### TL;DR
The **Bradford Hill Criteria** are a group of 9 princi...
### Austin Bradford Hill
Sir Austin Bradford Hill was an English...
In what circumstances can one infer causation from an observed asso...
> *"How in the first place do we detect these relationships between...
The first criterion for causation is **strength**. The larger an as...
The second criterion is **consistency**. Consistency is upheld when...
The third criterion is **specificity**. Associations are more likel...
The fourth criterion is **temporality**. The exposure must precede ...
The seventh criterion is **coherence**. This criterion is similar t...
The fifth criterion is **biological gradient**. When increased expo...
The sixth criterion is **plausibility**. Plausibility is satisfied ...
The eight criterion is **experiment**. When experimental manipulati...
The ninth (and final) criterion is **analogy**. When there is stron...
Bradford Hill’s **nine criteria are not intended to be viewed as ri...
Section
of
Occupational
Medicine
The
Environment
and
Disease:
Association
or
Causation?
by
Sir
Austin
Bradford
Hill
CBE
DSC
FRCP(hOn)
FRS
(Professor
Emeritus
of
Medical
Statistics,
University
of
London)
Amongst
the
objects
of
this
newly-founded
Section
of
Occupational
Medicine
are
firstly
'to
provide
a
means,
not
readily
afforded
elsewhere,
whereby
physicians
and
surgeons
with
a
special
knowledge
of
the
relationship
between
sickness
and
injury
and
conditions
of
work
may
discuss
their
prob-
lems,
not
only
with
each
other,
but
also
with
colleagues
in
other
fields,
by
holding
joint
meet-
ings
with
other
Sections
of
the
Society';
and,
secondly,
'to
make
available
information
about
the
physical,
chemical
and
psychological
hazards
of
occupation,
and
in
particular
about
those
that
are
rare
or
not
easily
recognized'.
At
this
first
meeting
of
the
Section
and
before,
with
however
laudable
intentions,
we
set
about
instructing
our
colleagues
in
other
fields,
it
will
be
proper
to
consider
a
problem
fundamental
to
our
own.
How
in
the
first
place
do
we
detect
these
relationships
between
sickness,
injury
and
conditions
of
work?
How
do
we
determine
what
are
physical,
chemical
and
psychological
hazards
of
occupation,
and
in
particular
those
that
are
rare
and
not
easily
recognized?
There
are,
of
course,
instances
in
which
we
can
reasonably
answer
these
questions
from
the
general
body
of
medical
knowledge.
A
particular,
and
perhaps
extreme,
physical
environment
can-
not
fail
to
be
harmful;
a
particular
chemical
is
known
to
be
toxic
to
man
and
therefore
suspect
on
the
factory
floor.
Sometimes,
alternatively,
we
may
be
able
to
consider
what
might
a
par-
-ticular
environment
do
to
man,
and
then
see
whether
such
consequences
are
indeed
to
be
found.
But
more
often
than
not
we
have
no
such
guidance,
no
such
means
of
proceeding;
more
often
than
not
we
are
dependent
upon
our
observation
and
enumeration
of
defined
events
for
which
we
then
seek
antecedents.
In
other
words
we
see
that
the
event
B
is
associated
with
the
environmental
feature
A,
that,
to
take
a
specific
example,
some
form
of
respiratory
illness
is
associated
with
a
dust
in
the
environment.
In
what
circumstances
can
we
pass
from
this
Meeting
January
141965
President's
Address
observed
association
to
a
verdict
of
causation?
Upon
what
basis
should
we
proceed
to
do
so?
I
have
no
wish,
nor
the
skill,
to
embark
upon
a
philosophical
discussion
of
the
meaning
of
'causation'.
The
'cause'
of
illness
may
be
imme-
diate
and
direct,
it
may
be
remote
and
indirect
underlying
the
observed
association.
But
with
the
aims
of
occupational,
and
alnost
synony-
mously
preventive,
medicine
in
mind
the
decisive
question
is
whether
the
frequency
of
the
un-
desirable
event
B
will
be
influenced
by
a
change
in
the
environmental
feature
A.
How
such
a
change
exerts
that
influence
may
call
for
a
great
deal
of
research.
However,
before
deducing
'causation'
and
taking
action
we
shall
not
invariably
have
to
sit
around
awaiting
the
results
of
that
research.
The
whole
chain
may
have
to
be
unravelled
or
a
few
links
may
suffice.
It
will
depend
upon
circumstances.
Disregarding
then
any
such
problem
in
semantics
we
have
this
situation.
Our
observa-
tions
reveal
an
association
between
two
variables,
perfectly
clear-cut
and
beyond
what
we
would
care
to
attribute
to
the
play
of
chance.
What
aspects
of
that
association
should
we
especially
consider
before
deciding
that
the
most
likely
interpretation
of
it
is
causation?
(1)
Strength.
