CAUSALITY, DESIGN STUDY,

QUANTIFYING OF RISK AND EBM

Dr Putu Moda Arsana SpPD – KEMD, FINASIM

Endocrinology & Metabolic section

Department of Internal Medicine
Brawijaya University
ASSESSMENT OF CAUSATION

• What is causation ?
• What study can show causation ?
• A direct test of causation
• Method of counting event
CAUSAL RELATIONSHIP IN
MEDICINE AND HEALTH CARE

• Physical sciences :
Metal :  temperature  length 
• Health : ( simple )
Infection with m. tuberculosis

Clinical tuberculosis ?
CAUSAL FACTOR

Infection M Tuberculosis

Poor nutrition

Age
Clinical tuberculosis

Genetic factors ?

Environmental condition
TYPES OF CAUSAL RELATIONSHIPS
• Necessary :
The outcome occurs only if the causal factor has operated
• Sufficient :
The operation of the causal factor always results in the
outcome
• Both :
The causal factor and the outcome have a fix relationship,
neither occurs without the other
• Neither :
The operation of the causal factor increases the frequency of
the outcome, but the outcome does not always result, and the
outcome can occur without the operation of the causal factor.
DEFINITION OF CAUSE

A factor is a cause of an event, if its

operation increases the frequency of
the event
NOTE

• Most situations in health and disease do

not fulfill the criteria of necessary or
sufficient
• Most of them were neither causal
factors
NOTE
If the time relationship is not clear,
and the concepts of necessary and
sufficient cause do not hold, we need
a quantitative assessment of the
relationship, base on observations,
not on one individual but on a number
of individual

( quantitative causation )
A DIRECT TEST OF CAUSATION
( RANDOMIZED CLINICAL TRIAL )

Take a group of
subject

Divide them into

two similar group

Apply the putative causal

factor to one group

Assess the frequency of the

outcome in both group

See if the frequency is higher in the group

exposed to the putative causal factor
STUDY DESIGN WHICH CAN DEMONSTRATE
AND TEST CAUSATION

Implication of the definition of causal factor :

1. People who are affected by the causal agent will have a higher
frequency of the defined outcome
2. Individuals with the defined outcome will have a greater
frequency of past exposure to the causal agent
Comparative study

Study design for the 1 st statement : “ Cohort study “

Compare a group of people exposed to the putative causative
factor with a group not exposed
Study design for the 2 nd statement : “ a case control study “
Compare a group of people who have already experienced the
outcome with a group of people without the outcome
A CLASSIFICATION OF COMPARATIVE STUDY

Cohort means a group of people with some characteristic.

• Observational study : the researchers observe the natural events,
they do not involved or do intervention.
• Intervention study : the investigators control the assignment of
individuals to the intervention.
Case – control study
• Group of individuals are defined in term of whether they have or
have not already experienced the outcome under consideration, and
the exposure is then measured.
Surveys
• From the sampling perspective, surveys are carried out on subjects
chosen as all members or a representative sample of a population but
the sampling is not based on any defined exposure or outcome
CLASSIFICATION BY TIME RELATIONSHIP

Present time only

( cross sectional study )

Past and present

( retrospective study )

Present and future

( prospective study )

Past Present Future

Information on past Time period during which Subjects followed in time
events found and subjects are entered in the and events recorded as
recorded study and data collection they occur, or as subjects
started are rechecked
Case – control studies :
• Cross-sectional or retrospective
Cohort studies :
• Can be prospective, cross-sectional or retrospective
Cross-sectional studies :
• All information is collected at one point in time
• Can be made if the putative causal factors and the
outcome state are stable. If the exposure or the
outcome change overtime, this design is weak.
 Study design : sampling, time relationship and
analysis
Sampling system Time relationship Type of analysis

Cohort : Prospective, retrospective Cohort

Select on exposure or cross-sectional

Prospective
Intervention : Cohort
Assign exposure
Retrospective or cross-
Case-control : sectional Case-control
Select on outcome

Survey : Cross-sectional or Survey, plus cohort or

retrospective case-control analyses
Total or sample of a comparing subgroups
defined population
QUANTIFYING OF RISK

Relative risk or risk ratio :

