patient selection into trial

3. Events recorded unbiased by knowledge of treatment received:

(1) Counting as end points only in indisputable events e.g. death

(2) Blinding investigator and patient to patients‟ treatment allocation

(3) Events requiring subjective judgement (e.g. CXR change)

determined by person ignorant of patients‟ treatment allocation

4. Ethical considerations

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Bias in Treatment Effects in Controlled Trials

Peto – non randomised trials exaggerate treatment benefit by 30%

Methodological issue Exaggeration of odds ratio (%)

Concealment of treatment

allocation:

Inadequate 40%

Unclear 30%

Trial not double blind 17%

After Saluz et al, 1995

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R.C.T. Streptomycin in pulmonary TB

n Deaths from TB

6mths 3yrs

Bed rest 52 14 32

Bed rest +

Sm 4 hrly 55 4 35

From Florey, 1961

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RCT‟s Streptomycin v Streptomycin + PAS in pulmonary TB

6 months 3 years

Treatment n Deaths Streptomycin Alive

resistance

†Streptomycin 55 4 33/49 (67%) 40%

*Streptomycin 53 1 5/48 (10.4%) 80%

+ PAS

† MRC, 1948

*MRC, 1950

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0

1000

2000

3000

4000

5000

6000

1921 1925 1930 1935 1940 1945

Deaths from lung cancer in men 1921 - 1945

16 fold increase

1921 : 361

1945 : 5982

EL and NM Kennaway, 1947

Aetiology of lung cancer

Knowledge before 1950

Lung cancer incidence in the UK :

Progressive increase since World War I

Men >> Women

Towns > Country

Putative causes :

Cars Exhaust fumes

Tar on roads

Cigarettes

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You ask me what is needed to

win this war. I answer tobacco,

as much as bullets. We must

have thousands of tons of it

without delay.

General Pershing, 1917

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Retrospective study

Patients with lung cancer (cases) questioned about

previous smoking habits.

Smoking histories in cases compared with smoking

histories in patients without lung cancer (controls)

Case control study of lung cancer in cigarette smokers

Cigarette Lung cancer

smoking Cases Controls Total

+ 1350 1296 2646

- 7 61 68

Odds ratio = 9

After Doll and Bradford Hill, 1952 24

0

50

100

150

200

250

Non-smoker 1-14g 15-24g >25g

Retrospective study, 1952

Amount smoked per day

Death rate

(age standardised)

% of unweighted average

Mortality from lung cancer in relation to amount smoked

After Doll and Bradford Hill, 1952

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“to determine the frequency with which the disease

lung cancer appeared in the future among groups

whose smoking habits were already known”

Bradford Hill

Doctors in UK on medical register

Willing to report smoking accurately

Easy to follow up because of need to remain on medical register

Usable replies from ⅔

20 years later : Peto + Doll able to determine vital status of 99.7%

Prospective study

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20

40

60

80

100

120

140

160

180

200

Non-smoker 1-14g 15-24g >25g

Prospective study, 1954

Amount smoked per day

Death rate

(age standardised)

% of unweighted average

Mortality from lung cancer in relation to amount smoked

After Doll and Bradford Hill, 1954

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0

50

100

150

200

250

Non-smoker 1-14g 15-24g >25g

Retrospective study, 1952 Prospective study, 1954

Amount smoked per day

Death rate

(age standardised)

% of unweighted average

Mortality from lung cancer in relation to amount smoked

After Doll and Bradford Hill, 1952, 1954

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British doctors (40,000) 10 years on

0

1

2

3

4

5

6

7

8

9

10

All causes Coronary heartdisease

Lung cancer Chronicbronchitis

Non smokers

Cigarette smokers

Cigarette smokers >25g/day

Death

per 105 yr

Cause of death

After Doll and Bradford Hill, 1964 29

Standardised death rate / 100,000

30

Death rate from lung cancer

0

0.5

1

1.5

2

2.5

3

3.5

5 10 15 20 25 30 35 40 45

Death rate from lung cancer

Average No of cigarettes smoked daily

Annual

death rate/1000 men

Doll and Bradford Hill, 1964

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Death rate from lung cancer

0

0.5

1

1.5

0 5 10 15 20 25 30

Death rate from lung cancer

Annual

death rate/1000 men

Years stopped smoking

Corresponding rate for non-smokers = 0.07/103 men

Doll and Bradford Hill, 1964

„Expected results‟ from retrospective study

Higher mortality in :

(1) Smokers than non-smokers

(2) Heavy smokers than light smokers

(3) Cigarette smokers than pipe smokers

(4) Those who continued to smoke than in those who gave it up

In each case “expected result has

appeared in this prospective study”

Doll R and Hill AB, 1956

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0

20

40

60

80

100

0 40 50 60 70 75 80 85 90 95 100

Age (years)

0

20

40

60

80

100

0

20

40

60

80

100

57

85

58

80

58

75

Non-smokers

Cigarette smokers

After Doll et al, 2004

UK male doctors : Survival from age 35 years

Doctors

Born

1900 - 1909

Doctors

Born

1910 - 1919

Doctors

Born

1920 - 1929

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UK cigarette consumption, 1890-2008

0

2

4

6

8

10

1900 1920 1940

Cigarettes per day

(per adult aged 15+)

1950 1960 1980 2000

10

8

6

4

2

0

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Excess mortality attributable to smoking in India

Respiratory disease ⅓

(chiefly TB RR4.5)

Vascular disease ⅓

„Smoking is a cause and an important cause of death from tuberculosis‟. Gajalakshmi V, Peto R et al, 2003

„Smoking is a factor and an important factor in the production of carcinoma of the lung‟.

Doll and Bradford Hill, 1950

Environment and disease : association or causation?

1. Strength Relative risk

2. Consistency Similar results from different studies

3. Biological gradient Risk increases with increasing exposure

4. Time relationship Exposure always precedes the

outcome

5. Specificity Association limited to specific disease

6. Biological plausibility Depends on biological knowledge of the day

(e.g. John Snow and cholera)

7. Experiment Risk reduces with reducing exposure

8. Coherence Does it all hang together

9. Reasoning by analogy e.g. Effects of drugs + viruses on developing foetus

following rubella and thalidomide

Is there any other way of explaining the set of facts before us, is there any other answer more likely than cause and effect?

Bradford Hill, 1965 36

Bradford Hill : Influence on Medical Science

Lancet articles on medical statistics Principles of Medical Statistics

Development of epidemiological methods to investigate

causes of non-infectious disease with guidelines for

deciding whether observed association is causal

Introduction of randomisation for conduct of clinical trials

„The greatest medical statistician of the 20th century

despite

the fact held no degree in either medicine or statistics‟

Doll R, 1992

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End