First
upon
my
list
I
would
put
the
strength
of
the
association.
To
take
a
very
old
example,
by
comparing
the
occupations
of
patients
with
scrotal
cancer
with
the
occupations
of
patients
presenting
with
other
diseases,
Percival
Pott
could
reach
a
correct
conclusion
because
of
the
enormous
increase
of
scrotal
cancer
in
the
chimney
sweeps.
'Even
as
late
as
the
second
decade
of
the
twentieth
century',
writes
Richard
Doll
(1964),
'the
mortality
of
chimney
sweeps
from
scrotal
cancer
was
some
200
times
that
of
workers
who
were
not
specially
exposed
to
tar
or
mineral
oils
and
in
the
eighteenth
century
the
relative
difference
is
likely
to
have
been
much
greater.'
To
take
a
more
modern
and
more
general
example
upon
which
I
have
now
reflected
for
over
fifteen
years,
prospective
inquiries
into
smoking
have
shown
that
the
death
rate
from
cancer
of
the
lung
in
cigarette
smokers
is
nine
to
ten
times
the
rate
in
non-smokers
and
the
rate
in
heavy
cigarette
smokers
is
twenty
to
thirty
times
7
295
296
Proceedings
of
the
Royal
Society
of
Medicine
as
great.
On
the
other
hand
the
death
rate
from
coronary
thrombosis
in
smokers
is
no
more
than
twice,
possibly
less,
the
death
rate
in
non-
smokers.
Though
there
is
good
evidence
to
support
causation
it
is
surely
much
easier
in
this
case
to
think
of
some
features
of
life
that
may
go
hand-in-hand
with
smoking
-
features
that
might
conceivably
be
the
real
underlying
cause
or,
at
the
least,
an
important
contributor,
whether
it
be
lack
of
exercise,
nature
of
diet
or
other
factors.
But
to
explain
the
pronounced
excess
in
cancer
of
the
lung
in
any
other
environmental
terms
requires
some
feature
of
life
so
intimately
linked
with
cigarette
smoking
and
with
the
amount
of
smoking
that
-such
a
feature
should
be
easily
detectable.
If
we
cannot
detect
it
or
reasonably
infer
a
specific
one,
then
in
such
circumstances
I
think
we
are
reasonably
entitled
to
reject
the
vague
contention
of
the
armchair
critic
'you
can't
prove
it,
there
may
be
such
a
feature'.
Certainly
in
this
situation
I
would
reject
the
argument
sometimes
advanced
that
what
matters
is
the
absolute
difference
between
the
death
rates
of
our
various
groups
and
not
the
ratio
of
one
to
other.
That
depends
upon
what
we
want
to
know.
If
we
want
to
know
how
many
extra
deaths
from
cancer
of
the
lung
will
take
place
through
smok-
ing
(i.e.
presuming
causation),
then
obviously
we
must
use
the
absolute
differences
between
the
death
rates
-
0
-07
per
1,000
per
year
in
non-
smoking
doctors,
0'57
in
those
smoking
1-14
cigarettes
daily,
1
39
for
15-24
cigarettes
daily
and
2-27
for
25
or
more
daily.
But
it
does
not
follow
here,
or
in
more
specifically
occupational
problems,
that
this
best
measure
of
the
effect
upon
mortality
is
also
the
best
measure
in
relation
to
atiology.
In
this
respect
the
ratios
of
8,
20
and
32
to
1
are
far
more
informative.
It
does
not,
of
course,
follow
that
the
differences
revealed
by
ratios
are
of
any
practical
importance.
Maybe
they
are,
maybe
they
are
not;
but
that
is
another
point
altogether.
We
may
recall
John
Snow's
classic
analysis
of
the
opening
weeks
of
the
cholera
epidemic
of
1854
(Snow
1855).
The
death
rate
that
he
recorded
in
the
customers
supplied
with
the
grossly
polluted
water
of
the
Southwark
and
Vauxhall
Company
was
in
truth
quite
low
-
71
deaths
in
each
10,000
houses.
What
stands
out
vividly
is
the
fact
that
the
small
rate
is
14
times
the
figure
of
5
deaths
per
10,000
houses
supplied
with
the
sewage-free
water
of
the
rival
Lambeth
Company.
In
thus
putting
emphasis
upon
the
strength
of
an
association
we
must,
nevertheless,
look
at
the
obverse
of
the
coin.
We
must
not
be
too
ready
to
dismiss
a
cause-and-effect
hypothesis
merely
on
the
grounds
that
the
observed
association
appears
to
be
slight.
There
are
many
occasions
in
medicine
when
this
is
in
truth
so.
Relatively
few
persons
harbouring
the
meningococcus
fall
sick
of
meningococcal
meningitis.
Relatively
few
persons
occupationally
exposed
to
rat's
urine
contract
Weil's
disease.
(2)
Consistency:
Next
on
my
list
of
features
to
be
specially
considered
I
would
place
the
consistency
of
the
observed
association.