• The ratio of the rate of disease among those exposed to the
rate in those not exposed
Odds ratio :
• The ratio of number of defined outcome to the undefined
outcome in the exposed group to the number of defined outcome
to the number of undefined outcome in the unexposed group
Risk difference (Absolut Risk Reduction=ARR) :
• The difference between the two rates
Number Needed to Treat (NNT)
• Number to treat to prevent one death = 1/AR
EXAMPLES

Result of the cohort study in pregnan women

Exposure Infant Infant not Total Prevalence of
malformed malformed malformation
(%)
Valproic acid 6 387 393 1.53

No valproic acid 7 1932 1939 0.36

Whole population 13 2319 2332 0.56

RR ( relative risk ) = 1.53/0.36 = 4.25

OR ( Odds ratio ) = 6/387 : 7/1932 = ( 6x1932 ) / ( 7 x 387 ) = 4.28
ARR (Absolut Risk Reduction) = 1.53 – 0.36 = 1.17 %
 THE USES OF RISK DIFFERENCE AND
RELATIVE RISK

Risk difference :
• Describe the absolute quantity of the outcome which is
associated with the exposure
• Useful in considering the practical implications of studies
• Describe more causal association then relative risk
Relative risk :
• Useful in considering the estimation of incidence or mortality
associated with a particular exposure in a different population,
because empiric finding showed those incidence or mortality
were relative constant
• More valuable in evaluating whether a particular relationship
is or is not likely to be causal
• Easier to predict the effect of non causal factors on the
observed relative risk than on the observed attributable risk
PREVENTIVE FACTORS AND IMPLICATION TO
INTERVENTION STUDIES ; NUMBER NEEDED
TO TREAT ( NNT )
If the factors under consideration is preventive, the rate of outcome in
the exposed group will be less then in the unexposed group, and therefore
the relative risk will be less then one, and the risk difference will be
negative.

Treatment Death Survivors Total Death rate

per 1000
Captopril 2088 26940 29028 71.9

Placebo 2231 26791 29022 76.9

Relative Risk = 71.9 / 76.9 = 0.94

Risk Difference per 1000 = 71.9 – 76.9 = - 5
Death averted per 1000 treated = 76.9 – 71.9 = 5
Number treated to prevent one death ( NNT ) = 1000 / 5 = 200
POPULATION AND STUDY PARTICIPANTS

• Target population
• Source population
• Eligible polpulation
• Study participants
TARGET POPULATION ( S )

The population ( s ) to which the result can be

applied
SOURCE POPULATION

• The population ( s ) defined in general terms and

enumerated if possible, from which eligible
subjects are drawn
ELIGIBLE POPULATION

• The population (s) of subjects eligible for

inclusion in the study ; should be defined
precisely and counted
STUDY PARTICIPANTS

• Those individuals who contribute data to the study

; the results apply directly only to this subjects
LEVELS OF SUBJECT SELECTION

Level of selection Main exclusions

Target population

Source population
Subjects not assessed
Subjects assessed and found not eligible
Subjects not classified because of inadequate data

Eligible population
Exclusions because of death, inability to cooperate,
administrative issues, confidentiality, voluntary non-
response... ( do not enter study )
Failure to complete study requirements, missing data...... ( do
not complete study )
Study participants
LEVELS OF SUBJECT SELECTION

Target population (s) : the population (s) to which the results can be applied

Direction of selection of Direction of application of

subjects results

Source population (s) : the population (s) defined in general terms and enumerated if possible,
from which eligible subjects are drawn

Selection Application

Eligible population (s) : the population (s) of subjects eligible for inclusion in the study , should
be defined precisely and counted

Selection Application

Study participants : those individuals who contribute data to the study , the results apply directly
only to these subjects
 CLINICAL DAILY PRACTICE

Good evening Doctor, Would

You like to help me please ?
What should I do ?
I have been suffering from
chest pain since 3 hours ago
and……………
 Diagnosis Treatment
Process process

Complaint Diagnose Treatment

Clinical Process
 TREATMENT
PROCESS

CLINICAL
DECISIAN MAKING
 Clinical
Expertise

Best Patient
Research CDM Values &
Evidence Preferences
 OLD MODEL FOR CLINICAL DECISIONS

