Validity of Epidemiologic Studies and Causal

Inference

Fessahaye Alemseged (MD, MPHE)

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 Session objectives

• Discuss the sources of error

• Explain criteria for establishing causation

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 References

• Ann Aschengrau. Essentials of epidemiology in public

health, 2020.

• Rothman K, et al. Modern Epidemiology, 3rded, 2008.

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 Validity of epidemiologic studies
• refers to correctness of study findings

• improved by reducing error from various sources (“Beasts of

epidemiology”):
– Sampling error

– Systematic error

– Confounding

– Interaction?

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 Sampling error/random error/chance

• Occurs when using sample to infer about population

• Refers to lack of precision or power

• How to minimize sampling error:

– By increasing the sample size

• Degree of sampling error has to be estimated

– Values of level of precision (CI) and power

 Systematic error/Bias
• Occurs due to deviation from plan

• more dangerous and more difficult to measure

• Types
– Selection bias
– Non-participation
– Information bias
 Selection bias
• Results from non-representative sample selection
– Due to non-random selection

• There are several types

 Selection bias: Types

• Biases related to institution-based researches

– Diagnostic bias: when using controls form hospitals

– Healthy worker effect: when taking cohorts from worksites

• Self-selection bias – volunteer bias

• Survival bias

• Temporal bias

Solution – population-based studies using random selection

 Non-participation
• Commonest known source of bias
• Results from non-response or loss-to-follow-up (LTF)
– Non-response could be due to rejection or unavailability

– LTF – major problem in cohort studies

• Non-participation leads to serious bias when

– non-participants are systematically different from participants
 Non-participation: Solutions
• Conducting pre-test

• Adding contingency in the sample

• Diligent efforts to make

– Revisits and

– Make participation as convenient and painless as possible – E.g.

mobile examination

• Evaluate non-respondents; Do extreme analysis

 Information bias/measurement error
• Sources of measurement error
– Observer/Interviewer bias

– Interviewee bias, Recall bias

– Invalid instrument/tool

• Solutions:
– Standardization of procedures

– intensive training, supervision, duplicate observation

– use of memory aids

– Pre-testing
 Confounding

• The distortion of measure of effect of exposure

– By other factors that are known as confounder variables

• For a factor to be a confounder it has to be

– associated with the exposure and

– independently associated with the outcome

• A confounder is not an intermediate variable or

consequence of the disease
 Illustration of confounder

Coffee association of interest

Cancer
Drinking

association association

Smoking

Smoking can confound association between coffee and cancer

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 Confounding: solutions

• Solutions:
– prevent during design: restriction, matching or randomization

– Control during analysis: stratified analysis

• Restriction: conducting the study in only one group of the confounder

variable

• Randomization: prevents confounding by known and unknown factors

• Stratified analysis? will be discussed in the last session

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 Confounding: solutions

• Matching: selecting comparison groups that are

similar with regard to values the confounder variable

• Types:
– Individual matching: for continuous variables like
age
– Frequency matching: for categorical variables like
sex

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 Interaction/Effect modification

• Refers to varying effect of exposure in presence and

absence of another factor
• If present, the adjusted measure can’t adequately
summarize the association
– Assess association separately for each group

• E.g. Asbestos and cigarette smoking

 Establishing Causation

• Approaches for making causal inference

– Classic approach: using Bradford Hill’s criteria

– Potential outcome approach

• Bradford Hill’s criteria:

– Guides, not rules – help to rule out erroneous association and make
causal inference

– Include: strength, consistency, temporality, dose-response relationship,

biologic plausibility, experimental evidence

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 Temporality
• Refers to the necessity that the cause occurs preceding the

effect

• Which type of observational study is best for documenting time

sequence?

• Such time sequence does not in itself establish causation

– could be confounded

• Reverse time order does not rule out causal relationship

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 Strength of association
• Refers to magnitude of measure of association

• Strong association is more likely to be causal

– If it was due to confounder, it would, likely, have been obvious

• Weak associations could be causal

– E.g. smoking and cardiovascular disease

• Even strong associations might not be causal

– E.g. – down syndrome Vs birth order is confounded by maternal age

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 Dose-response relationship

• Presence of outcome incidence gradient with

increase in level of exposure
– E.g. As BP level increases and risk of IHD increases

• But some causes have all-or-none or non-linear effect

– E.g. – DES and adenocarcinoma of vagina

• Dose-response relation could be due to confounding

– E.g. gray hair Vs death by age
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 Consistency
• Refers to presence of similar findings in different

populations
– From systematic reviews and meta-analysis

• Lack of consistency does not rule out causal

association
– It might be due to missing unknown component cause

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 Biologic Plausibility (1)
• Coherence with current scientific knowledge on
pathogenesis of the disease
– E.g. 1– smoking and lung ca; substances in the cigarette
smoke have been shown to cause histopathological changes
in respiratory epithelium of animals

– E.g. 2- presence of viral genome in liver cells supports

association between Hepatatis B and liver cancer

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 Biologic Plausibility (2)
• However, lack of plausibility may reflect lack of current
scientific knowledge on pathogenesis
• Doubts about acupuncture and homeopathy is partly due to
absence plausible biological mechanism

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 Reversibility
• removal of the factor results in a reduced disease risk
– E.g. – cessation of smoking reduces risk of HTN
• for causes that leads to rapid irreversible changes
– reversibility cannot be a condition for causality

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 Study Design

Relative ability of different types of study to “prove”

causation: Hierarchy of Causation
Type of study Strength of
evidence
Systematic review and
Meta-analysis
Randomized controlled
Cohort
Case-control
Cross-sectional
Ecological

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 Judging the evidence
• There are no completely reliable criteria, uncertainty remains
• Evidence is stronger when several criteria are met
– More weight is given to plausibility, consistency and dose–response
relationship; correct temporality is essential

• Based on evaluation criteria, evidence is ranked as:

• Sufficient, Suggestive but not sufficient, Inadequate, Suggestive of
no causal relationship

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