Has
it
been
repeatedly
observed
by
different
persons,
in
different
places,
circumstances
and
times?
This
requirement
may
be
of
special
importance
for
those
rare
hazards
singled
out
in
the
Section's
terms
of
reference.
With
many
alert
minds
at
work
in
industry
today
many
an
environmental
association
may
be
thrown
up.
Some
of
them
on
the
customary
tests
of
statistical
significance
will
appear
to
be
unlikely
to
be
due
to
chance.
Never-
theless
whether
chance
is
the
explanation
or
whether
a
true
hazard
has
been
revealed
may
sometimes
be
answered
only
by
a
repetition
of
the
circumstances
and
the
observations.
Returning
to
my
more
general
example,
the
Advisory
Committee
to
the
Surgeon-General
of
the
United
States
Public
Health
Service
found
the
association
of
smoking
with
cancer
of
the
lung
in
29
retrospective
and
7
prospective
inquiries
(US
Department
of
Health,
Education
&
Welfare
1964).
The
lesson
here
is
that
broadly
the
same
answer
has
been
reached
in
quite
a
wide
variety
of
situations
and
techniques.
In
other
words
we
can
justifiably
infer
that
the
association
is
not
due
to
some
constant
error
or
fallacy
that
permeates
every
inquiry.
And
we
have
indeed
to
be
on
our
guard
against
that.
Take,
for
instance,
an
example
given
by
Heady
(1958).
Patients
admitted
to
hospital
for
opera-
tion
for
peptic
ulcer
are
questioned
about
recent
domestic
anxieties
or
crises
that
may
have
pre-
cipitated
the
acute
illness.
As
controls, patients
admitted
for
operation
for
a
simple
hernia
are
similarly
quizzed.
But,
as
Heady
points
out,
the
two
groups
may
not
be
in
pari
materia.
If
your
wife
ran
off
with
the
lodger
last
week
you
still
have
to
take
your
perforated
ulcer
to
hospital
without
delay.
But
with
a
hernia
you
might
prefer
to
stay
at
home
for
a
while
-
to
mourn
(or
celebrate)
the
event.
No
number
of
exact
repeti-
tions
would
remove
or
necessarily
reveal
that
fallacy.
We
have,
therefore,
the
somewhat
paradoxical
position
that
the
different
results
of
a
different
inquiry
certainly
cannot
be
held
to
refute
the
8
Section
oj
Occupational
Medicine
original
evidence;
yet
the
same
results
from
pre-
cisely
the
same
form
of
inquiry
will
not
invariably
greatly
strengthen
the
original
evidence.
I
would
myself
put
a
good
deal
of
weight
upon
similar
results
reached
in
quite
different
ways,
e.g.
pros-
pectively
and
retrospectively.
Once
again
looking
at
the
obverse
of
the
coin
there
will
be
occasions
when
repetition
is
absent
or
impossible
and
yet
we
should
not
hesitate
to
draw
conclusions.
The
experience
of
the
nickel
refiners
of
South
Wales
is
an
outstanding
example.
I
quote
from
the
Alfred
Watson
Memorial
Lecture
that
I
gave
in
1962
to
the
Institute
of
Actuaries:
'The
population
at
risk,
workers
and
pensioners,
numbered
about
one
thousand.
During
the
ten
years
1929
to
1938,
sixteen
of
them
had
died
from
cancer
of
the
lung,
eleven
of
them
had
died
from
cancer
of
the
nasal
sinuses.
At
the
age
specific
death
rates
of
England
and
Wales
at
that
time,
one
might
have
anticipated
one
death
from
cancer
of
the
lung
(to
compare
with
the
16),
and
a
fraction
of
a
death
from
cancer
of
the
nose
(to
compare
with
the
11).
In
all
other
bodily
sites
cancer
had
appeared
on
the
death
certificate
11
times
and
one
would
have
expected
it
to
do
so
10-11
times.
There
had
been
67
deaths
from
all
other
causes
of
mortality
and
over
the
ten
years'
period
72
would
have
been
expected
at
the
national
death
rates.
Finally
division
of
the
population
at
risk
in
relation
to
their
jobs
showed
that
the
excess
of
cancer
of
the
lung
and
nose
had
fallen
wholly
upon
the
workers
employed
in
the
chemical
processes.
'More
recently
my
colleague,
Dr
Richard
Doll,
has
brought
this
story
a
stage
further.
In
the
nine
years
1948
to
1956
there
had
been,
he
found,
48
deaths
from
cancer
of
the
lung
and
13
deaths
from
cancer
of
the
nose.
He
assessed
the
numbers
expected
at
normal
rates
of
mortality
as,
respectively
10
and
0
1.
'In
1923,
long
before
any
special
hazard
had
been
recognized,
certain
changes
in
the
refinery
took
place.