• Unsystematic observations/clinical
experience
• Pathophysiology plus pharmacology
• Extrapolation from intermediate
outcomes
• Authority of local experts
• Practitioners and patients not “equals”

EBM Working Group. JAMA 1992;268:2420-2425

 NEW MODEL FOR CLINICAL
DECISIONS
• Systematic recording of observations -
reproducible and unbiased
• Mechanism of disease - necessary but not
sufficient
• Critical literature appraisal Vs authority
• Apply rules of evidence
• Full informed participation by patients

EBM Working Group. JAMA 1992;268:2420-2425

 SO, HOW SHOULD WE CARE
OUR PATIENT ?

• Clinical Expertise ?  Yes

• Patient Values and
Preferences ?  Yes
• Best Research
 Yes
Evidence ?
EVIDENCE BASE
MEDICINE ?
 EVIDENCE BASED MEDICINE

• • Definition: “The conscientious, explicit and

judicious use of current best evidence in
making decisions about the care of individual
patients” Sackett 1996
• • The practice of evidence based medicine
requires the integration of individual clinical
expertise, judgment and patient choice with
the best external evidence from systematic
research
BUT…IT’S A JUNGLE OUT THERE!

New information
available daily
The public has a high
interest and demand
 And… the real world is…
• Haynes (An Intern Med 1986; 309 :105) ; 800
research articles in 4 famous journals 
valid only 19%
• Reid (JAMA 1995; 274: 651 ) ; 1300 research
articles on accuracy of diagnostic tools from urine
dipstick to MRI and CT scan 
valid only 6%

• Cohrane Collaboration (1996): 16,000 studies on

tx of mild hypertension  valid only 22 studies
What is in the real world?
Publication Bias
Research 1 Research 2 Research 3 Research 4 Research 5

Good results  published

Poor results not published

AHRQ  48% medical research were not published

 WHAT SHOULD WE DO?

EVIDENCE EVIDENCE
TYPE OF STUDY

Meta Analysis

Systemic Review

Randomized Controlled Trial

Cohort studies

Case Control studies

Case Series/Case Report

Animal Research
 Classification of Recommendations and
Level of Evidence

Class I Class IIa Class IIb Class III

Benefit >>> Risk Benefit >> Risk Benefit ≥ Risk Risk ≥ Benefit
Additional studies with Additional studies with No additional studies
focused objectives broad objectives needed; needed
needed Additional registry data
would be helpful Procedure/Treatment
Procedure/ Treatment IT IS REASONABLE to should NOT be
SHOULD be perform Procedure/Treatment performed/administered
performed/ procedure/administer MAY BE CONSIDERED SINCE IT IS NOT
administered treatment HELPFUL AND MAY
BE HARMFUL

Level A Multiple (3-5) population risk strata evaluated

General consistency of direction and magnitude of effect

Level B Limited (2-3) population risk strata evaluated

Level C Very limited (1-2) population risk strata evaluated

 Applying Classification of
Recommendations and Level of Evidence

Class I Class IIa Class IIb Class III

Benefit >>> Risk Benefit >> Risk Benefit ≥ Risk Risk ≥ Benefit
Additional studies with Additional studies with No additional studies
focused objectives broad objectives needed
needed needed; Additional
registry data would be Procedure/Treatment
Procedure/ Treatment IT IS REASONABLE helpful should NOT be
SHOULD be to perform performed/administered
performed/ procedure/administer Procedure/Treatment SINCE IT IS NOT
administered treatment MAY BE CONSIDERED HELPFUL AND MAY BE
HARMFUL

should is reasonable may/might be considered is not recommended

is recommended can be useful/effective/ may/might be reasonable is not indicated
is indicated beneficial usefulness/effectiveness is should not
is useful/effective/ is probably recommended unknown /unclear/uncertain is not
beneficial or indicated or not well established useful/effective/beneficial
may be harmful
CHALLENGES TO USING EBM IN
DAILY PRACTICE
• Lack of time
• Lack of access to information
• Lack of evidence
• Integrating patients values in decisions making
• Organizational barriers
• Financial barriers
EBM IN DAILY PRACTICE?

ACT LOCALLY
THINK GLOBALLY