No
case
of
cancer
of
the
nose
has
been
observed
in
any
man
who
first
entered
the
works
after
that
year,
and
in
these
men
there
has
been
no
excess
of
cancer
of
the
lung.
In
other
words,
the
excess
in
both
sites
is
uniquely
a
feature
in
men
who
entered
the
refinery
in,
roughly,
the
first
23
years
of
the
present
century.
'No
causal
agent
of
these
neoplasms
has
been
identified.
Until
recently
no
animal
experimentation
had
given
any
clue
or
any
support
to
this
wholly
statistical
evidence.
Yet
I
wonder
if
any
of
us
would
hesitate
to
accept
it
as
proof
of
a
grave
industrial
hazard?'
(Hill
1962).
In
relation
to
my
present
discussion
I
know
of
no
parallel
investigation.
We
have
(or
certainly
had)
to
make
up
our
minds
on
a
unique
event;
and
there
is
no
difficulty
in
doing
so.
(3)
Specificity:
One
reason,
needless
to
say,
is
the
specificity
of
the
association,
the
third
character-
istic
which
invariably
we
must
consider.
If,
as
here,
the
association
is
limited
to
specific
workers
and
to
particular
sites
and
types
of
disease
and
there
is
no
association
between
the
work
and
other
modes
of
dying,
then
clearly
that
is
a
strong
argument
in
favour
of
causation.
We
must
not,
however,
over-emphasize
the
importance
of
the
characteristic.
Even
in
my
present
example
there
is
a
cause
and
effect
rela-
tionship
with
two
different
sites
of
cancer
-
the
lung
and
the
nose.
Milk
as
a
carrier
of
infection
and,
in
that
sense,
the
cause
of
disease
can
pro-
duce
such
a
disparate
galaxy
as
scarlet
fever,
diphtheria,
tuberculosis,
undulant
fever,
sore
throat,
dysentery
and
typhoid
fever.
Before
the
discovery
of
the
underlying
factor,
the
bacterial
origin
of
disease,
harm
would
have
been
done
by
pushing
too
firmly
the
need
for
specificity
as
a
necessary
feature
before
convicting
the
dairy.
Coming
to
modern
times
the
prospective
investigations
of
smoking
and
cancer
of
the
lung
have
been
cr_iticized
for
not
showing
specificity
-
in
other
words
the
death
rate
of
smokers
is
higher
than
the
death
rate
of
non-smokers
from
many
causes
of
death
(though
in
fact
the
results
of
Doll
&
Hill,
1964,
do
not
show
that).
But
here
surely
one
must
return
to
my
first
characteristic,
the
strength
of
the
association.
If
other
causes
of
death
are
raised
10,
20
or
even
50%
in
smokers
whereas
cancer
of
the
lung
is
raised
900-1,000
%
we
have
specificity
-
a
specificity
in
the
magnitude
of
the
association.
We
must
also
keep
in
mind
that
diseases
may
have
more
than
one
cause.
It
has
always
been
possible
to
acquire
a
cancer
of
the
scrotum
without
sweeping
chimneys
or
taking
to
mule-
spinning
in
Lancashire.
One-to-one
relationships
are
not
frequent.
Indeed
I
believe
that
multi-
causation
is
generally
more
likely
than
single
causation
though
possibly
if
we
knew
all
the
answers
we
might
get
back
to
a
single
factor.
In
short,
if
specificity
exists
we
may
be
able
to
draw
conclusions
without
hesitation;
if
it
is
not
apparent,
we
are
not
thereby
necessarily
left
sitting
irresolutely
on
the
fence.
(4)
Temporality:
My
fourth
characteristic
is
the
temporal
relationship
of
the
association
--which
is
the
cart
and
which
the
horse?
This
is
a
question
which
might
be
particularly
relevant
with
diseases
of
slow
development.
Does
a
particular
diet
lead
to
disease
or
do
the
early
stages
of
the
disease
lead
to
those
peculiar
dietetic
habits?
Does
a
9
9
297
298
Proceedings
of
the
Royal
Society
of
Medicine
particular
occupation
or
occupational
environ-
ment
promote
infection
by
the
tubercle
bacillus
or
are
the
men
and
women
who
select
that
kind
of
work
more
liable
to
contract
tuberculosis
whatever
the
environment
-
or,
indeed,
have
they
already
contracted
it?
This
temporal
problem
may
not
arise
often
but
it
certainly
needs
to
be
remembered,
particularly
with
selective
factors
at
work
in
industry.
(5)
Biological
gradient:
Fifthly,
if
the
association
is
one
which
can
reveal
a
biological
gradient,
or
dose-response
curve,
then
we
should
look
most
carefully
for
such
evidence.
For
instance,
the
fact
that
the
death
rate
from
cancer
of
the
lung
rises
linearly
with
the
number
of
cigarettes
smoked
daily,
adds
a
very
great
deal
to
the
simpler
evidence
that
cigarette
smokers
have
a
higher
death
rate
than non-smokers.
That
com-
parison
would
be
weakened,
though
not
neces-
sarily
destroyed,
if
it
depended
upon,
say,
a
much
heavier
death
rate
in
light
smokers
and
a
lower
rate
in
heavier
smokers.
We
should
then
need
to
envisage
some
much
more
complex
relationship
to
satisfy
the
cause-and-effect
hypothesis.
The
clear
dose-response
curve
admits
of
a
simple
explanation
and
obviously
puts
the
case
in
a
clearer
light.
The
same
would
clearly
be
true
of
an
alleged
dust
hazard
in
industry.
The
dustier
the
environ-
ment
the
greater
the
incidence
of
disease
we
would
expect
to
see.
Often
the
difficulty
is
to
secure
some
satisfactory
quantitative
measure
of
the
environment
which
will
permit
us
to
explore
this
dose-response.
But
we
should
invariably
seek
it.
(6)
Plausibility:
It
will
be
helpful
if
the
causation
we
suspect
is
biologically
plausible.
But
this
is
a
feature
I
am
convinced
we
cannot
demand.
What
is
biologically
plausible
depends
upon
the
bio-
logical
knowledge
of
the
day.
To
quote
again
from
my
Alfred
Watson
Memorial
Lecture
(Hill
1962),
there
was
'.
.
.
no
biological
knowledge
to
support
(or
to
refute)
Pott's
observation
in
the
18th
century
of
the
excess
of
cancer
in
chimney
sweeps.
It
was
lack
of
biological
knowledge
in
the
19th
that
led
a
prize
essayist
writing
on
the
value
and
the
fallacy
of
statistics
to
conclude,
amongst
other
"absurd"
associations,
that
"it
could
be
no
more
ridiculous
for
the
stranger
who
passed
the
night
in
the
steerage
of
an
emigrant
ship
to
ascribe
the
typhus,
which
he
there
contracted,
to
the
vermin
with
which
bodies
of
the
sick
might
be
infected".
And
coming
to
nearer
times,
in
the
20th
century
there
was
no
biological
knowledge
to
support
the
evidence
against
rubella.'
In
short,
the
association
we
observe
may
be
one
new
to
science
or
medicine
and
we
must
not
dismiss
it
too
light-heartedly
as
just
too
odd.
As
Sherlock
Holmes
advised
Dr
Watson,
'when
you
have
eliminated
the
impossible,
whatever
remains,
however
improbable,
must
be
the
truth.'
(7)
Coherence:
On
the
other
hand
the
cause-and-
effect
interpretation
of
our
data
should
not
seriously
conflict
with
the
generally
known
facts
of
the
natural
history
and
biology
of
the
disease
-
in
the
expression
of
the
Advisory
Committee
to
the
Surgeon-General
it
should
have
coherence.
Thus
in
the
discussion
of
lung
cancer
the
Committee
finds
its
association
with
cigarette
smoking
coherent
with
the
temporal
rise
that
has
taken
place
in
the
two
variables
over
the
last
generation
and
with
the
sex
difference
in
mortality
-
features
that
might
well
apply
in
an
occupational
problem.
The
known
urban/rural
ratio
of
lung
cancer
mortality
does
not
detract
from
coherence,
nor
the
restriction
of
the
effect
to
the
lung.
Personally,
I
regard
as
greatly
contributing
to
coherence
the
histopathological
evidence
from
the
bronchial
epithelium
of
smokers
and
the
isolation
from
cigarette
smoke
of
factors
car-
cinogenic
for
the
skin
of
laboratory
animals.
Nevertheless,
while
such
laboratory
evidence
can
enormously
strengthen
the
hypothesis
and,
indeed,
may
determine
the
actual
causative
agent,
the
lack
of
such
evidence
cannot
nullify
the
epidemiological
observations
in
man.
Arsenic
can
undoubtedly
cause
cancer
of
the
skin
in
man
but
it
has
never
been
possible
to
demonstrate
such
an
effect
on
any
other
animal.
In
a
wider
field
John
Snow's
epidemiological
observations
on
the
conveyance
of
cholera
by
the
water
from
the
Broad
Street
pump
would
have
been
put
almost
beyond
dispute
if
Robert
Koch
had
been
then
around
to
isolate
the
vibrio
from
the
baby's
nappies,
the
well
itself
and
the
gentleman
in
delicate
health
from
Brighton.
Yet
the
fact
that
Koch's
work
was
to
be
awaited
another
thirty
years
did
not
really
weaken
the
epidemiological
case
though
it
made
it
more
difficult
to
establish
against
the
criticisms
of
the
day
-
both
just
and
unjust.
(8)
Experiment:
Occasionally
it
is
possible
to
appeal
to
experimental,
or
semi-experimental,
evidence.
For
example,
because
of
an
observed
association
some
preventive
action
is
taken.
Does
it
in
fact
prevent?
The
dust
in
the
workshop
is
reduced,
lubricating
oils
are
changed,
persons
stop
smoking
cigarettes.
Is
the
frequency
of
the
associated
events
affected?
Here
the
strongest
10
Section
of
Occupational
Medicine
support
for
the
causation
hypothesis
may
be
revealed.
(9)
Analogy:
In
some
circumstances
it
would
be
fair
to
judge
by
analogy.
With
the
effects
of
thalidomide
and
rubella
before
us
we
would
surely
be
ready
to
accept
slighter
but
similar
evidence
with
another
drug
or
another
viral
disease
in
pregnancy.
Here
then
are
nine
different
viewpoints
from
all
of
which
we
should
study
association
before
we
cry
causation.
What
I
do
not
believe
-
and
this
has
been
suggested
-
is
that
we
can
usefully
lay
down
some
hard-and-fast
rules
of
evidence
that
must
be
obeved
before
we
accept
cause
ard
effect.
None
of
my
nine
viewpoints
can
bring
indisputable
evidence
for
or
against
the
cause-
and-effect
hypothesis
and
none
can
be
required
as
a
sine
qua
non.
What
they
can
do,
with
greater
or
less
strength,
is
to
help
us
to
make
up
our
minds
on
the
fundamental
question
-
is
there
any
other
way
of
explaining
the
set
of
facts
before
us,
is
there
any
other
answer
equally,
or
more,
likely
than
cause
and
effect?
Tests
of
Significance
No
formal
tests
of
significance
can
answer
those
questions.
Such
tests
can,
and
should,
remind
us
of
the
effects
that
the
play
of
chance
can
create,
and
they
will
instruct
us
in
the
likely
magnitude
of
those
effects.
Beyond
that
they
contribute
nothing
to
the
'proof'
of
our
hypothesis.
Nearly
forty
years
ago,
amongst
the
studies
of
occupational
health
that
I
made
for
the
Industrial
Health
Research
Board
of
the
Medical
Research
Council
was
one
that
concerned
the
workers
in
the
cotton-spinning
mills
of
Lancashire
(Hill
1930).
The
question
that
I
had
to
answer,
by
the
use
of
the
National
Health
Insurance
records
of
that
time,
was
this:
Do
the
workers
in
the
card-
room
of
the
spinning
mill,
who
tend
the
machines
that
clean
the
raw
cotton,
have
a
sickness
experi-
ence
in
any
way
different
from
that
of
other
operatives
in
the
same
mills
who
are
relatively
unexposed
to
the
dust
and
fibre
that
were
features
of
the
cardroom?
The
answer
was
an
unqualified
'Yes'.
From
age
30
to
age
60
the
cardroom
workers
suffered
over
three
times
as
much
from
respiratory
causes
of
illness
whereas
from
non-respiratory
causes
their
experience
was
not
different
from
that
of
the
other
workers.
This
pronounced
difference
with
the
respiratory
causes
was
derived
not
from
abnormally
long
periods
of
sickness
but
rather
from
an
excessive
number
of
repeated
absences
from
work
of
the
cardroom
workers.
All
this
has
rightly
passed
into
the
limbo
of
forgotten
things.
What
interests
me
today
is
this:
My
results
were
set
out
for
men
and
women
separately
and
for
half
a
dozen
age
groups
in
36
tables.
So
there
were
plenty
of
sums.
Yet
I
cannot
find
that
anywhere
I
thought
it
necessary
to
use
a
test
of
significance.
The
evidence
was
so
clear-cut,
the
differences
between
the
groups
were
mainly
so
large,
the
contrast
between
respiratory
and
non-
respiratory
causes
of
illness
so
specific,
that
no
formal
tests
could
really
contribute
anything
of
value
to
the
argument.
So
why
use
them?
Would
we
think
or
act
that
way
today
?
I
rather
doubt
it.
Between
the
two
world
wars
there
was
a
strong
case
for
emphasizing
to
the
clinician
and
other
research
workers
the
importance
of
not
overlooking
the
effects
of
the
play
of
chance
upon
their
data.
Perhaps
too
often
generalities
were
based
upon
two
men
and
a
laboratory
dog
while
the
treatment
of
choice
was
deduced
from
a
difference
between
two
bedfuls
of
patients
and
might
easily
have
no
true
meaning.
It
was
there-
fore
a
useful
corrective
for
statisticians
to
stress,
and
to
teach
the
need
for,
tests
of
significance
merely
to
serve
as
guides
to
caution
before
draw-
ing
a
conclusion,
before
inflating
the
particular
to
the
general.
I
wonder
whether
the
pendulum
has
not
swung
too
far
-
not
only
with
the
attentive
pupils
but
even
with
the
statisticians
themselves.
To
decline
to
draw
conclusions
without
standard
errors
can
surely
be
just
as
silly?
Fortunately
I
believe
we
have
not
yet
gone
so
far
as
our
friends
in
the
USA
where,
I
am
told,
some
editors
of
journals
will
return
an
article
because
tests
of
significance
have
not
been
applied.
Yet
there
are
innumerable
situations
in
which
they
are
totally
unnecessary
-
because
the
difference
is
grotesquely
obvious,
because
it
is
negligible,
or
because,
whether
it
be
formally
significant
or
not,
it
is
too
small
to
be
of
any
practical
importance.
What
is
worse
the
glitter
of
the
t
table
diverts
attention
from
the
inadequacies
of
the
fare.
Only
a
tithe,
and
an
unknown
tithe,
of
the
factory
personnel
volunteer
for
some
procedure
or
interview,
20
%
of
patients
treated
in
some
particular
way
are
lost
to
sight,
30
%
of a
randomly-drawn
sample
are
never
con-
tacted.
The
sample
may,
indeed,
be
akin
to
that
of
the
man
who,
according
to
Swift,
'had
a
mind
to
sell
his
house
and
carried
a
piece
of
brick
in
his
pocket,
which
he
showed
as
a
pattern
to
en-
courage
purchasers'.
The
writer,
the
editor
and
the
reader
are
unmoved.
The
magic
formulae
are
there.
Of
course
I
exaggerate.
Yet
too
often
I
suspect
we
waste
a
deal
of
time,
we
grasp
the
shadow
and
11
299
300
Proceedings
of
the
Royal
Society
of
Medicine
12
lose
the
substance,
we
weaken
our
capacity
to
interpret
data
and
to
take
reasonable
decisions
whatever
the
value
of
P.
And
far
too
often
we
deduce
'no
difference'
from
'no
significant
difference'.
Like
fire,
the
X2
test
is
an
excellent
servant
and
a
bad
master.
The
Case
for
Action
Finally,
in
passing
from
association
to
causation
I
believe
in
'real
life'
we
shall
have
to
consider
what
flows
from
that
decision.
On
scientific
grounds
we
should
do
no
such
thing.
The
evi-
dence
is
there
to
be
judged
on
its
merits
and
the
judgment
(in
that
sense)
should
be
utterly
independent
of
what
hangs
upon
it
-
or
who
hangs
because
of
it.
But
in
another
and
more
practical
sense
we
may
surely
ask
what
is
involved
in
our
decision.
In
occupational
medicine
our
object
is
usually
-to
take
action.
If
this
be
opera-
tive
cause
and
that
be
deleterious
effect,
then
we
shall
wish
to
intervene
to
abolish
or
reduce
death
or
disease.
While
that
is
a
commendable
ambition
it
almost
inevitably
leads
us
to
introduce
differen-
tial
standards
before
we
convict.
Thus
on
relatively
slight
evidence
we
might
decide
to
restrict
the
use
of
a
drug
for
early-moMing
sick-
ness
in
pregnant
women.
If
we
are
wrong
in
deducing
causation
from
association
no
great
harm
will
be
done.
The
good
lady
and
the
pharmaceutical
industry
will
doubtless
survive.
On
fair
evidence
we
might
take
action
on
what
appears
to
be
an
occupational
hazard,
e.g.
we
might
change
from
a
probably
carcinogenic
oil
to
a
non-carcinogenic
oil
in
a
limited
environment
and
without
too
much
injustice
if
we
are
wrong.
But
we
should
need
very
strong
evidence
before
we
made
people
burn
a
fuel
in
their
homes
that
they
do
not
like
or
stop
smoking
thecigarettes
and
eating
the
fats
and
sugar
that
they
do
like.
In
asking
for
very
strong
evidence
I
would,
however,
repeat
emphatically
that
this
does
not
imply
crossing
every
't',
and
swords
with
every
critic,
before
we
act.
All
scientific
work
is
incomplete
-
whether
it
be
observational
or
experimental.
All
scientific
work
is
liable
to
be
upset
or
modified
by
advancing
knowledge.
That
does
not
confer
upon
us
a
free-
dom
to
ignore
the
knowledge
we
already
have,
or
to
postponethe
action
that
it
appears
to
demand
at
a
given
time.
Who
knows,
asked
Robert
Browning,
but
the
world
may
end
tonight?
True,
but
on
available
evidence
most
of
us
make
ready
to
commute
on
the
8.30
next
day.
REFERENCES
Doll
R
(1964)
In:
Medical
Surveys
and
Clinical
Trials.
Ed.
L
J
Witts.
2nd
ed.
London;
p
333
Doll
R
&
Hill
A
B
(1964)
Brit.
med.
J.
i,
1399,
1460
Heady
J
A
(1958)
Med.
World,
Lond.
89,
305
Hill
A
B
(1930)
Sickness
amongst
Operatives
in
Lancashire
Spinning
Mills.
Industrial
Health
Research
Board
Report
No.
59.
HMSO,
London
(1962)
J.
Inst.
Actu.
88,
178
Snow
J
(1855)
On
the
Mode
of
Communication
of
Cholera.
2nd
ed.
London
(Reprinted
1936,
New
York)
US
Department
of
Health,
Education
&
Welfare
(1964)
Smoking
and
Health.
Public
Health
Service
Publication
No.
1103.
Washing-
ton
> *"How in the first place do we detect these relationships between sickness, injury and conditions of work? How do we determine what are physical, chemical and psychological hazards of occupation, and in particular those that are rare and not easily recognised?"*
[...]
> *"In other words, we see that the event B is associated with the environmental feature A, that, to take a specific example, some form of respiratory illness is associated with a dust in the environment. In what circumstances can we pass from this observed association to a verdict of causation? Upon what basis should we proceed to do so?"*
In what circumstances can one infer causation from an observed association? Bradford Hill wanted to provide a framework and flexible guidelines meant to guide epidemiologic investigations.
For a great discussion and overview of the Bradford Hill criteria listen to: [Beside Rounds - Episode 47: The Criteria](http://bedside-rounds.org/episode-47-the-criteria/)
> *"Our observations reveal an association between two variables, perfectly clearcut and beyond what we would care to attribute to the play of chance. What aspects of that association should we especially consider before deciding that the most likely interpretation of it is causation?"*
The first criterion for causation is **strength**. The larger an association between exposure and outcome, the more likely it is to be causal.
The fourth criterion is **temporality**. The exposure must precede the outcome in order for an exposure-outcome relationship to be causal. It is perhaps the only criterion which epidemiologists nowadays universally agree is essential to causal inference.
The fifth criterion is **biological gradient**. When increased exposure results in increased incidence of disease, it provides the clearest evidence of a causal relationship.
> *"if a dose response is seen, it is more likely that the association is causal."*
The sixth criterion is **plausibility**. Plausibility is satisfied if the relationship is consistent with the current body of knowledge and implies that epidemiology and biology must interact. This criterion of biological plausibility is dependent on the current state of knowledge.
The seventh criterion is **coherence**. This criterion is similar to biological plausibility. The cause-and-effect relationship needs to make sense with all knowledge about natural history and biology of the disease.
The second criterion is **consistency**. Consistency is upheld when multiple epidemiologic studies using a variety of locations, populations, and methods show a consistent association between two variables with respect to the null hypothesis.
The ninth (and final) criterion is **analogy**. When there is strong evidence of a causal relationship between a particular agent and a specific outcome then a similar agent may cause a similar disease. When we find one causal agent then standards should be lowered for a second causal agent that is similar to the first we found.
The eight criterion is **experiment**. When experimental manipulation with exposure changes the
outcomes then it suggests a strong support for causal inference.
### TL;DR
The **Bradford Hill Criteria** are a group of 9 principles that can be used in order to establish epidemiologic evidence of a causal relationship between a presumed cause and an observed outcome. The Bradford Hill Criteria are the most frequently cited framework for causal inference in epidemiologic studies.
In this seminal paper published in 1965 Bradford Hill established the following criteria:
**1. Strength:** What is the difference in the illness rate between the exposed and not exposed? The absolute and relative differences should be taken into account.
**2. Consistency:** Has the outcome been observed in different people in different locations?
**3. Specificity:** Can we find that particular type of exposure is linked with a specific outcome?
**4. Temporality:** Is there a temporal relationship? Does the exposure precede or follow the outcome?
**5. Biological gradient:** Is there dose-response curve? Is there a significant difference between the "amount/intensity" of exposure and the outcome?
**6. Plausibility:** Does the relationship between exposure and outcomes seem likely given our present knowledge?
**7. Coherence:** Is the relationship detected coherent with the natural history and biology of the disease?
**8. Experiment:** Do preventive actions change the frequency or intensity of outcomes?
**9. Analogy:** Are there similar agents known to cause similar outcomes?
### Austin Bradford Hill
Sir Austin Bradford Hill was an English epidemiologist and statistician. He served as a pilot in the Royal Navy Air Service during World War I. During the war he contracted tuberculosis and was sent 'home to die'. In spite of the odds he recovered and started a career in medical statistics. He made medical statistics an essential part of modern epidemiology and pioneered the randomised clinical trial. He is best known for demonstrating the connection between cigarette smoking and lung cancer - together with British physician Richard Doll.
The third criterion is **specificity**. Associations are more likely to be causal when they are specific which in this case means when the exposure causes only one disease. Bradford Hill understood that diseases might have multiple causes but he believes that if we know all the answers then we might be able to get back to one single factor.
Bradford Hill’s **nine criteria are not intended to be viewed as rigid checklist for causal inference**. Bradford Hill wanted to create flexible guidelines and considerations meant to help epidemiologic investigations and aid in the determination of causation.
> *"None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question – is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?"*